Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease

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Abstract

Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation.

Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly.

Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation.

Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

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Most cited references 39

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Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

K E Snider, S. Becker, L Boyajian … (2013)

Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Our objective was to correlate genotype with phenotype in 417 children with HI. Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1. Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity. Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI.

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Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy.

I M Ariel, Keith B. Glaser, I Scheimberg … (2000)

Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in approximately 1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, beta-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of beta-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of beta-cell function. Using double immunostaining, we examined the proportion of beta-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in beta-cell proliferation from 3.2 +/- 0.5% between 17 and 32 weeks of gestation to 0.13 +/- 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 +/- 0.2%) in weeks 17-32 of gestation, elevated (1.3 +/- 0.3% ) during the perinatal period, and again low (0.08 +/- 0.3%) after 6 months of age. HI beta-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of beta-cell apoptosis that occurs at that time. In HI, our findings of persistently increased beta-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of beta-cell mass.

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Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

Ritika R Kapoor, Sarah Flanagan, Ved Arya … (2013)

Background Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. Aim To characterise the clinical and molecular aspects of a large cohort of patients with CHI. Methodology Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). Results Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). Conclusions A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

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Journal

Journal ID (nlm-ta): Am J Clin Pathol

Journal ID (iso-abbrev): Am. J. Clin. Pathol

Journal ID (publisher-id): ajcp

Journal ID (hwp): ajcpath

Title: American Journal of Clinical Pathology

Publisher: Oxford University Press

ISSN (Print): 0002-9173

ISSN (Electronic): 1943-7722

Publication date (Print): June 2016

Publication date (Electronic): 22 June 2016

Publication date PMC-release: 22 June 2016

Volume: 145

Issue: 6

Pages: 757-768

Affiliations

From the ¹Faculty of Life Sciences, University of Manchester, Manchester, UK

²Paediatric Histopathology

³Paediatric Surgery

⁴Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK.

Author notes

Corresponding authors: Karen Cosgrove, karen.e.cosgrove@ 123456manchester.ac.uk ; Mark Dunne, mark.j.dunne@ 123456manchester.ac.uk .

The authors received support from the NORCHI Charitable Fund (M.J.D, I.B., R.P. and K.E.C.), research and innovation supporting funds from Central Manchester University Hospitals and University of Manchester (M.J.D., I.B., and K.E.C.), The National Institute for Health Research (M.J.D., I.B., R.P., and K.E.C.), Diabetes UK (M.J.D. and K.E.C.), the NC3Rs (M.J.D. and K.E.C.), and the Wellcome Trust (K.E.K. and T.S.). K.E.C. was supported by a RCUK Academic Research Fellowship.

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Publisher ID: aqw075

DOI: 10.1093/ajcp/aqw075

PMC ID: 4922485

PubMed ID: 27334808

SO-VID: 6e9aad6d-e56a-4d41-b931-f6a5b86315e5

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease

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Most cited references 39

Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy.

Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

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