ESPE Abstracts (2019) 92 RFC9.4

Correlation Between Genotype and Phenotype Characteristics in Children with Congenital Hyperinsulinism (CHI) in a Specialist Centre

Laura Bosch1, Jasmina Kallefullah Mohammad1, Antonia Dastamani1, Clare Gilbert1, Kate Morgan1, Jayne Houghton2, Sian Ellard2, Sarah Flanagan2, Pratik Shah1,3


1Department of Paediatric Endocrinology, Great Ormond Street Hospital, London, United Kingdom. 2Genetic Laboratory, Royal Devon & Exeter NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom. 3Genetics and Epigenetics in Health and Disease Section, Genetics and Genomics Medicine Program, UCL GOS Institute of Child Health, London, United Kingdom


Introduction and Aim: Congenital hyperinsulinism (CHI) is the most common cause of hypoglycaemia in early infancy and represents a heterogeneous disorder with respect to clinical presentation, histology and genetics. The aim of our study is to review correlation between genotype and phenotypic characteristics of children with CHI.

Methods: Retrospective review of CHI patients with positive genetics during the last 8 years in a specialist referral centre.

Results: Total of 71 children have so far been identified with positive genetic mutation (40 males). The majority had KATP channel (ABCC8/KCNJ11) mutation (n=55). 15 had compound heterozygous/homozygous KATP channel mutation. 30 had paternal and 10 maternal inherited KATP mutation. The rest were 9 HNF4a, 4 PMM2, 2 GLUD1 and 1 GCK mutation respectively. The median age of presentation with hypoglycaemia was 0-2 days in all mutations except GLUD1 (259.5 days). The median birthweight was significantly higher in children with KATP channel mutations than in GLUD1 and GCK. Diazoxide responsiveness was seen in 4 (26.7%) compound heterozygous KATP, 7 (23.3%) paternal inherited and 7 (70%) maternal inherited KATP channel mutation. 9 (88.9%) with HNF4a, 2 (100%) with GLUD1 and 1 (25%) with PMM2 showed complete response to diazoxide. Partial response to diazoxide was noted in 2 (13.3%) compound heterozygous, 3 (10%) paternal inherited and 1 (10%) with maternal inherited KATP channel mutation respectively. 3 (75%) with PMM2 mutation had good response to Nifedipine when used in conjunction with Diazoxide. 12 children with KATP channel mutation were managed on octreotide, sirolimus and Lanreotide. Natural remission was seen in 1 compound KATP (1.56 years), 5 (18.5%) in paternal KATP (median age 2.19 years), 5 (50%) in maternal KATP (median age 0.33 years) and 1 in HNF4a (0.66 years) mutation respectively. 21 patients (29.6%) underwent pancreatectomy (16 partial pancreatectomy for focal CHI and 5 subtotal pancreatectomy for diffuse form of CHI).

Conclusion: There is no significant difference noted in age of presentation amongst all except GLUD1 mutation which presents much later in life. Most children with KATP channel mutation require frequent feeds with multiple medications to manage severe form of CHI. Knowledge of genotype might help to determine pharmacotherapy. The odds of being fully responsive to diazoxide was greater in patients with maternal KATP channel than in homozygous, compound heterozygous and paternal inherited KATP channel mutation respectively.