Genotype-Phenotype Associations in Patients with Severe Hyperinsulinism of Infancy

Greer, Ristan M.; Shah, Janaki; Jeske, Y.; Brown, David; Walker, Rosslyn M.; Cowley, David; Bowling, Francis; Liaskou, Daphne; Harris, Mark; Thomsett, M. J.; Choong, Catherine S.; Bell, John R.; Jack, Michelle; Cotterill, Andrew

doi:10.2350/06-04-0083.1

Cited by 14 publications

(9 citation statements)

References 35 publications

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“…This mutation is likely to result in a protein which will either be retained in the endoplasmic recticulum or which will reach the cell membrane but will not function properly. The R168C mutation has been previously reported in a patient with CHI [14]. …”

Section: Resultsmentioning

confidence: 99%

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Congenital Hyperinsulinism due to a Compound Heterozygous <i>ABCC8 </i>Mutation with Spontaneous Resolution at Eight Weeks

et al. 2010

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Background: Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate-sensitive potassium (KATP) channels in β-cells) are the most common cause of medically unresponsive congenital hyperinsulinism (CHI) which requires a near-total pancreatectomy. Methods/Results: A patient born at term with marked macrosomia (5,900 g) presented at the age of 2 h with severe hyperinsulinaemic hypoglycaemia. He failed to respond to treatment with the KATP agonist, diazoxide. An ^18FDOPA-PET scan showed intense diffuse uptake of ^18FDOPA (consistent with diffuse disease) and genetic analysis of the ABCC8 gene confirmed a compound heterozygote missense ABCC8 mutation (R168C/S606T). However, unexpectedly in this patient the hyperinsulinaemic hypoglycaemia started to improve spontaneously at 7 weeks of age prior to planned pancreatic surgery. Conclusions: This is the first report of a patient with clinically severe autosomal-recessive diffuse CHI due to a compound heterozygous ABCC8 mutation that has resulted in spontaneous resolution at such an early age. Compound heterozygote ABCC8 mutations result in complex interactions, and it is possible that this interaction may modify the potential disease pathogenesis. It is important that physicians are aware of this unusual outcome in order to avoid unnecessary early pancreatic surgery with potential life-long implications.

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Section: Resultsmentioning

confidence: 99%

“…Greer et al [14] have reported a patient who was compound heterozygote for the R168C/R1421C mutations in the ABCC8 gene and had severe, medically unresponsive CHI. No functional characterisation of the R168C mutation has yet been undertaken.…”

Section: Discussionmentioning

confidence: 99%

Congenital Hyperinsulinism due to a Compound Heterozygous <i>ABCC8 </i>Mutation with Spontaneous Resolution at Eight Weeks

et al. 2010

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“…It is possible that this patient has recessively inherited HI with the accompanying mutation being undetected (23,30).…”

Section: Inheritance Of Abcc8 and Kcnj11 Mutationsmentioning

confidence: 99%

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

Park

Flanagan

Hussain

et al. 2011

European Journal of Endocrinology

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Objective: Congenital hyperinsulinism (CHI) is characterized by persistent hypoglycemia due to the inappropriate insulin secretion. Inactivating mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor 1 and Kir6.2 subunits of the ATP-sensitive K C (K ATP ) channel in pancreatic b-cell, are the most common cause of CHI. We studied the genetic etiology and phenotypes of CHI in Korean patients. Methods: ABCC8 and KCNJ11 mutational analysis was performed in 17 patients with CHI. Medical records were retrospectively reviewed to identify phenotypes. Results: Mutations (12 ABCC8 and three KCNJ11) were identified in 82% (14/17) of patients. Of these, nine ABCC8 mutations (E100X, W430X, c.1630C1GOC, D813N, Q923X, E1087_A1094de-linsDKSDT, Q1134H, H1135W, and E1209Rfs) and one KCNJ11 mutation (W91X) were novel. Of the 14 patients, four had confirming recessively inherited CHI. The remaining ten patients had single heterozygous mutations. The majority (12/17) of patients were medically responsive. Of the five diazoxide-responsive patients, four had an ABCC8 mutation. The five patients unresponsive to medical management and one diazoxide-responsive patient underwent pancreatectomy and had diffuse histology. Of the operated six patients, two had recessively inherited mutations; three patients had a single heterozygous mutation (one maternally and two paternally inherited); and one patient had no identifiable K ATP channel mutation. Conclusions: This is the first study to report genotype and phenotype correlations among Korean patients with CHI. Mutations in ABCC8 and KCNJ11 are the most common causes of CHI in Korean patients. Similar to other studies, there is marked genetic heterogeneity and no clear genotypephenotype correlation.European Journal of Endocrinology 164 919-926

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“…Mutations in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, subunits: Kir6.2 encoded by KCNJ11 and SUR1 encoded by ABCC8 gene (2). Both genes are localised in the 11p15.1 region and mutations in these accounts for the majority of CHI patients (3,4,5,6,7,8,9,10,11).…”

Section: Introductionmentioning

confidence: 99%

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

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

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Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography ( 18 F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (nZ8) or 18

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Genotype-Phenotype Associations in Patients with Severe Hyperinsulinism of Infancy

Cited by 14 publications

References 35 publications

Congenital Hyperinsulinism due to a Compound Heterozygous <i>ABCC8 </i>Mutation with Spontaneous Resolution at Eight Weeks

Congenital Hyperinsulinism due to a Compound Heterozygous <i>ABCC8 </i>Mutation with Spontaneous Resolution at Eight Weeks

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

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

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