ESPE Abstracts (2021) 94 P1-75

1University of Exeter Medical School, Exeter, United Kingdom; 2The Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom

Background: Congenital hyperinsulinism (HI) is characterised by inappropriate insulin secretion despite low blood glucose which is commonly diagnosed in infancy (before the age of 12 months). Screening of the >20 known genes identifies a mutation in over 45% of cases. The likelihood of identifying a mutation in a known gene in individuals diagnosed after 12 months is not currently known.

Aim: We aimed to identify the prevalence of monogenic hyperinsulinism due to a mutation in a known gene, in patients diagnosed with HI in childhood (aged 1 to 16 years).

Methods: We searched for patients diagnosed with HI between 1 and 16 years of age who had been referred to the Exeter Laboratory for genetic testing. In all patients, we screened for mutations in the known HI genes using Sanger sequencing for first-line testing, followed by targeted next generation sequencing of all known causes if a mutation was not identified. We compared the clinical features of monogenic HI diagnosed in childhood to those diagnosed in infancy.

Results/Discussion: We identified 173 individuals within the Exeter cohort who had been diagnosed with hyperinsulinism between the ages of 1 and 16 (median 1.8 [IQR 1.2 to 4.0]) years. Pathogenic variants were identified in 24% (41/173) of cases (ABCC8 (n = 11), GCK (n = 7), GLUD1 (n = 15), HADH (n = 1), KMT2D (n = 1), PMM2 (n = 4), TRMT10A (n = 1) and an X-chromosome deletion (n = 1)). The median (IQR) age at diagnosis of hyperinsulinism in individuals with a mutation was 1.7 (1.0 to 2.8) years. For individuals with mutations in ABCC8, the median birthweight corrected for gestational age was significantly lower than in those diagnosed before 12 months (3356g vs 4245g, P=0.0019, Wilcoxon rank-sum). Given that insulin is a growth factor during gestation, this finding is in keeping with these individuals not having increased insulin secretion in utero and suggests their later diagnosis of HI is a result of later disease onset rather than a missed earlier diagnosis.

Conclusion: Screening of the known genes identified mutations in 24% of individuals within our cohort who were diagnosed with hyperinsulinism outside of infancy. These results highlight the need to consider genetic testing for all individuals diagnosed with persistent hyperinsulinism regardless of their age at presentation.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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