Diazoxide-unresponsive Hyperinsulinemic Hypoglycaemia in a Preterm Infant with Heterozygous Insulin Receptor Gene...

Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and Rabson-Mendenhall syndrome, conditions which are associated with significant morbidity early in life. In contrast, heterozygous INSR variants result in a milder phenotype, known as type A insulin resistance syndrome. While presentation in adults with this condition is well reported, phenotypes in infant are less well-characterized. Herein, we report an infant presenting with hyperinsulinemic hypoglycaemia who did not respond to diazoxide therapy. She was subsequently found to have a heterozygous INSR gene mutation. The patient was a female infant born at 29 weeks of gestation who developed recurrent hypoglycaemia in early infancy. Workup showed hyperinsulinism and she was started on first-line therapy with diazoxide and high-calorie feeds. However, continuous blood glucose monitoring showed post-prandial hyperglycaemia followed by rapid fall to hypogylcaemia. Whole exome sequencing was performed to investigate for diazoxide-unresponsive hyperinsulinism, which revealed a likely pathogenic mutation in the INSR gene, c.1246C>T p. (R416X). This nonsense mutation was inherited from the father. With the molecular diagnosis, diazoxide was stopped and she followed a diet with low glycaemic-index food. Subsequent monitoring showed stable glucose profile. This case highlights the importance of considering type A insulin resistance syndrome when no mutation is found in the ABCC8/KCNJ11 genes in diazoxide-unresponsive hyperinsulinism. With autosomal dominant inheritance, cascade screening should be performed in family members to identify those harbouring the mutation as they are at risk of early onset diabetes.