title: Genotype-phenotype associations in patients with severe hyperinsulinism of infancy.
abstract: In hyperinsulinism of infancy (HI), unregulated insulin secretion causes hypoglycemia. Pancreatectomy may be required in severe cases, most of which result from a defect in the beta-cell KATP channel, encoded by ABCC8 and KCNJ11. Pancreatic histology may be classified as diffuse or focal disease (the latter associated with single paternal ABCC8 mutations), indicated by the presence of islet cell nuclear enlargement in areas of diffuse abnormality. We investigated genotype-phenotype associations in a heterogeneous Australian cohort. ABCC8 and KCNJ11 genes were sequenced and case histology was reviewed in 21 infants who had pancreatectomy. Ninety-eight control DNA samples were tested by single nucleotide polymorphism analysis. Eighteen ABCC8 mutations were identified, 10 novel. Eleven patients (4 compound heterozygote, 4 single mutation, 3 no mutation detected) had diffuse hyperinsulinism. Nine patients had focal hyperinsulinism (6 single paternal mutation, 2 single mutation of undetermined parental origin, 1 none found) with absence of islet cell nuclear enlargement outside the focal area, although centroacinar cell proliferation and/or nesidiodysplasia was present in 7 cases. Regeneration after near-total pancreatectomy was documented in 4 patients, with aggregates of endocrine tissue observed at subsequent operations in 3. Although the absence of enlarged islet cell nuclei is a useful discriminant of focal hyperinsulinism associated with a paternal ABCC8 mutation, further research is needed to understand the pathophysiology of other histological abnormalities in patients with HI, which may have implications for mechanisms of ductal and islet cell proliferation. Previous surgery should be taken into account when interpreting pancreatic histology.
authors: Department of Paediatrics and Child Health, University of Queensland, Brisbane, and Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Western Australia, Australia. r.greer@uq.edu.au
authors: Ristan M
authors: RM
authors: Greer
authors: Janaki
authors: J
authors: Shah
authors: Yvette W
authors: YW
authors: Jeske
authors: David
authors: D
authors: Brown
authors: Rosslyn M
authors: RM
authors: Walker
authors: David
authors: D
authors: Cowley
authors: Francis G
authors: FG
authors: Bowling
authors: Daphne
authors: D
authors: Liaskou
authors: Mark
authors: M
authors: Harris
authors: Michael J
authors: MJ
authors: Thomsett
authors: Catherine
authors: C
authors: Choong
authors: John R
authors: JR
authors: Bell
authors: Michelle M
authors: MM
authors: Jack
authors: Andrew M
authors: AM
authors: Cotterill
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D044903:Congenital Hyperinsulinism / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010179:Pancreas / Q000473:pathology / Q000502:physiology; D010180:Pancreatectomy; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012038:Regeneration; D000099161:Kcnj11 Channel
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C419353:ABCG1 protein, human