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.

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

“…Fernandez-Marmiesse et al (10) reported five patients with paternally inherited K ATP mutations and whose post pancreatectomy pathology result was not consistent with that of focal lesion. Similar findings have been reported by other studies (1,21,27,30). There are a number of possible mechanisms as to how a heterozygous ABCC8/KCNJ11 mutation can lead to diffuse disease.…”

“…The resulting loss of heterozygosity (LOH) renders the b-cells biallelic for the abnormal foci, altering the K ATP channel and resulting in dysregulated insulin secretion within the focal lesion (16,17,18). The consequent imbalance in the expression of adjacent imprinted genes implicated in cell proliferation (such as CDKN1C and H19 normally expressed from the maternal allele and IGF2 paternally expressed) within the 11p15.5 region leads to focal islet cell adenomatous hyperplasia (19,20,21,22). Focal CHI is usually medically unresponsive, although diazoxide-responsive focal CHI has been recently described (23).…”

Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism

“…[10][11][12] Surrounded by normal pancreas, these cells express a paternally derived SUR1 mutation in association with specific loss of imprinted maternal alleles of chromosome 11p, the region that includes SUR1. [13][14][15] The focal loss of maternally imprinted 11p tumor suppressor genes may be responsible for proliferation of islet cells, which are disomic for a paternally derived SUR1 mutation (SUR1 p-). 11,13 It is important to distinguish infants with diffuse SUR1 −/− and those with focal SUR1 p-lesions before surgery, because the latter are potentially curable with local resection.…”

“…[13][14][15] The focal loss of maternally imprinted 11p tumor suppressor genes may be responsible for proliferation of islet cells, which are disomic for a paternally derived SUR1 mutation (SUR1 p-). 11,13 It is important to distinguish infants with diffuse SUR1 −/− and those with focal SUR1 p-lesions before surgery, because the latter are potentially curable with local resection. 16,17 The K ATP complex is a major pathway for coupling extracellular glucose concentration to insulin secretion.…”

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression

“…[7][8][9] In recent years, a number of genes including SUR1, Kir6.2, GCK, GLUD1, and short-chain 3-hydroxyacyl CoA dehydrogenase have been identified in infantile nesidioblastosis. [10][11][12] An association with Beckwith-Weideman syndrome has also been identified. 13,14 These genetic mutations have only rarely been identified in adult cases.…”