title: Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.
abstract: Congenital hyperinsulinism is a rare pancreatic endocrine cell disorder that has been categorized histologically into diffuse and focal forms. In focal hyperinsulinism, the pancreas contains a focus of endocrine cell adenomatous hyperplasia, and the patients have been reported to possess paternally inherited mutations of the ABCC8 and KCNJ11 genes, which encode subunits of an ATP-sensitive potassium channel (K(ATP)). In addition, the hyperplastic endocrine cells show loss of maternal 11p15, where imprinted genes such as p57(kip2) reside. In order to evaluate whether all cases of focal hyperinsulinism are caused by this mechanism, 56 pancreatectomy specimens with focal hyperinsulinism were tested for the loss of maternal allele by two methods: immunohistochemistry for p57(kip2) (n=56) and microsatellite marker analysis (n=27). Additionally, 49 patients were analyzed for K(ATP) mutations. Out of 56 focal lesions, 48 demonstrated clear loss of p57(kip2) expression by immunohistochemistry. The other eight lesions similarly showed no nuclear labeling, but the available tissue was not ideal for definitive interpretation. Five of these eight patients had paternal K(ATP) mutations, of which four demonstrated loss of maternal 11p15 within the lesion by microsatellite marker analysis. All of the other three without a paternal K(ATP) mutation showed loss of maternal 11p15. K(ATP) mutation analysis identified 32/49 cases with paternal mutations. There were seven patients with nonmaternal mutations whose paternal DNA material was not available, and one patient with a mutation that was not present in either parent's DNA. These eight patients showed either loss of p57(kip2) expression or loss of maternal 11p15 region by microsatellite marker analysis, as did the remaining nine patients with no identifiable K(ATP) coding region mutations. The combined results from the immunohistochemical and molecular methods indicate that maternal 11p15 loss together with paternal K(ATP) mutation is the predominant causative mechanism of focal hyperinsulinism.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Childrens' Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA. msuchi@mcw.edu
authors.forename: Mariko
authors.initials: M
authors.lastname: Suchi
authors.forename: Courtney M
authors.initials: CM
authors.lastname: MacMullen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Thornton
authors.forename: N Scott
authors.initials: NS
authors.lastname: Adzick
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Ruchelli
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D044903:Congenital Hyperinsulinism / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D010180:Pancreatectomy; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D050761:Cyclin-Dependent Kinase Inhibitor p57; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel