Loss of Imprinted Genes and Paternal SUR1 or KIR6.2 Mutations Lead to Focal Form of Congenital Hyperinsulinism

Claudine Junien
Clinique Maurice Lamy (secteur bleu) Porte 15; Hospital Necker Enfants Malades

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) ("nesidioblastosis") is a heterogeneous disorder characterized by profound hypoglycemia 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 management differ significantly. The intriguing similarity between islet cell hyperplasia and tumorigenesis prompted us to investigate whether the imprinted genes in the 11p15 region were involved. We observed a somatic uniparental disomy of the chromosomal region 11p15 resulting in two simultaneous hits in FoPHHI but not In DiPHHI: 1) The first hit is a specific loss of maternal 11p15 alleles in 15/15 FoPHHI cases resulting in disruption of genomic imprinting balance leading to b cell proliferation, as observed in the Beckwith-Wiedemann syndrome (BWS), characterized by predisposition to embryonal tumors and also by neonatal but transient hyperinsulinism. 2) The second hit is a somatic reduction to homozygosity of a mutated paternal allele of either the sulfonylurea receptor (SUR1) gene, or of the K+ inward rectifier KIR6.2 gene resulting in persistent hyperinsulinemia, as observed in familial forms of PHHI associated with constitutional recessive mutations in either of the two genes which both map in 11p15.1. The severe treatment-resistant HI seen in FoPHHI patients is in sharp contrast with the transient neonatal HI seen in 30-50% of BWS patients. Thus HI in BWS, which has never been observed in numerous animal models tying to reproduce the BWS phenotype, remains unexplained. Understanding the role of alteration of imprinted genes in HI will require further investigations. We provide the first molecular explanation of the morphologic heterogeneity of PHHI: diffuse forms are caused by constitutional homozygous or compound heterozygous, mutations of the SUR1 gene; focal forms are caused by the somatic reduction to hemizygosity or homozygosity of a paternally inherited SUR1 or KIR6.2 mutation, limited to the lesion. Thus, this somatic event which leads both to b cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy (UPD) associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder. According to a mean follow-up of 6 years in twenty-two patients with FoPHHI, the somatic nature of the second hit explains that it is possible to perform only partial pancreatectomy limited to the lesion, avoiding the occurrence of iatrogenic diabetes.