Seminars in Pediatric Surgery (2011) 20, 3-12

Morphologic analysis of focal and diffuse forms of

congenital hyperinsulinism
Jacques Rahier, MD, PhD, Yves Guiot, PhD, Christine Sempoux, MD, PhD

From the Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Tour Rosalind
Franklin, Brussels, Belgium.

KEYWORDS Congenital hyperinsulinism is clinically characterized by an inappropriate insulin secretion resulting in

Hypoglycemia; recurrent severe hypoglycemia. Nesidioblastosis, the proliferation of islet cells budding off from ducts,
Histology; has been considered for years as the histologic lesion responsible for the syndrome. In our morphologic
Islets of Langerhans; studies, we demonstrate that nesidioblastosis is not specific of the disease, which is actually not a single
Nesidioblastosis; entity. Indeed, we recognize the existence of 2 different forms—a diffuse form and a focal form—and
Congenital demonstrate that they can be differentiated by morphologic criteria, even on frozen sections during
hyperinsulinism surgery. This histologic distinction directs the therapeutic approach because the patients experiencing
the focal form of the syndrome can be completely cured by a very limited pancreatectomy. Molecular
findings confirmed the reliability of this histologic distinction, showing a specific background for each
form.
© 2011 Elsevier Inc. All rights reserved.

Hypoglycemia is not a rare event in neonates and infants
and has various causes.1 It can be the result of a lack of
hepatic production of glucose, mostly related to congenital
metabolic diseases, or the consequence of hormonal imbal-
ance linked to pituitary, adrenal, or thyroid deficiency. Hy-
poglycemia is also observed in small-for-date neonates,
after salicylate consumption or in Reye syndrome. How-
ever, recurrent severe hypoglycemia may also be related to
inappropriately elevated plasma insulin levels, which is the
topic of this review.
The syndrome of persistent hyperinsulinemic hypogly-
cemia of infancy (PHHI) was recognized more than 50
years ago by McQuarrie.2 The estimated incidence of PHHI
in the general population is 1/30,000 to 1/50,000 but it
increases to 1/2500 in communities with substantial in-
Address reprint requests and correspondence: Jacques Rahier, MD,
PhD, Department of Pathology, Cliniques Universitaires Saint-Luc, Uni-
versité catholique de Louvain, Tour Rosalind Franklin, 10 Avenue Hip-
pocrate, 1200, Brussels, Belgium.
E-mail address: jacques.rahier@uclouvain.be.
breeding. Despite the number of studies devoted to this
subject, the pathogenicity of the disease remained unsolved
for several decades.3,4 Fortunately, major progress in ge-
netic and molecular biology has brought enlightenment in
most cases.5-13
The age at onset is quite variable: the vast majority of
cases are revealed early in life, a few hours or days after
birth, but occasionally, symptoms can take as long as 5 or 6
months to become apparent. Most infants with an early
onset of symptoms have a heavy birth weight. The severity
of the disease is quite variable but tends to be greater in the
neonatal form, many patients remaining unresponsive to
diazoxide.14
In those infants who remain nonresponsive to medical
treatment, persistent hyperinsulinic hypoglycemia can cause
great neurological damage.5,15 For many years, surgery was
the only therapeutic option. The extent of surgical resection
has long been a matter of debate, with some surgeons
recommending a 95% pancreatic resection to avoid recur-
rence of the disease. However, subsequent diabetes is a
major side effect of resection.16-18

1055-8586/$ -see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1053/j.sempedsurg.2010.10.010
4 Seminars in Pediatric Surgery, Vol 20, No 1, February 2011
Figure 1 Nesidioblastosis B cells budding off from ducts in a
case of diffuse PHHI. (Color version of figure is available online.)
The 2 first cases we encountered in the 1980s were of
particular interest, with very curious clinical progress: both
were of neonatal onset, had a high birth weight and were
insensitive to diazoxide.19 Both pancreases were apparently
macroscopically normal, with no evident lesion at microscopy,
but the first one was not cured despite a near-total pancreate-
ctomy (in 2 steps) and the second case was cured by a
hemipancreatectomy. At that time, people used to consider that
“nesidioblastosis” was the underlying pathologic condition re-
sponsible for the disease. Nesidioblastosis was defined by G.
Laidlaw20 as a diffuse and disseminated proliferation of islet
cells budding off from ducts (Figure 1) and the PHHI syn-
drome was also called nesidioblastosis. Judging by the strange
Figure 2 Small focal adenomatous hyperplasia not recognized on hematoxylin and eosin staining. (Color version of figure is available online.)
evolution of these cases, we were at that time already con-
vinced that PHHI was not a single entity. By conducting
further investigations in the patient cured by partial pancrea-
tectomy, we realized that, although there was no visible lesion
either macroscopically or after conventional Hemalun Eosine
staining, immunohistochemical analysis with the use of an
antibody directed against insulin revealed a small focal endo-
crine “tumor-like” lesion (Figure 2), the removal of which was
sufficient and necessary for the patient to be cured.19 However,
despite careful analysis, such a focal lesion was never found in
the other patient who remained sick despite near-total pancre-
atectomy.
Investigations of the pathogenicity of the nonfocal, also
called the diffuse type of PHHI, were the next step: first we
wondered whether “nesidioblastosis” really existed at all
and whether that process could be responsible for hyperin-
sulinism. Morphologic analysis clearly showed that nesid-
ioblastosis, as defined previously, was present not only in
symptomatic but also in normoglycemic control patients of
a similar age (Figure 3): it could thus not be considered
pathognomonic of this syndrome. Quantitative double im-
munohistochemical techniques with simultaneously anti-in-
sulin and Ki-67 antibodies enabled Sempoux et al21 to
demonstrate that there was no proliferation in these small
groups of B cells in PHHI (Figure 4). Furthermore, when
the number of B cells was measured by the point counting
method, we observed that there was no significant differ-
ence in the numbers of pancreatic B cells between normo-
glycemic infants and patients with the diffuse type of PHHI
(Figure 5). We therefore suggested that the nonfocal or
diffuse type of PHHI was related to a B-cell functional
abnormality.19
Rahier et al Morphologic Analysis of Focal and Diffuse Forms of CHI
Figure 3 Nesidioblastosis in cases of normoglycemic infant (A)
or infant with diffuse PHHI (B). (Color version of figure is avail-
able online.)
We were therefore able to conclude at that time in the
early eighties that different types of PHHI indeed do exist:
one is secondary to a focal tumor-like lesion and can be
cured by partial resection, the other appears to be a diffuse
lesion that cannot be cured by partial pancreatectomy. It was
Figure 4 Nesidioblastosis: not a permanent proliferation of B cells. (Color version of figure is available online.)
5
Figure 5 The amount of B cells is similar in normoglycemic
controls and in infants with diffuse PHHI.
further concluded that nesidioblastosis does exist, but that it
is not specific to PHHI and does not correspond to perma-
nent B cell proliferation.
Subclassification and characteristics of the
different PHHI types
PHHI does not actually correspond to a single entity.5-13,19
Many different forms have now been reported on the basis
of specific genetic defects. According to the type of genetic
abnormality, the histologic feature may be different and the
morphologic pattern may help to differentiate the various
entities. On a practical or surgical point of view, one of the
most important distinction remains that of focal versus dif-
fuse character of the lesion because a focal lesion may be
cured by a resection limited to the abnormal focus.
6 Seminars in Pediatric Surgery, Vol 20, No 1, February 2011

Figure 6 Focal adenomatous hyperplasia is made by the confluence of hyperplastic but normally structured islets with a peripheral rim
of non-B cells. (Color version of figure is available online.)

Focal type of PHHI
The focal type is a focal adenomatous hyperplasia,19,22 char-
acterized by the presence of a small endocrine lesion in the
pancreas, histologically corresponding to the confluence of
hyperplastic but apparently normally structured islets, with a
large core of B cells and a peripheral rim of endocrine non-B
cells (Figure 6). Within the focal lesion, the B cells are hyper-
active, with an enlarged cytoplasm and a large Golgi region
full of proinsulin but relatively few insulin granules and little
insulin labeling because the lesion hypersecretes and does not
store insulin. The lesion may be very small and its limits are
sometimes irregular. Outside the focus the islets are small, their
B cells are resting with a high storage of insulin and a weak
production of proinsulin (Figure 7). Their cytoplasm is
shrunken and their nuclei are small.23,24 The focal adenoma-
tous hyperplasia is different from adenoma: adenoma do not
seem to be formed by the confluence of true islets and we have
never observed adenomas in neonates or infants. Focal adeno-
matous hyperplasia is related to an loss of heterozygosity of
11p15 on the maternal allele and a sulfonylurea receptor (SUR)
mutation on the paternal one.25-28 This can be easily demon-
strated because p57 is located in this region and is thus not
expressed in cases with 11p15 loss of heterozygosity (Figure
8).29,30 Focal adenomatous hyperplasia differs from adenoma
or insulinoma both morphologically and by molecular biolo-
gy.30 Selective resection restricted to the lesion cures the pa-
tient provided the resection is complete and the lesion solitary.
Diffuse type of PHHI
In the diffuse type of PHHI the pancreas appears normal both
macro- and microscopically, but even near-total pancreatec-
tomy can be insufficient to cure the patient.19,22 Careful anal-
ysis of the morphology of the islets of Langerhans uncovers the
presence of large B cells with abnormally large nuclei as
observed in hyperactive endocrine cells (Figure 9). Immuno-
staining with a specific antibody to proinsulin reveals the
labeling of a large Golgi apparatus reflecting a very high
activity of proinsulin synthesis. However, there is only very
weak labeling with insulin antibody, traducing low insulin
storage because of a major nonregulated insulin release. This

Figure 7 (A) Islets from outside a focal lesion. (B) Cells have reduced cytoplasm and small nuclei and low proinsulin production. (Color
version of figure is available online.)
Rahier et al Morphologic Analysis of Focal and Diffuse Forms of CHI 7

Figure 8 p57 within the focal lesion (A) or outside (B). (Color version of figure is available online.)

Figure 9 Islets from diffuse type of PHHI (A and C) and from normoglycemic control (B). (Color version of figure is available on-
line.)
8 Seminars in Pediatric Surgery, Vol 20, No 1, February 2011
Figure 10 Normal insulin content (A), proinsulin production (B), and SUR 1 expression (C) in a case of GLUD overactivity. (Color
version of figure is available online.)
particular aspect contrasts very much with that of islets located
outside the lesion in cases of focal adenomatous hyperplasia.
It is now well demonstrated that these diffuse lesions
are secondary to a mutation of one of the genes of the
KATP-dependent channel.31,32 The KATP-dependent
channels are composed of 2 subunits: the sulfonylurea
receptor, ABCC8 (previously SUR 1), and a member of
the inwardly rectifying potassium channels, KCNJ11
(previously Kir 6.2). The permanent closure of these
channels caused by their absence or inefficiency in-
creases intracellular K⫹ and depolarizes the B-cell mem-
brane. This leads to the opening of the voltage-dependent Ca2⫹
channels, which in turn, activates the exocytic machinery for
insulin secretion. Only in cases of SUR mutation leading to a
total lack of SUR synthesis, the negativity of SUR immuno-
cytochemistry is useful for diagnosis.
The diffuse type of PHHI used to represent 60% of all
operated cases before the distinction of the various types of
PHHI was made. This percentage is nowadays greater because
the tendency is to be conservative as much as possible in the
diffuse form.
Other forms of PHHI
The 2 types we described in the previous chapter are both
related to a pathology of the sulfonylurea receptor (the K⫹
channel) and represent the more frequent types of PHHI in the
material we analyzed (nearly 90%). Other causes exist but their
frequency is much lower in the material we analyzed.
Glutamate deshydrogenase hyperactivity
Increased insulin secretion can also be consecutive to over-
activity of glutamate deshydrogenase. This is the case of
patients with autosomal dominant hyperinsulinism-hyper-
ammonemia syndrome. It results from genomic mutations
in the regulatory domain of the GLUD1 gene with resulting
impaired sensitivity of the enzyme to the inhibition by
guanosine triphosphate.13,33 Insulin secretion, in infants with
this abnormality, is triggered by the consumption of high-
protein diets. These infants therefore present a severe hypo-
glycemia after an oral leucine load, known in the early PHHI
literature as leucine sensitive hypoglycemia. The 2 cases we
were able to analyze were macroscopically unremarkable. Mi-
croscopically, a few B-cell nuclei showed a moderate increase
in size, but the cytoplasm remained unchanged. At immuno-
histochemistry, insulin staining was not lowered as in the
classical diffuse form, proinsulin production was high and
SUR1 expression was normal (Figure 10).
Glucokinase overactivity
In 1998, Glaser et al34 reported a family with autosomal
dominant familial hyperinsulinism suggesting a defect in
the glucose threshold at which insulin secretion is switched
off. Other cases were reported by the group of Cuesta-
Munoz and that Stanley.35-37 It is a very rare cause of PHHI.
In the 2 cases we had the opportunity to analyze, the pan-
creas was reported as macroscopically normal. At micros-
copy, a few rare B-cell nuclei were slightly increased in
size, and immunohistochemistry staining for insulin and
proinsulin was normal. The only difference with the pan-
creas of age-matched controls was a major increase in the
islet size (Figure 11). This peculiarity was not reported in
the cases analyzed in by researchers in Philadelphia.36
Atypical forms
A few cases have been classified as atypical because they
did not fit the described categories. Symptoms of most of
these patients do not appear at birth but later, at 5 or 6
Rahier et al Morphologic Analysis of Focal and Diffuse Forms of CHI 9

Figure 11 Normoglycemic control (A) and a case with glucokinase overactivity (B). The size of the islets is higher in this type of PHHI
than in control patients. (Color version of figure is available online.)

months, and are less prominent than in the usual diffuse pathology. Some islets show signs of hyperactivity but
form. These infants are often improved by diazoxide ther- others appear normal. The genetic abnormalities underlying
apy, suggesting that KATP channels are not involved in this this type of PHHI are so far unknown.38

Figure 12 Mean radius of 50 selected B-cell nuclei measured outside a focal lesion or in cases devoid of focal lesion.
10 Seminars in Pediatric Surgery, Vol 20, No 1, February 2011

Figure 13 B cells from inside (A) or outside (B) a focal lesion and in diffuse type of PHHI in frozen sections; the B cells abnormalities
(C) are easily recognized with toluidine blue staining. (Color version of figure is available online.)

The challenge in all cases with neonatal onset, large birth weight, and
resistance to diazoxide.39,40 Before the arrival of selective
The distinction between the focal and diffuse types of PHHI is venous samplings and later, of the 18-fluorodopa positron
very important because it has a major impact on the therapeutic emission tomography scan, it was the only way to distin-
management of the patient. The differential diagnosis long guish focal from diffuse disease before pancreatectomy.
relied on morphologic analysis, and because the focal lesion Nowadays, intraoperative frozen sections remain very use-
might be very small, multiple sections were required to ascer- ful to ascertain the adequacy of the diagnosis, recognize the
tain that the lesion was actually diffuse rather than focal. atypical or bizarre forms and most of all to check during
Furthermore, the diagnosis always arrived after the pancreas surgery whether the resection margins are free from lesion.
had been removed, sometimes after total pancreatectomy had
been performed for a very small lesion susceptible to be cured
by a small resection restricted to the focal lesion.
We therefore decided to reanalyze our series of pancre- Difficulties in management
ases removed for PHHI with to analyze whether differences
existed between islets of the diffuse types and islets outside Some cases may be very difficult to manage by the pathol-
a focal lesion. It was then observed that in diffuse PHHI the ogist during surgery. Cases with a pathology related to
islets consisted of hyperactive B cells while those outside a
focal lesion were resting islets.
The existence of objective differences between resting and
hyperactive B cells was first evaluated on paraffin retrospective
material by measuring the size of the B-cell nuclei and the
nuclear B-cell crowding (which is the main number of B cell
nuclei per 100 squared micrometers). Figure 12 shows major
and highly significant differences for both parameters between
B cells from diffuse and focal types of PHHI.23
In a second step, a prospective study was performed.
Frozen sections were made during surgery on small speci-
mens (3-4 mm in large axis) obtained from the head, isth-
mus, corpus and tail of the pancreas, with the objective of
assessing the presence of resting islets with shrunken B-cell
cytoplasm or that of islets with hyperactive B cells with
abnormally large cytoplasm and B cell nuclei (Figure 13).
This technique enabled us to make the right distinction in Figure 14 The limits of a focal lesion may be very irregular.
most cases between focal versus diffuse types of PHHI and (Color version of figure is available online.)
Rahier et al Morphologic Analysis of Focal and Diffuse Forms of CHI
Figure 15 The focal lesions are sometimes very small and
difficult to share for the various analyses. (Color version of figure
is available online.)
KATP channels are usually easy to analyze. Sometimes the
frequency of B-cell occurrence with large nuclei is not as
high as usual and the recognition of a lesion as a diffuse
type may not be so evident. On fortunately rare occasions,
hyperinsulinism results from bifocal lesions that are only
revealed after surgery, because the infant was not cured by
an apparently complete resection of the lesion. More fre-
quently, the focal lesion is small, not actually recognizable
at the naked eye, but the limits of the abnormal focus is
markedly irregular (Figure 14), making it difficult to ascer-
tain whether resection is complete. One case of a focal
lesion involving more than 90% of the pancreas has also
been observed, the absence of p57 labeling and its persis-
tence in the healthy part of the pancreas enabled the con-
firmation of the diagnosis of focal PHHI in this particular
case.
In general, atypical cases, such as glucokinase or gluta-
mate dehydrogenase activation are always more difficult to
diagnose on per surgical frozen sections than hypoglyce-
mias secondary to K channelopathy.
Last but not least, the pathologist also has to share the
material and that is not easy, because the lesion, when focal,
may be very small, and physiological studies (electrophys-
iology or insulin secretion studies) require that the tissue
given to physiologists must not only be well characterized
but also still living (Figure 15).
References
1. Haymond MW. Hypoglycemia in infants and children. Endocrinol
Metab Clin North Am 1989;18:211-52.
2. McQuarrie I. Idiopathic spontaneously occurring hypoglycemia in
infants: clinical significance of problem and treatment. Am J Dis Child
1954;87:399-428.
3. Aynsley-Green A. Nesidioblastosis of the pancreas in infancy. Dev
Med Child Neurol 1981;23:372-9.
4. Landau H, Perlman M, Meyer S, et al. Persistent neonatal hypoglyce-
mia due to hyperinsulinism: medical aspects. Pediatrics 1982;70:
440-6.
11
5. de Lonlay-Debeney P, Fournet J-C, Touati G, et al. Heterogeneity of
persistent hyperinsulinaemic hypoglycemia. A series of 175 cases. Eur
J Pediatr 2002;161:37-48.
6. Aguilar-Bryan L, Bryan J, Nakazaki M. Of mice and men: K(ATP)
channels and insulin secretion. Recent Prog Horm Res 2001;56:47-68.
7. Aguilar-Bryan L, Nichols C, Wechsler S, et al. Cloning of the beta cell
high-affinity sulfonylurea receptor: a regulator of insulin secretion.
Science 1995;268:423-6.
8. Glaser B, Chiu KC, Anker R, et al. Familial hyperinsulinism maps to
chromosome 11p14-15.1, 30 cM centromeric to the insulin gene. Nat
Genet 1994;7:185-8.
9. Glaser B, Thornton P, Otonkoski T, et al. Genetics of neonatal hyper-
insulinism. Arch Disord Child Fetal Neonat 2000;82:F79-86.
10. Meissner T, Brune W, Mayatepek E. Persistent hyperinsulinemic hy-
poglycemia of infancy: therapy, clinical outcome and mutational anal-
ysis. Eur J Pediatr 1997;156:754-7.
11. Otonkoski T, ämmälä C, Huopio H, et al. A point mutation inactivating
the sulfonylurea receptor causes the severe form of persistent hyper-
insulinemic hypoglycemia of infancy in Finland. Diabetes 1999;48:
408-15.
12. Nestorowicz A, Wilson BA, Schoor KP, et al. Mutations in the sulfo-
nylurea receptor gene are associated with familial hyperinsulinism in
Ashkenazi Jews. Hum Mol Genet 1996;5:1813-22.
13. Stanley C, Lieu Y, Hsu B, et al. Hyperinsulinism and hyperammone-
mia in infants with regulatory mutations of the glutamate dehydroge-
nase gene. N Engl J Med 1998;338:1352-7.
14. de Lonlay-Debeney P, Fournet JC, Martin D, et al. Hypoglycémie
hyperinsulinémique persistante du nouveau-né et du nourrisson. Arch
Pediatr 1998;5:1347-52.
15. Aynsley-Green A, Polak JM, Bloom SR, et al. Nesidioblastosis of the
pancreas: definition of the syndrome and the management of the severe
neonatal hyperinsulinemic hypoglycemia. Arch Dis Child 1981;56:
496-508.
16. Shilyansky J, Fisher S, Cutz E, et al. Is 95% pancreatectomy the
procedure of choice for treatment of persistent hyperinsulinemic hy-
poglycaemia of the neonate? J Pediatr Surg 1997;32:342-6.
17. Lovvorn HN, Nance ML, Ferry RJ, et al. Congenital hyperinsulinism
and the surgeon: lessons learned over 35 years. J Pediatr Surg 1999;
34:786-92.
18. Cade A, Walters M, Puntis JW, et al. Pancreatic exocrine and endo-
crine function after pancreatectomy for persistent hyperinsulinaemic
hypoglycaemia of infancy. Arch Dis Child 1998;79:435-9.
19. Rahier J, Fält K, Müntefering H, et al. The basic structural lesion of
persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of
pancreatic D cells or hyperactivity of B-cells? Diabetologia 1984;26:
282-9.
20. Laidlaw GF. Nesidioblastoma, the islet tumor of the pancreas. Am J
Pathol 1938;14:125-34.
21. Sempoux C, Guiot Y, Dubois D, et al. Pancreatic B-cell proliferation
in persistent hyperinsulinemic hypoglycemia of infancy : an immuno-
histochemical study of 18 cases. Mod Pathol 1998;11:444-9.
22. Goossens A, Gepts W, Saudubray JM, et al. Diffuse and focal nesid-
ioblastosis. A clinicopathological study of 24 patients with persistent
neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 1989;13:
766-75.
23. Sempoux C, Guiot Y, Lefebre A, et al. Neonatal hyperinsulinemic
hypoglycemia: heterogeneity of the syndrome and keys for differential
diagnosis. J Clin Endocrinol Metab 1998;83:1455-61.
24. Sempoux C, Guiot Y, Rahier J. The focal form of persistent hyperin-
sulinemic hypoglycemia of infancy. Diabetes 2001;50:S182-183.
25. de Lonlay P, Fournet JC, Rahier J, et al. Somatic deletion of the
imprinted 11p15 region in sporadic persistent hyperinsulinemic hypo-
glycemia of infancy is specific of focal adenomatous hyperplasia and
endorses partial pancreatectomy. J Clin Invest 1997;100:802-7.
26. Verkarre V, Fournet JC, de Lonlay P, et al. Paternal mutation of the
sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 im-
printed genes lead to persistent hyperinsulinism in focal adenomatous
hyperplasia. J Clin Invest 1998;102:1286-91.
12
27. Ryan F, Devaney D, Joyce C, et al. Hyperinsulinism: molecular aeti-
ology of focal disease. Arch Dis Child 1998;79:445-7.
28. Fournet JC, Mayaud C, de Lonlay P, et al. Unbalanced expression of
11p15 imprinted genes in focal form of congenital hyperinsulinism:
association with a reduction to homozygosity of a mutation in ABCC8
or KCNJ11. Am J Pathol 2001;158:2177-84.
29. Kassem SA, Ariel I, Thornton PS, et al. p57KIP2 expression in normal
islet cells and in hyperinsulinism of infancy. Diabetes 2001;50:2763-9.
30. Sempoux C, Guiot Y, Dahan K, et al. The focal form of persistent
hyperinsulinemic hypoglycemia of infancy: morphological and molec-
ular studies show structural and functional differences with insuli-
noma. Diabetes 2003;52:784-94.
31. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward
rectifier Kir 6.2 also leads to familial persistent hyperinsulinemic
hypoglycemia of infancy. Hum Mol Genet 1996;5:1809-12.
32. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea
receptor gene in familial persistent hyperinsulinemic hypoglycemia of
infancy. Science 1995;268:426-9.
33. Stanley CA, Fang J, Kutyna K, et al. Molecular basis and character-
ization of the hyperinsulinism/hyperammonemia syndrome. Predomi-
nance of mutations in exons 11 and 12 of the glutamate dehydrogenase
Gene. Diabetes 2000;49:667-73.
Seminars in Pediatric Surgery, Vol 20, No 1, February 2011
34. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism
caused by an activating glucokinase mutation. N Engl J Med 1998;
338:226-30.
35. Cuesta-Muñoz AL, Huopio H, Otonkoski T, et al. Severe persistent
hyperinsulinemic hypoglycemia due to a de novo glucokinase muta-
tion. Diabetes 2004;53:2164-8.
36. Sayed S, Langdon DR, Odili S, et al. Extremes of clinical and enzy-
matic phenotypes in children with hyperinsulinism caused by glucoki-
nase activating mutations. Diabetes 2009;58:1419-27.
37. Kassem S, Heyman M, Glaser B, et al. Large islets, beta-cell
proliferation, and a glucokinase mutation. N Engl J Med 2010;362:
1348-50.
38. Sempoux C, Guiot Y, Cosgrove K, et al. A new morphological form
of persistent hyperinsulinaemic hypoglycaemia of infancy: corre-
lation with the clinical and phydiological data. Horm Res 2002;58:
44.
39. Rahier J, Sempoux C, Fournet JC, et al. Partial or near-total pancre-
atectomy for persistent neonatal hyperinsulinemic hypoglycemia: the
pathologist’s role. Histopathology 1998;32:15-9.
40. Suchi M, Thornton PS, Adzick NS, et al. Congenital hyperinsulinism:
intraoperative biopsy interpretation can direct the extent of pancreate-
ctomy. Am J Surg Pathol 2004;28:1326-35.