Enhanced Islet Cell Nucleomegaly Defines Diffuse ... Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other ... a third form of the condition ...
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Enhanced Islet Cell Nucleomegaly Defines DiffuseCongenital Hyperinsulinism in Infancy but Not OtherForms of the Disease
months) who died of nonpancreatic disease and showed
Table 1Clinical Characteristics of the CHI Patient Cohorta
Manuscript Code Sex Presentation
Age at
Surgery, mo
Birth
Weight, kg Histology Gene Defect Genotype
CHI-1 M 1 d 2 6.5 Diffuse ABCC8 p.?(c.3992-9G>A)/p?(c.3992-9G>A)
CHI-2 M 1 d 2 4.1 Diffuse KCNJ11 p.Q299R (c.896A>G)/p.Q299R (c.896A>G)
CHI-3 M 1 d 2 4.5 Diffuse ABCC8 p.? (c.1818-?_1923þ?del)/p.T172fs (c.512dup)
CHI-4 F 1 d 2 3.5 Diffuse ABCC8 p.S581T (c.1741T>A)/p.?(c.3992-9G>A)
CHI-5 M 1 d 2 4.4 Diffuse ABCC8 p.A30V(c.89C>T)
CHI-6 M 1 d 4 2.9 Diffuse ABCC8 p.H36R (c.107A>G)/p.? (c.1630þ1G>T)
CHI-7 M 1 d 6 2.9 Diffuse ABCC8 p.? (c.148þ1G>A)/p.? (c.148þ1G>A)
CHI-8 M 1 d 6 1.9 Diffuse ABCC8 p.I1512T (c.4535T>C)/? (AD)
CHI-9 F 1 d 13 and 34 4.6 Diffuse ABCC8 p.? (c.4612-1G>T)/p.A4V (c.11C>T)
CHI-10 M 1 d 2 3.3 Focal ABCC8 p.E128K, c.382G>A/None
CHI-11 M 1 d 3 3.9 Focal ABCC8 c.3512delT/None
CHI-12 M 1 d 3 3.5 Focal ABCC8 c.1879delC/None
CHI-13 F 5 mo 7 3.9 Focal ABCC8 c.2116þ1G>C/None
CHI-14 M 3 mo 10 3.6 Focal ABCC8 c.2995C>T/None
CHI-15 M 7 mo 12 3.4 Atypical Unknown Unknown
CHI-16 F 11 mo 17 2.6 Atypical Unknown Unknown
CHI-17 M 30 mo 36 3.6 Atypical Unknown Unknown
CHI, congenital hyperinsulinism in infancy; p.?, intronic mutation resulting in unknown protein.aAll patients were treated for hypoglycemia and classified as having diffuse, focal, or atypical CHI based on clinical characteristics, including the age of presentation of symp-
toms (“Presentation”), genotyping, positron emission tomography–computed tomography diagnosis, or pancreatic histology following surgery. All patients underwent surgery to
Islets with �1 enlarged nuclei, % 22 6 0.4 71 6 6c NA 32 6 5 32 6 14.7
Islets with �2 enlarged nuclei, % 2 6 1.6 45 6 7c NA 8 6 2 8 6 4.3
Islets with �3 enlarged nuclei, % 0 24 6 6c NA 3 6 1.4 1 6 1.1
CHI, congenital hyperinsulinism in infancy; NA, not applicable.aSummary data for the occurrence of enlarged nuclei in both islet structures. (n¼ 80-179) and in the population of islet cells (n¼ 12,576-47,598) from either control or CHI tis-
sues. For cases of focal CHI, data were obtained from the lesion and the nonlesion domains of the pancreas. Values are presented as mean 6 SEM unless otherwise indicated.bP< .001.cP< .0001 vs control values.
0 1 2 3 4 5 6 7 8 9 10
1,200
1,000
800
600
400
2000
Isle
t S
ize
(No
. of
Cel
ls)
No. of Enlarged Nuclei
0 1 2 3 4 5 6 7 8 9 10
1,200
1,000
800
600
400
2000
Isle
t S
ize
(No
. of
Cel
ls)
No. of Enlarged Nuclei0 1 2 3 4 5 6 7 8 9 10
1,200
1,000
800
600
400
2000
Isle
t S
ize
(No
. of
Cel
ls)
No. of Enlarged Nuclei
0 1 2 3 4 5 6 7 8 9 10
1,200
1,000
800
600
400
2000
Isle
t S
ize
(No
. of
Cel
ls)
No. of Enlarged Nuclei
A B
C D
Figure 3 The incidence of nucleomegaly in islet cells. These panels summarize the range of enlarged nuclei observed in islet
structures using tissue sections for each congenital hyperinsulinism in infancy (CHI) cohort and age-matched control tissue.
The number of enlarged nuclei per islet surface area has been expressed relative to the number of cells within the islet. Only
diffuse CHI (CHI-D) islets (B) had a high incidence of more than four enlarged nuclei per islet surface area. Indeed, some CHI-D
islets were found to contain up to nine nucleomegalic cells in a single field of view. A, Control. B, CHI-D. C, Atypical CHI. D,
BelgiumLouvain, Belgium) for help with the histopathology of
focal and atypical CHI cases in our studies. We thank Roger
Meadows from the Bioimaging Core Facility in the Faculty of Life
Sciences, University of Manchester, UK, for help with the light
microscopy/image analysis. We thank the Wellcome Trust for
equipment grant support to the Electron Microscopy Core
Facility, Faculty of Life Sciences, University of Manchester, UK.
We are also grateful to research nurses and clinical colleagues at
Central Manchester University Hospitals NHS Trust and the
Manchester Biomedical Research Centre.
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