Loss of imprinted genes and paternal SUR1 mutations lead to focal form of congenital hyperinsulinism

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogen eous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish p atients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) fr om those with a diffuse abnormality of islets (DiPHHI), because the managem ent differs significantly. The intriguing similarity between islet cell hyp erplasia and tumourigenesis prompted us to investigate whether the imprinte d 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 mater nally inherited 11p15 region, resulting in both loss of the maternally expr essed tumour suppressor genes accounting for hyperplasia and somatic reduct ion to hemizygosity or homozygosity of the paternally inherited SUR1, limit ed to the lesion. Thus, this somatic disorder, which leads both to P-cell p roliferation and to hyperinsulinism, can be considered the somatic equivale nt, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation. Copy right (C) 2000 S. Karger AG, Basel.