ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2020 Apr 1;105(4). PMID: 32170320

In congenital hyperinsulinism (CHI) there is dysregulation of insulin secretion that leads to persistent hypoglycaemia. Mutations in the ABCC8/KCNJ11 genes which encode the pancreatic K_ATP channels proteins (SUR1/KIR6.2 respectively) are the most common causes of CHI. Mutations in these genes typically lead to diazoxide unresponsive CHI. In this study, the authors looked at the clinical characteristics and genetic causes of hypoglycaemia in 153 patients with persistent and transient CHI. They undertook sequencing of the 10 known genes associated with CHI and also selected another 104 genes associated with abnormalities in glucose metabolism (presumably looking for novel mechanisms of CHI). Pathogenic variants were found in the genes ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 (all known CHI genes) in patients with persistent CHI, but no genetic mutations were found in patients with transient CHI. No mutations were identified in the 104 genes which were selected as potentially novel genes for CHI. The transient CHI group included infants who had risk factors for secondary hyperinsulinaemic hypoglycaemia.

These results agree with two previously published studies (1, 2) which analyzed the genotype and phenotype characteristics of a large cohort of CHI patients. The majority of patients (~90%) with persistent CHI, who are typically unresponsive to diazoxide therapy, have an underlying genetic cause detected (typically in ABCC8 or KCNJ11 ). In contrast, an underlying genetic cause is not found in the majority of patients with either transient or diazoxide responsive CHI. This study and the previous two studies (1, 2) suggest that genetic testing for CHI should focus on those patients with persistent CHI and are unresponsive to therapy with diazoxide. However, it would be interesting to know the mechanisms of transient and diazoxide responsive CHI as these will provide new insights into the physiology of insulin secretion and glucose metabolism. Thus, whole genome analysis, epigenetic studies and given the role of miRNA in insulin secretion, these avenues should be explored in this unique group of patients with transient CHI.

References:

1. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013;168(4):557–564.

2. Snider KE, Becker S, Boyajian L, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013;98(2):E355–E363.