Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis

The syndrome of persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) was described more than 40 years ago by Mc Quarrie.1 Despite the inordinate amount of interest in this syndrome, the pathogenesis of the disease has not yet been completely elucidated.

For decades, the disease has been ascribed to nesidioblastosis. This term, first coined by Laidlaw, describes the persistence of a diffuse and disseminated proliferation of islet cells budding off from ducts.2 The concept of nesidioblastosis as the underlying condition of hyperinsulinism is still deeply rooted in the mind of many clinicians, although it has been questioned by several authors.3-5 Indeed, observations based on quantitative immunohistochemical investigations have shown that nesidioblastosis is a common feature of the pancreas in normoglycaemic neonates and infants (fig 1).3

Progress in genetics and molecular biology has increased our understanding of the syndrome. By means of linkage analysis, hyperinsulinism in familial cases has been mapped to chromosome 11.6 Genetic molecular analyses have demonstrated mutations of the genes encoding both the sulphonylurea receptor7-10 and the Kir 6.2 subunit,11 as well as maternal loss of the imprinted gene at the 11p15 region, which might explain the insulin hypersecretion characteristic of this syndrome.12-14

In addition, physiological analysis has demonstrated the absence of functional ATP dependent potassium channels in some of these infants with hypoglycaemia.10 15

Several studies have clearly demonstrated the existence of two forms of PHHI. One corresponds to a focal pancreatic adenomatous hyperplasia (focal PHHI) and the other is characterised by a diffuse β cell abnormality (diffuse PHHI).16-18 Up until now, these two forms could not be differentiated by clinical or biochemical data, although …