Loss of Imprinted Genes and Paternal SUR1 Mutations Lead to Focal Form of Congenital Hyperinsulinism

Abstract

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder, which leads both to β-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation.