Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse
insulin hypersecretion or focal adenomatous
hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic
ATP-sensitive potassium channel (K(+)(
ATP)). The two subunits of the K(+)(
ATP) channel are encoded by the
sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying
potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely
glutamate dehydrogenase (with associated hyperammonaemia),
glucokinase, short-chain L-3-hydroxyacyl-CoA
dehydrogenase, and
insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as
Beckwith-Wiedemann syndrome (BWS),
Perlman syndrome, and, more rarely,
Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of
hyperinsulinism have to be considered such as
fatty acid oxidation deficiency,
congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.