Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation

Congenital hyperinsulinism (CHI) is the most common cause of persistent severe hypoglycaemia in neonates and infants. The most severe forms of CHI are caused by inactivating mutations of two KATP channel genes, KCNJ11 and ABCC8. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly in those with diffuse disease due to biallelic mutations in KATP channel genes. We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous novel 1-bp deletion around the splice acceptor site at the exon 35 mutation of ABCC8, which exhibited markedly distinct phenotypes. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by modifying genes, and epigenetic and environmental factors, or related to differences in splicing factor machinery. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction on normal pancreas tissue and a patient's lymphocytes, which revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery. Based on clinical experience, we proposed that severe CHI should be managed by early multimodality therapeutic intervention along with careful management of tunnelled central venous catheterization. Moreover, deliberate selection of therapeutic options based on early genetic diagnosis and appropriate reduction in therapy based on continuous glucose monitoring by a sensor augmented pump could avoid the need for treatment escalation, such as subtotal pancreatectomy.