Consensus Statement

Hormone Research
in Paediatrics Received: November 1, 2022
Horm Res Paediatr 2024;97:279–298
Accepted: May 16, 2023
DOI: 10.1159/000531766 Published online: July 14, 2023

International Guidelines for the

Diagnosis and Management of
Hyperinsulinism
Diva D. De Leon a Jean Baptiste Arnoux b Indraneel Banerjee c

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Ignacio Bergada d Tricia Bhatti e Louise S. Conwell f Junfen Fu g
Sarah E. Flanagan h David Gillis i Thomas Meissner j Klaus Mohnike k
Tai L.S. Pasquini l Pratik Shah m Charles A. Stanley a Adrian Vella n
Tohru Yorifuji o Paul S. Thornton p
aCongenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics,

Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania,

Philadelphia, PA, USA; bReference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital,
AP-HP, University of Paris-Cité, Paris, France; cPaediatric Endocrinology, Royal Manchester Children’s Hospital,
University of Manchester, Manchester, UK; dCentro de Investigaciones Endocrinológicas “Dr. César Bergadá”
(CONICET – FEI), Division de Endrocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina;
e
Department of Clinical Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and Perelman
School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; fAustralia and Children’s Health
Queensland Clinical Unit, Department of Endocrinology and Diabetes, Queensland Children’s Hospital, Children’s
Health Queensland, Greater Brisbane Clinical School, Medical School, Faculty of Medicine, University of
Queensland, Brisbane, QLD, Australia; gNational Clinical Research Center for Child Health, Department of
Endocrinology, The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China; hInstitute of
Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; iHadassah Medical Center,
Department of Pediatrics, Ein-Kerem, Jerusalem and Faculty of Medicine, Hebrew-University, Jerusalem, Israel;
j
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical
Faculty, Heinrich Heine University, Duesseldorf, Germany; kDepartment of General Pediatrics, Otto-von-
Guericke University Magdeburg, Magdeburg, Germany; lResearch and Policy Director, Congenital Hyperinsulinism
International, Glen Ridge, NJ, USA; mPediatric Endocrinology, The Royal London Children’s Hospital, Queen Mary
University of London, London, UK; nDivision of Diabetes, Endocrinology and Metabolism, Mayo Clinic, Rochester,
MN, USA; oPediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital,
Osaka, Japan; pCongenital Hyperinsulinism Center, Cook Children’s Medical Center and Texas Christian University
Burnett School of Medicine, Fort Worth, TX, USA

Keywords Abstract
Hyperinsulinism · Guidelines · Hypoglycemia · Insulin Background: Hyperinsulinism (HI) due to dysregulation of
pancreatic beta-cell insulin secretion is the most common
and most severe cause of persistent hypoglycemia in infants

[email protected] © 2023 The Author(s). Correspondence to:

www.karger.com/hrp Published by S. Karger AG, Basel Paul S. Thornton, Paul.thornton @ cookchildrens.org
This article is licensed under the Creative Commons Attribution 4.0
International License (CC BY) (http://www.karger.com/Services/
OpenAccessLicense). Usage, derivative works and distribution are
permitted provided that proper credit is given to the author and the
original publisher.
and children. In the 65 years since HI in children was first using the framework of Grading of Recommendations,
described, there has been a dramatic advancement in the Assessment, Development, and Evaluation (GRADE),
diagnostic tools available, including new genetic techniques describing both the strength of recommendations and the
and novel radiologic imaging for focal HI; however, there quality of the evidence [1]. A detailed description of the
have been almost no new therapeutic modalities since the grading scheme has been previously published [2].
development of diazoxide. Summary: Recent advances in In terms of strength of recommendations, strong
neonatal research and genetics have improved our under- recommendations used the phrase “‘we recommend’” and
standing of the pathophysiology of both transient and the number 1, and conditional recommendations used
persistent forms of neonatal hyperinsulinism. Rapid turn- the phrase “‘we suggest’” and the number 2. Cross-filled
around of genetic test results combined with advanced circles indicate the quality of the evidence such that ⊕○○○
radiologic imaging can permit identification and localization denotes very low-quality evidence; ⊕⊕○○, low-quality;
of surgically-curable focal lesions in a large proportion of ⊕⊕⊕○, moderate-quality, and ⊕⊕⊕⊕, high-quality. In the
children with congenital forms of HI, but are only available in absence of sufficient evidence, conclusions were based on
certain centers in “developed” countries. Diazoxide, the only expert opinion.
drug currently approved for treating HI, was recently des- High-quality evidence is defined as “well-performed
ignated as an “essential medicine” by the World Health Randomized Controlled Trials (RCTs) or very strong

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Organization but has been approved in only 16% of Latin evidence from unbiased observational studies”; moder-
American countries and remains unavailable in many under- ate-quality is defined as “RCTs with some limitations or
developed areas of the world. Novel treatments for HI are strong evidence from unbiased observational studies”;
emerging, but they await completion of safety and efficacy low-quality is defined as “RCTs with serious flaws or
trials before being considered for clinical use. Key Messages: some evidence from observational studies”; and very low-
This international consensus statement on diagnosis and quality is defined as “unsystematic clinical observations
management of HI was developed in order to assist spe- or very indirect evidence observational studies” [2].
cialists, general pediatricians, and neonatologists in early
recognition and treatment of HI with the ultimate aim of
reducing the prevalence of brain injury caused by hypo- 1. The Diagnosis of Hyperinsulinism
glycemia. A previous statement on diagnosis and man-
agement of HI in Japan was published in 2017. The current 1.1 We Recommend Making a Specific Diagnosis of
document provides an updated guideline for management Hyperinsulinism Based on Measurements, at a Time of
of infants and children with HI and includes potential ac- Hypoglycemia, of Plasma Levels of Metabolic Fuels
commodations for less-developed regions of the world (Beta-Hydroxybutyrate [BOHB] and Free Fatty Acids
where resources may be limited. © 2023 The Author(s). [FFA]) and Hormones (Insulin, Growth Hormone,
Published by S. Karger AG, Basel Cortisol) and Determination of the Glycemic Response
to a Pharmacologic Dose of Glucagon [Grade 1 ⊕⊕⊕○]
The diagnosis of HI is made on the basis of increased
Method of Development of Evidence-Based Clinical insulin action and/or inadequate suppression of plasma
Practice Guidelines insulin during either spontaneous or fasting-induced
hypoglycemia. Insulin should be measured using a high-
The guideline-writing committee comprised a group of sensitivity assay [3]. Increased insulin action can be
17 members including 13 pediatric endocrinologists, an demonstrated by increased glucose requirement (e.g., >8
adult endocrinologist, a pathologist, a genetic scientist, and mg/kg/min in a neonate normal 4–6 mg/kg/mi [4]),
a representative of an international patient advocacy or- inappropriately suppressed plasma concentrations of
ganization for HI. Following a preparatory meeting FFA and BOHB during hypoglycemia, and an inappro-
(September 2019), working groups were assigned, and priate glycemic response to glucagon at a time of hy-
each undertook a literature review. The combined work poglycemia (Table 1) [5–7]. Suppression of BOHB and
was collated into a single document which was revised by preservation of a large glycemic response to glucagon are
all members of the writing committee over a 3-year period. particularly sensitive markers of inappropriate insulin
Participating pediatric endocrine societies of the Inter- action. In the absence of multiple pituitary hormone de-
national Consortium of Pediatric Endocrinology (ICPE) ficiencies in neonates, an inappropriately large glycemic
were invited to review the document with feedback in- response to glucagon stimulation may be considered di-
corporated into the final version. The evidence was graded agnostic, particularly when plasma insulin concentration is

280 Horm Res Paediatr 2024;97:279–298 De Leon et al.

DOI: 10.1159/000531766
low (Table 1). Newborn infants, tested before 72 h of life because these conditions can cause transient hyper-
during the time of transitional hypoglycemia, should be re- insulinism in the newborn period [19–21]. In children
tested after 72 h if hypoglycemia is still present to confirm older than 2 years of age with acquired HI, the pos-
the diagnosis [8]. Provocative stimulation tests with glu- sibility of an insulinoma should be considered [22, 23].
cose, leucine, or protein are not useful for establishing the Insulinomas are usually solitary and benign, but they
diagnosis of HI but may be helpful in defining the subtype can be multiple and are rarely malignant. Insulinomas
of HI [9–11]. Occasionally, there will be a discrepancy can be a component of multiple endocrine neoplasia
between markers of insulin action and insulin levels with type 1, and genetic investigations should be directed
elevated insulin levels in the presence of high ketones and accordingly [24].
absent glucagon response. In these cases, it is possible the Genetically inherited forms of HI cause isolated
insulin assay is not as sensitive as it could be, and the focus pancreatic dysfunction but also may be associated with
should be on the markers of insulin action, not the insulin syndromes affecting multiple organs (Syndromic HI)
level itself. (Table 3). Genetic forms of HI may present in the
newborn period, but may not be detected until later in
1.2 We Recommend Genetic Testing for all Children life. Non-syndromic genetic HI is estimated to occur in
except for Those Likely to Have an Acquired Form of approximately 1:25,000–1:45,000 newborns [70–73].

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Hyperinsulinism [GRADE 1⊕⊕⊕○] Loss-of-function variants in the ABCC8 and KCNJ11
genes, which encode the beta-cell ATP-sensitive po-
1.3 We Recommend Evaluation of Infants with tassium (KATP) channel (shown in Fig. 1), are the most
Hyperinsulinism for Multi-System Syndromes frequent cause [74]. Most recently, heterozygous non-
Associated with Hyperinsulinism [GRADE 1⊕⊕○○] coding variants which prevent silencing of Hexokinase
1 within the pancreatic beta-cell have also been shown
1.4 We Recommend Screening all Children Whose to be an important cause of isolated HI [75]. Certain
Hyperinsulinism Occurs after the Age of 2 years of Life genetic types of HI have characteristic phenotypes that
for Insulinoma [Grade 1⊕⊕○○] can assist in their diagnosis; glutamate dehydrogenase
It is important to determine the precise etiology of (GDH) HI is associated with moderately elevated
HI because the diagnosis may direct choice of therapy plasma ammonia concentrations [76] and short-chain
and need for long-term follow-up [12]. HI presenting hydroxyacyl-CoA dehydrogenase (SCHAD) HI may be
in the immediate neonatal period may be caused by associated with elevated plasma C4-OH acyl carnitine
either genetic or acquired conditions (Table 2). Ac- and urine 3-OH-glutarate levels [77]. Protein-induced
quired HI may be secondary to perinatal factors such as hypoglycemia is part of the phenotype in GDH-HI,
maternal diabetes, perinatal stress, birth asphyxia, in- SCHAD-HI, and KATP-HI [11, 60, 78]. Anaerobic
trauterine growth restriction, exposure to maternal exercise can induce hypoglycemia in some patients
drugs, or high rates of maternal glucose infusions with activating variants in the promoter region of
during delivery. Cases of Perinatal Stress-Induced SLC16A1, the gene encoding the monocarboxylate
Hyperinsulinism (PSHI) typically present in the first 24 transporter 1 (MCT1) pyruvate transporter reported in
h of life and affect approximately 1 in 1,200–1,700 a small number of cases [79]. Patients with glucokinase
newborns [13, 14]; they often resolve within the first (GCK) HI may develop ketotic hypoglycemia with
10–14 days of life. PSHI is an exaggerated form of prolonged fasting, in contrast to the hypoketotic hy-
transitional hypoglycemia triggered by hypoxia-me- poglycemia usually found in HI, especially in the
diated reduction of the beta-cell glucose threshold for setting of glucose levels dropping below the altered
suppression of insulin secretion [8, 15, 16]. In ap- threshold for insulin secretion [27]. Patients with
proximately 1 in 12,000–13,600 newborns, a more somatic mutations associated with localized islet nu-
severe form of PSHI occurs which persists beyond the clear enlargement (LINE) pathology usually present at
first 2 weeks of life and may require treatment with a later age [80].
diazoxide [17, 18]. Genetic testing is not usually rec-
ommended for infants with PSHI because there is no Alternate Classification of HI
current evidence of a genetic etiology. HI may usefully be classified according to the re-
When there is a family history suggestive of matu- sponse to diazoxide, the first-line drug for controlling
rity-onset diabetes of the young (MODY), genetic hypoglycemia in children with HI. In the diazoxide-
testing for HNF1A and HNF4A should be considered unresponsive group up to 90% of cases have pathogenic

Hyperinsulinism Guidelines Horm Res Paediatr 2024;97:279–298 281

DOI: 10.1159/000531766
Table 1. Diagnostic features of HI at
the time of hypoglycemia (plasma Evidence of excessive insulin action at the time of hypoglycemia
glucose <50 mg/dL [2.8 mmol/L]) 1. Suppressed plasma β-hydroxybutyrate (<1.8 mmol/L)
2. Suppressed plasma free fatty acids (<1.7 mmol/L)
3. Inappropriately large glycemic response to glucagon (≥30 mg/dL [≥1.7 mmol/L])
4. Increased glucose infusion rate required to maintain euglycemia above normal
for age
>8 mg/kg/min for neonates
>3 mg/kg/min for adults
Evidence of excessive insulin secretion/inadequate suppression of insulin secretion
at the time of hypoglycemia (these are less definitive than evidence of excessive
insulin action)
1. Plasma insulin >1.25 μU/mL (8.7 pmol/L)
2. C-peptide >0.5 ng/mL (>0.17 nmol/L)

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variant(s) in ABCC8 or KCNJ11 [74] with diffuse or life. Rapid testing of the ABCC8 and KCNJ11 genes is
focal pancreatic histopathology. Recessive bi-allelic crucial for the management of children with diazoxide-
variants or dominant mono-allelic ABCC8 or KCNJ11 unresponsive HI because the presence of a paternally
pathogenic variants cause diffuse HI. In contrast, focal inherited pathogenic variant predicts a focal lesion with a
HI results from the combination of a paternally in- sensitivity of 97% [74]. Pancreatic imaging (see Rec-
herited recessive ABCC8 or KCNJ11 pathogenic variant ommendation 1.5 below) can then be performed to lo-
and paternal isodisomy of the 11p15 chromosomal calize the lesion prior to surgery which is curative in the
region confined to the pancreatic lesion [81]. In some majority of cases. For centers unable to perform such
cases, paternal isodisomy of chromosome 11p15 occurs imaging, rapid genetic testing of ABCC8 and KCNJ11 will
in multiple tissues, causing Beckwith-Wiedemann provide information on cases likely to benefit from
Syndrome spectrum (BWSp); severe diazoxide-unre- transfer to a center with appropriate imaging and surgical
sponsive HI can occur in BWSp due to 11pUPD when capacities [87]. If access to rapid testing of these genes is
there is a concurrent paternally inherited ABCC8 or limited, effort should be made to contact one of several
KCNJ11 disease-causing variant [82]. Therefore, di- international laboratories able to screen the ABCC8 and
azoxide unresponsiveness indicates a higher likelihood KCNJ11 genes, sometimes at reduced cost on compas-
of finding a genetic etiology. The classification of HI sionate grounds.
into diazoxide responsive or not presumes access to and When no pathogenic variant in ABCC8 or KCNJ11 is
treatment with diazoxide. However, in some circum- found on rapid testing or when HI has persisted beyond
stances, diazoxide may not be available, or the person 3 months, genetic testing of all known HI genes should
with HI may be intolerant or experience unacceptable be performed. The current method of choice is next-
side effects. In such cases, the decision to undertake generation sequencing by either targeted panel analysis
genetic testing should be made on the merits of the or whole exome/genome sequencing since these provide
individual case. rapid and cost-effective screening of multiple genes in
Some “atypical” histological forms of HI with localized parallel. It is important to emphasize that no single test is
islet pancreatic involvement (named Localized Islet able to detect all forms of genetic variation reported in
Nuclear Enlargement [LINE] HI or “mosaic” HI) are HI [88]. For example, Sanger sequencing is unable to
caused by somatic dominant variants of the ABCC8 and detect large copy number variants that may occur in
GCK genes [80, 83–86]. Increased Hexokinase 1 (HK1) some HI genes; in addition, non-coding variants deep
protein expression has also been identified in pancreatic within intronic regions will not be detected by exome
tissue, suggesting a role for pancreatic HK1 in HI sequencing or gene panels that do not target these re-
pathogenesis [85]. gions (e.g., deep intronic variants in ABCC8, HADH, and
Genetic testing is recommended whenever acquired HI HK1) [89]. Also important to note is that separate
is unlikely. This should include children with diazoxide- methylation testing for imprinting defects in the 11p
unresponsive HI as well as those with diazoxide-re- BWS region will be required for children with clinical
sponsive HI which persists beyond the first 3 months of suspicion of BWSp [90].

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DOI: 10.1159/000531766
Table 2. Classification of hyperinsulinism disorders in infants and children

Risk factors Clinical features

(a) Acquired Maternal diabetes, including Large for gestational age (LGA)
neonatal HI gestational diabetes

Perinatal stress-induced HI Small for gestational age (SGA)

Maternal hypertension, pre-eclampsia, eclampsia

Maternal drugs Ritodrine, sulfonylurea, high GIR during labor, etc.

(b) Acquired non- Paraneoplastic HI Insulinoma (sporadic or MEN1)

neonatal HI
Surgically-induced HI Post-gastric bypass, post-fundoplication for gastro-
esophageal reflux (NIPHS: non insulinoma pancreatogenous
hypoglycemia syndrome)

Drug-induced HI Antidiabetic medications (Insulin, sulfonylureas)

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Autoimmune HI (anti-insulin or insulin Spontaneous or associated with drugs or viral infections)
receptor-activating antibodies) Hirata’s disease (insulin autoimmune syndrome: anti-insulin
antibodies post sulphydryl medications: methimazole,
carbimazole, alpha-lipoic acid and post measles virus, mumps
virus, rubella virus, varicella zoster virus, coxsackie B virus and
hepatitis C virus)

Histology Genes

(c) Genetic HI: Diffuse form ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, HADH, SLC16A1,
isolated HI INSR

Focal form Paternally inherited AR variants of ABCC8 or KCNJ11

LINE- HI (mosaic HI, atypical HI) Sporadic mosaic AD variants of ABCC8, GCK, and inappropriate
expression of HK1

Syndrome Gene

(d) Genetic HI: Beckwith-Wiedemann syndrome Genetic or epigenetic changes of imprinted region 11p15.5.
syndromic HI (especially paternal UPD11p; also mutations of imprinting
control genes). Pat UPD11p combined with paternal recessive
ABCC8 or KCNJ11 mutation

Kabuki syndrome KMT2D, KDM6A (usually mosaic)

Turner syndrome Mosaic partial or complete X chromosome monosomy

See complete list of syndromal HI in

table 2

(e) HI mimickers: Autoimmune mimicker Insulin resistance syndrome type B (anti-insulin receptor
hypoinsulinemic antibodies post viral infection (HIV, HTLV1, hepatitis C) or
hypoketotic lymphoproliferative disease, or autoimmune disease (lupus))
hypoglycemia
Paraneoplastic secretion of pro-IGF2 Non-islets cells tumor hypoglycemia (NICTH, Doege-Potter
syndrome)

Genetic disorders of insulin signaling Mutations in AKT2, AKT3, PIK3CA, PIK3R2, CCND2, INSR.

Fatty acid oxidation disorders Abnormalities in the carnitine cycle, beta-oxidation, electron
transfer, and ketone synthesis

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DOI: 10.1159/000531766
Table 3. The genetic etiology of hyperinsulinism

Gene/genetic loci Phenotype MIM Phenotype Mode of inheritance Histology Ref

number

ABCC8 # 256450 Isolated AR Diffuse [25]

AD/mosaic Diffuse [26]
Atypical [27, 28]
AR LOH* Focal [29]

# 606528 Hyperinsulinism with AR (contiguous deletion Diffuse [30]

enteropathy and deafness including USH1C)
ADK # 614300 ADK deficiency syndrome AR Diffuse [31]
ALG3 # 601110 Congenital disorder of AR Diffuse [32]
glycosylation type 1d
ALG6 # 603147 Congenital disorder of AR Diffuse [33]
glycosylation type 1c

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CACNA1C # 601005 Timothy syndrome AD Diffuse [34]
CACNA1D # 615474 PASNA syndrome AD Diffuse [35]
CDKN1C # 130650 Beckwith-Wiedemann Spectrum AD Diffuse [36]
CREBBP # 180849 Rubinstein Taybi syndrome 1 AD Diffuse [37]
DIS3L2 # 267000 Perlman syndrome AR Diffuse [38]
EIF2S3 # 300148 MEHMO syndrome XLR Diffuse [39]
EP300 # 613684 Rubinstein Taybi syndrome 2 AD Diffuse [37]
FAH # 276700 Tyrosinaemia type I AR Diffuse [40]
FOXA2 – Syndromic AD Diffuse [41]
GCK # 602485 Isolated AD/mosaic Diffuse/ [42]
atypical
GLUD1 # 606762 Hyperinsulinism- AD Diffuse [43]
hyperammonaemia syndrome
GPC3 # 312870 Simpson-Golabi-Behmel syndrome XLR Diffuse [44]
HADH # 609975 Isolated AR Diffuse [45]
HK1 – Isolated AD Diffuse [46]
HNF1A # 600496 Isolated AD Diffuse [21]
HNF4A # 125850 Isolated AD Diffuse [19]

# 616026 Fanconi renotubular syndrome AD (p.Arg76Trp) Diffuse [21]

HRAS # 218040 Costello syndrome AD Diffuse [47]

INSR # 609968 Isolated AD Diffuse [48]
KCNJ11 # 601820 Isolated AR Diffuse [49]
AD Diffuse [50]
AR LOH* Focal [29]
KCNQ1 # 192500 Long QT syndrome AD Diffuse [51]
KMT2D # 147920 Kabuki syndrome AD Diffuse [52]
KDM6A # 300867 Kabuki syndrome XLD Diffuse [53]
MPI # 602579 Congenital disorder of AR Diffuse [54]
glycosylation type 1b
PGM1 # 614921 Congenital disorder of AR Diffuse [55]
glycosylation type 1 t

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Table 3 (continued)

Gene/genetic loci Phenotype MIM Phenotype Mode of inheritance Histology Ref

number

PMM2 # 212065 Congenital disorder of AR Diffuse [56]

glycosylation type 1a

– HI and polycystic kidney disease AR (c.-167G>T) Diffuse [57]

PHOX2B # 209880 Central hypoventilation syndrome AD Diffuse [58]
NSD1 # 117550 Sotos syndrome AD Diffuse [59]
SLC16A1 # 610021 Isolated (exercise-induced HI) AD Diffuse [60]
TRMT10A # 616033 Syndromic AR Diffuse [61]
YARS1 # 619418 Yars-related disease AR Diffuse [62]
Chr5q35 deletion # 117550 Sotos syndrome AD Diffuse [63]
Chr9p24 deletion # 151870 9p deletion syndrome AD Diffuse [64]

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Chr11p15 # 130650 Beckwith-Wiedemann Spectrum Sporadic Diffuse [65]
imprinting
abnormality
Chr13 trisomy – Patau syndrome Sporadic Diffuse [66]
ChrX monosomy – Turner syndrome Sporadic Diffuse [67]

*Loss of the maternal 11p15 allele within pancreas in combination with a paternally inherited recessive ABCC8 or KCNJ11 mutation.

1.5 We Recommend that Pancreatic Imaging Studies need for pancreatic imaging with an 18F-DOPA PET
(e.g., 18F-DOPA PET Scan) to Localize a Potentially scan. Recently, 68Gallium-NOGADA-exendin-4-PET/
Resectable Focal Lesion Be Performed in Infants with CT has been reported as a beta-cell-specific tracer but
Diazoxide-Unresponsive Hyperinsulinism, except in has to be further evaluated before being recommended
Those with Genetic Evidence of Diffuse Disease as an additional option [94]. Imaging of the pancreas
[GRADE 1 ⊕⊕⊕○] using conventional techniques such as ultrasound,
The finding of a single paternally-inherited recessive computerized tomography (CT), and magnetic reso-
ABCC8 or KCNJ11 pathogenic variant offers a positive nance imaging (MRI) is not helpful in detecting focal
predictive value up to 94% for focal HI [74, 91]. For lesions in children with congenital HI and should be
these infants and for diazoxide-unresponsive infants restricted to older children in whom an acquired in-
with negative or inconclusive genetic testing, we rec- sulinoma is suspected.
ommend imaging of the pancreas using 6-fluoro-(18F)-
L-3,4-dihydroxyphenylalanine positron emission to-
mography (18F-DOPA PET scan) in combination with 2. Medical Management
CT or MRI to help localize the focal lesion [92, 93].
Published studies of 286 histologically assessed cases 2.1 We Recommend that the Goal of Treatment for
have reported a sensitivity ranging from 75% to 100% Hyperinsulinism Is to Maintain Plasma Glucose
and specificity ranging from 88% to 100% for focal HI Concentrations within the Normal Range of 70–100
[93]. When a focal lesion is detected, the accuracy of mg/dL (3.9–5.6 mmol/L) [Grade 1⊕⊕○○]
localization with 18F-DOPA PET scan is greater than The immediate goal of therapy is to promptly restore
90% [93], but it is highly dependent on the experience of plasma glucose to the normal range of 70–100 mg/dL
the reader. Very small lesions may not be detected by (3.9–5.6 mmol/L) [95]. Following stabilization of glucose,
18
F-DOPA PET scan; thus, a negative study does not efforts should be directed at identifying the optimal treatment
rule out focal HI. For infants with genetic evidence of regimen according to the type of HI. The Pediatric Endocrine
diffuse disease (e.g., dominant variants, bi-allelic KATP Society (PES) guidelines established a treatment goal of >70
channel variants, or glucokinase variants), there is no mg/dL (3.9 mmol/L) for the management of children with

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DOI: 10.1159/000531766
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Fig. 1. Schematic beta-cell with pathways involved in insulin se- triggering pathway to “amplify” insulin release. Drugs such as
cretion. Pathways of glucose and amino acid stimulation of beta- diazoxide and glyburide bind to the KATP channel to inhibit or
cell insulin secretion showing sites of the more common genetic activate insulin release, respectively. GK, glucokinase; HK1,
forms of hyperinsulinism, such as the ATP-sensitive (KATP) po- hexokinase 1; GDH, glutamate dehydrogenase; SCHAD, short-
tassium channel, comprised of SUR1 and Kir6.2 subunits encoded chain acyl-CoA dehydrogenase; MCT1, mono-carboxylate
by the ABCC8 and KCNJ11 genes. Most genetic forms of hy- transporter 1; ATP, adenosine triphosphate; HNF1A & HNF4A,
perinsulinism affect steps by which increased ATP generation hepatic nuclear factors 1 alpha and 4 alpha; SUR1, sulfonylurea
closes KATP channels to depolarize the plasma membrane and receptor 1; Kir6.2, potassium channel subunit; KATP channel, ATP-
activate an influx of calcium to “trigger” release of insulin from sensitive potassium channel; K+, potassium ion; Ca++, calcium ion;
storage granules into the circulation. Additional factors, such as Ins, insulin; GLP1, glucagon-like peptide 1. Dotted line with dash
stimulation by the gut incretin, GLP1, can act downstream of the indicates inhibit, Solid line with + indicates stimulates.

hypoglycemia disorders in order to prevent hypoglycemia meals and bedtime supplemented by additional testing
unawareness [95] and to have a safe margin above the when needed. There is not enough current evidence to
threshold of hypoglycemia that causes brain damage. make a suggestion regarding the use of continuous
Despite attempts to meet the PES glycemic targets, glucose monitoring by subcutaneous sensors.
studies have shown that glucose levels may be found
below this range (70–100 mg/dL, 3.9–5.6 mmol/L) in 2.2 We Recommend that Intravenous Glucose
children with severe forms of hyperinsulinism in up to (Dextrose) Infusion Be Used as the Initial Treatment to
15–20% measurements [96]. In circumstances such as Promptly Restore Euglycaemia for Neonates with
these, a lower hypoglycemia threshold of 63 mg/dL (3.5 Hyperinsulinism [Grade 1 ⊕⊕⊕○]
mmol/L) may need to be accepted in individual patients, Intravenous glucose (dextrose) should be used for
depending on the severity and frequency of hypoglycemia initial treatment of hypoglycemia to restore plasma
and the availability of alternative treatment. glucose levels to the normal range without delay. The
The frequency of monitoring for the presence of hy- usual dose is 200 mg/kg (2 mL/kg of 10% dextrose so-
poglycemia by glucometer testing should be tailored to lution), followed by continuous infusion of dextrose at a
the individuals’ needs with typical monitoring before rate sufficient to maintain plasma glucose above 70 mg/

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DOI: 10.1159/000531766
dL (typically 8 mg/kg/min or greater) [97]. In cases where to its suppressive effect on insulin secretion [106]. In
the child is known to have hypoglycemia caused by 1976, diazoxide was approved in the USA by the Food
hyperinsulinism and IV therapy is not immediately and Drug Administration (FDA) for HI in children.
available, pharmacologic doses of glucagon (0.5–1 mg or Diazoxide suppresses insulin secretion by opening the
20–30 μg/kg) can be used as an alternative acute therapy, beta-cell KATP channels [107]. The therapeutic dose range
given either intramuscularly or subcutaneously, with an of diazoxide in infants and children is 5–15 mg/kg/day po
effect lasting up to 40–60 min allowing time for IV in- with higher doses offering no additional benefits but
sertion [95]. Since the rates of glucose consumption can greater side effects. In adults, a dose range of 3–8 mg/kg/
be as high as 20–30 mg/kg/min in infants with HI, rapid day is recommended (diazoxide prescribing information,
increases in the glucose infusion rate (GIR) may be re- accessdata.fda.gov). The half-life of diazoxide in children
quired. In such children, with clear evidence of increased was recently estimated to be 15 ± 5.3 h [108]; thus, di-
glucose utilization, we suggest rapidly increasing glucose azoxide may be administered two or three times daily. To
infusion rates by increments of 4 mg/kg/min or greater, avoid diazoxide-associated fluid retention, particularly in
taking care not to induce fluid overload [98]. Following a newborn infants [109, 110], a diuretic should be started
200 mg/kg dextrose bolus and an infusion of 8 mg/kg/min concomitantly with the initiation of diazoxide. Doses of
dextrose steady state levels in glucose are reached in 10 chlorothiazide of 10 mg/kg/day or hydrochlorothiazide of

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min, allowing repeat testing to be accurate and avoid over 1–2 mg/kg/day may be used, particularly when giving
treatment [99]. To avoid fluid overload, central venous higher (>10 mg/kg/day) doses of diazoxide [111].
catheters may be required in order to provide dextrose Responsiveness to diazoxide can be demonstrated
solutions in high concentration. by showing that the cardinal feature of HI, hypoketotic
hypoglycemia, has been reversed. In practice, this
2.3 We Recommend Continuous Intravenous Infusion means demonstrating that the infant or child can fast
of Glucagon for Infants at Risk of Fluid Overload and generate hyperketonemia (BOHB levels >1.8
because of a High Glucose Requirement mmol/L) prior to developing hypoglycemia (plasma
[Grade 1⊕⊕○○] glucose levels below 50–60 mg/dL [<2.8–3.3 mmol/L])
When high-dose intravenous glucose is required, [112]. In patients in whom the rate of dextrose infusion
continuous intravenous infusion of glucagon as an cannot be reduced after 5 days of treatment with di-
additional therapy can help control hypoglycemia and azoxide at a dose of 15 mg/kg/day or in whom unre-
prevent complications from fluid overload by reducing sponsiveness has been confirmed by a fasting test,
the rate of intravenous dextrose infusions required to diazoxide should be discontinued. Unresponsiveness
prevent hypoglycemia [100]. An intravenous infusion to diazoxide suggests a KATP channel defect [74], al-
of glucagon (dose range 2.5–20 μg/kg/h) can aid in though other genetic forms of HI may also be diazo-
maintaining euglycemia in HI by stimulation of he- xide-unresponsive, such as glucokinase HI and
patic glucose production from glycogenolysis and hexokinase HI.
inhibition of hepatic glucose uptake [101, 102]. Ad- The acute side effects of diazoxide include salt and water
verse side effects of glucagon infusion may include retention which may lead to fluid overload, edema, hypo-
vomiting (13%), rash (2%), and respiratory distress natremia, tachypnea, and respiratory failure [109]. Pulmo-
(19%) [100]. A rare but important side effect associated nary hypertension has also been described with diazoxide
with glucagon is a necrolytic migratory erythema skin [113–115]; in a large cohort of infants [109] the frequency of
rash (NME) [103, 104]. Long-term continuous infu- diazoxide-related pulmonary hypertension was 2.4%. The
sion of glucagon by subcutaneous pumps has been most common long-term side effect of diazoxide is hy-
reported but is currently unreliable because of the pertrichosis recently reported to occur in 84.1% of children
formation of fibrils and crystals that block infusion [116]. Coarsening of facial features has been reported in 24%
lines [105]. [111, 117]. Other rarer adverse events include neutropenia
(15.6%), thrombocytopenia (4.7%), and hyperuricemia
2.4 We Recommend Diazoxide as the First-Line (5.0%). The clinical significance of the neutropenia is not
Treatment for Patients with an Established Diagnosis of known, and the level of neutropenia that deserves discon-
Hyperinsulinism [Grade 1⊕⊕⊕○] tinuation of diazoxide is also not known. A CBC may be
Diazoxide is a benzothiadiazide related to thiazide drawn prior to starting diazoxide to ensure there is no
diuretics that was initially developed for treatment of evidence of pre-existing neutropenia or thrombocytopenia.
hypertension but later found to be useful to treat HI due The overall frequency of serious adverse events requiring

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DOI: 10.1159/000531766
diazoxide discontinuation is estimated at 9.7% [110]. The dose of long-acting SSA preparations required to control
rate of side effects appears to be higher in infants treated for hypoglycemia is variable, and there are insufficient data
perinatal stress-induced HI or premature babies [110]. For available to make a recommendation, but expert consensus
these reasons, screening for side effects during diazoxide suggests calculating the total monthly dose of octreotide and
therapy is recommended, including an echocardiogram 1 administrating it as a single dose of Octreotide LAR once
week after initiation of therapy with diazoxide and for per month. For lanreotide, the calculation is not equivalent;
symptoms of pulmonary hypertension. In addition, a thus, 30–60 mg once per month is a typical starting dose.
complete blood count with differential and serum uric acid Screening for side effects while on SSA therapy is recom-
levels should be done every 6 months [111]. While there are mended, including growth monitoring, obtaining a gall
no published data to evaluate the clinical significance of bladder ultrasound to evaluate for cholelithiasis, and lab-
elevated uric acid levels associated with the use of diazoxide, oratory evaluation for liver enzymes, growth factors, and
studies in other populations have shown that chronic hy- thyroid function at least every 6 months.
peruricemia in children can lead to monosodium urate
deposits that may progress to gout, just as in adults [118]. 2.6 We Suggest that Medications Which Lack Adequate
Thus, we consider it important to screen for hyperuricemia Proof of Efficacy (i.e., Nifedipine, Sirolimus, etc.) Not Be
in children treated with diazoxide given the reported 5% Used to Treat Hyperinsulinism unless Part of an

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frequency of hyperuricemia in this population [109]. Approved Investigational Protocol [Grade 2⊕⊕○○]
Despite in vitro studies showing inhibition of insulin
2.5 We Suggest the Use of Somatostatin Analogues as secretion by calcium-channel blockers and early reports
Second-Line Treatment for Infants with suggesting beneficial effects of nifedipine in infants with
Hyperinsulinism Who Are Diazoxide-Unresponsive or HI, most major centers have not found it useful and do
Have Unacceptable Diazoxide Side Effects or Are not recommend its use [140]. However, in patients with
Unable to Obtain Diazoxide [Grade 2⊕⊕○○] HI due to genetic defects of the CACNA1D calcium
Short- or long-acting somatostatin analogs (SSA) used in channel, it has been suggested that nifedipine may im-
patients with HI include octreotide [119, 120], long-acting prove not only hypoglycemia but also neuromuscular
octreotide (octreotide LAR) [121, 122], and lanreotide manifestations [141, 142].
[122–126]. Octreotide has been used since the late 1980s as Sirolimus, an inhibitor of mammalian target of ra-
a long-term therapy for HI to avoid the need for pancre- pamycin (mTOR), has been used in some children with
atectomy or in cases that could not be controlled following HI resistant to conventional medical therapies, based
subtotal pancreatectomy [119, 120, 127, 128, 129]. However, on reports of beneficial responses in adults with in-
the use of octreotide therapy is limited by loss of efficacy due sulinoma [143]. However, due to serious concerns over
to tachyphylaxis [120, 130] and the occurrence of important the risk of life-threatening infections, such as hepatitis,
side effects [131–134], including necrotizing enterocolitis diabetes mellitus, and pancreatic insufficiency
(NEC), particularly in premature and high-risk infants with [144–148], and the absence of robust clinical effec-
hemodynamic instability or sepsis [132, 135–137]. While tiveness data, the Guideline Committee cannot rec-
somatostatin analogs are commonly used as second-line ommend sirolimus for routine clinical use in HI. Ex-
treatment of HI, this indication has not been approved by ceptions should only be made for studies of the drug
the United States FDA. carried out under approved investigational protocols.
Octreotide can be administrated in 2–4 subcutaneous Glucocorticoids have been used in the past in an effort
doses/day or by continuous subcutaneous infusion using to increase glucose levels by inducing insulin resistance;
commercial pumps intended for insulin administration however, we suggest that they are not effective in
[127, 129]. The starting dose of octreotide is 5–10 μg/kg/day, treatment of HI and should be avoided since the risks of
and it can be titrated up to a maximum of 20 μg/kg/day [138, this therapy strongly outweigh any benefits.
139]. In an effort to prevent the development of tachy-
phylaxis, some centers use two doses of octreotide during the 2.7 We Suggest Carbohydrate Supplementation to
daytime in combination with continuous overnight dextrose Maintain Euglycaemia in Infants and Children with
administered through a gastrostomy tube [35]. Hyperinsulinism Who Are Not Adequately Controlled
A single monthly injection of a long-acting SSA can have on Pharmacologic Therapy Alone [Grade 2⊕⊕○○]
a therapeutic advantage over multiple daily octreotide in- Many children with HI continue to have unstable
jections or continuous subcutaneous octreotide by a pump hypoglycemia requiring continuous intravenous treat-
with attendant risk of pump disconnection and failure. The ment with glucose despite maximal medical and/or

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DOI: 10.1159/000531766
surgical treatment. For these children, continuous in- underlying focal lesion. Diffuse HI can be recognized by
tragastric infusion of glucose may be used, either via increased numbers of islet cells with large nuclei (nucleo-
nasogastric tube or, preferably, via gastrostomy using megaly) throughout the pancreas; ascertainment of islet
portable pumps [149]. Solutions containing glucose nucelomegaly is ideally undertaken by a pathologist ex-
(dextrose or maltodextrin polymer powder) at concen- perienced in the recognition of HI. Focal lesions are typi-
trations up to 20% may be tolerated. In some cases, cally small, 0.5–1 cm in diameter, and contain increased
glucose supplementation of formula feedings to increase masses of endocrine cells often interspersed with acinar cells
the total carbohydrate content to 15% may be helpful and duct structures; biopsies from the remaining pancreas
[150]; however, care should be taken when using glucose are histologically unremarkable. Focal HI lesions are often
supplementation to avoid interfering with appetite and unencapsulated and frequently extend into the adjacent
normal feeding behavior or inducing obesity due to the normal parenchyma, creating a challenge for assessing
excess calories [151]. involvement of resection margins. In BWSp, there is a
Some reports have suggested that drinks containing similar expansion of islet cell tissue, extending over large
uncooked cornstarch may increase fasting tolerance in areas of the pancreas, making complete resection more
older children and adults with HI who have unstable difficult. In some cases of HI, histologic changes typical of
control of hypoglycemia, similar to the use of uncooked diffuse HI occur only in localized regions of the pancreas;

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cornstarch in children with glycogen storage disorders. this has been termed LINE-HI, mosaic, or “atypical” hy-
Doses of 1–2 gm/kg may be used, but only in children perinsulinism and may be associated with somatic variants
over 9 months old since cornstarch is poorly digested in of HI genes, such as ABCC8, GCK, and inappropriate ex-
younger infants. In the absence of controlled studies pression of HK1 [80, 85]. Due to the variety of histologic
demonstrating its effectiveness in HI, the Guideline forms of congenital HI, the choice and plan for pancreatic
Committee was unable to provide a consensus recom- resection should be in close collaboration with a pathologist
mendation on use of cornstarch in children with HI. experienced in HI and with access to a high-quality labo-
ratory and suitable protocols for rapid and accurate review
of pancreatic biopsies.
3. Surgical Management In cases of diffuse HI that have been diagnosed by
genetic testing, medical treatment is the first choice;
3.1 We Recommend that Surgery Be Considered for however, if hypoglycemia cannot be adequately con-
Children Suspected to Have a Resectable Focal Lesion trolled, pancreatectomy may be required. For diffuse HI, a
[GRADE 1⊕⊕⊕○] 90–98% pancreatectomy is recommended to strike a
balance between control of hypoglycemia and the delayed
3.2 We Suggest that Infants with Hyperinsulinism due development of diabetes, while preserving bile duct
to Diffuse Pancreatic Disease Should Undergo Surgery if drainage [155, 156].
Hypoglycemia Is Not Adequately Controlled despite Following surgery, immunohistochemical staining of
Maximal Medical Therapy [GRADE 2⊕⊕○○] permanent sections should be performed using neuro-
When genetic tests and radiologic imaging studies endocrine markers (chromogranin and synaptophysin)
suggest the likelihood of a focal lesion, surgical resection to highlight endocrine tissue and for assessment of
is the approach of choice since infants can be cured and margin involvement. In focal lesions and in regions of
avoid either ongoing hypoglycemia or the development of endocrine cell overgrowth in BWSp, loss of maternal
diabetes mellitus. This is especially true if the location of heterozygosity at 11p15 can be demonstrated by loss of
the lesion allows complete resection and if the surgical nuclear p57 staining in lesion cells [157].
team has the necessary expertise, including a protocol for The immediate postsurgical management of children
intraoperative examination of frozen biopsies to guide the with HI may be complicated and, thus, should be in an
operative strategy [152–154]. For example, in some cases, appropriate intensive care setting. Intraoperative and
removal of lesions in the pancreatic head may require a postoperative plasma glucose fluctuations are common and
Roux-en-Y pancreatojejunostomy that preserves pan- do not reflect the ultimate glycemic outcome of surgery.
creatic duct connections from the body and tail of the However, prevention of postoperative hypoglycemia during
pancreas [87]. this period is important to minimize neuroglycopenia.
At surgery for suspected focal HI, biopsies should be Plasma glucose levels should be monitored closely, with a
taken from the pancreatic head, body, and tail to clearly goal of preventing hypo or hyperglycemia [158]. Insulin
establish whether there is diffuse disease versus an therapy by either subcutaneous injection or intravenous

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DOI: 10.1159/000531766
Table 4. Diagnostic fasting test
Perform test only on a unit with trained medical/nursing staff who are experienced
in the performance of fasting studies
1. Have IV access and D10% (2–5 mL/kg) for emergency resuscitation
2. Measure glucose by POC meter every 2–3 h until glucose <70 mg/dL (<3.9 mmol/
L); then every 2 h until <60 mg/dL (<3.3 mmol/L); then hourly until ≤50 mg/dL
(<2.8 mmol/L)
a. When glucose <60 mg/dL (<3.3 mmol/L) send specimen for laboratory
confirmation of plasma glucose
3. Measure beta-hydroxybutyrate every 2–3 h and when glucose <50 mg/dL (<2.8
mmol/L)
a. When plasma glucose ≤50 mg/dL (<2.8 mmol/L) draw blood for the CRITICAL
sample
i. Glucose, insulin, beta-hydroxybutyrate, free fatty acids
ii. Ammonia, cortisol, growth hormone, lactate, acyl carnitine profile, urine
organic acids
iii. Special circumstances: C-peptide, proinsulin, sulphonylurea screen,
toxicology screen, serum amino-acids
4. Perform Glucagon Stimulation Test once CRITICAL samples are obtained

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1. Measure glucose using POC meter and then give glucagon 30 μg/kg or 0.5–1
mg by IM or IV push as long as glucose is < 50 mg/dL (<2.8 mmol/L)
2. Monitor glucose using POC meter every 10 min for 40 min
3. Terminate test if glucose is still below 50 mg/dL (<2.8 mmol/L) after 30 min
4. After 40 min, may feed and resume treatment to maintain plasma glucose >70
mg/dL (3.9 mmol/L)

Table 5. Safety/cure fasting test

1. Have blood drawing IV line in place
2. Check glucose (POC meter) and beta-hydroxybutyrate every 2–3 h until glucose
<70 mg/dL; then every 2 h until <60 mg/dL; then hourly until <50 mg/dL When
glucose <60 mg/dL (by POC meter), send specimen for laboratory confirmation
of plasma glucose
a. Terminate fast when
1. Plasma BOHB >2 mmol/L on two separate samples 1 h apart
2. Plasma glucose <50 mg/dL
3. Duration of fasting >18 h in <1 year old or >36 h in children 1–10 years old
or 72 h in >10 years old

insulin infusion should be started if there is persistent Children who are weaned from IV glucose without hypo-
hyperglycemia postoperatively (>250 mg/dL [>14 mmol/ glycemia should have a fasting study performed to dem-
L]) [158] that does not respond to fluid therapy or if there is onstrate whether they are cured or need further medical
hyperglycemia with hyperketonemia (beta-hydrox- management. Details on how to perform either diagnostic or
ybutyrate levels >2 mmol/L). If there is a persisting insulin safety/cure fasts are summarized in Tables 4 and 5 [159].
requirement at the time of conversion to enteral feeding, Cure of HI can be demonstrated by the development of
insulin administration can be transitioned to the sub- hyperketonemia (beta-hydroxybutyrate >1.8 mmol/L) prior
cutaneous route. Conversely, children who cannot be to development of hypoglycemia (glucose <50 mg/dL [2.8
weaned from intravenous glucose-containing infusions mmol/L]). Further resection of pancreatic tissue may be
without hypoglycemia may require further medical required in medically unmanageable cases [160].
management for persisting hyperinsulinism. The cure rate of surgery for focal HI is high and is
Following pancreatectomy, regardless of underlying di- reported to be >95% in some studies [87]. This can be
agnosis, all children should be evaluated to determine achieved without the risk of subsequent diabetes when
whether they are euglycemic, have persistent hypoglycemia, just the focal lesion is removed. Following 95–98%
or have hyperglycemia requiring insulin treatment. pancreatectomy for diffuse disease, hypoglycemia may

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DOI: 10.1159/000531766
recur in up to 50–60% of patients: in such cases, addi- we suggest providing psychological resources to families
tional medical therapies are usually sufficient to achieve and offering them connections to hyperinsulinism patient
euglycemia, although some may require second surgery. organizations for support [167]. Referral for genetic
Approximately 25% of the patients in the post-operative consultation and counseling may also be indicated [168].
period have permanent diabetes, and this number can rise
to 91% by 14 years of age [86, 87, 161–164].
Children who have undergone greater than 50% pan- 5. Long-Term Management of Patients
createctomy or a pancreatecojejunostomy are at risk for with Hyperinsulinism
exocrine pancreatic insufficiency requiring pancreatic en-
zyme replacement [73]. A fecal elastase assay is commonly 5.1 We Suggest Regular Follow-Up and Monitoring to
used for screening [165]. Other recommended monitoring Assess Glycemic Control, Medication Side Effects, and
includes plasma levels of fat-soluble vitamins (vitamins A, D, the Development of Diabetes or Pancreatic Insufficiency
and E) and coagulation tests for vitamin K deficiency [166]. [Grade 2⊕⊕⊕○]
All children with HI need regular monitoring of their
plasma glucose levels at home to guide treatment ad-
justments. In a patient driven report, more than 65.2% of

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4. Discharge Planning
patients required adjustments to the regimen in the first 3
4.1 We Suggest that Discharge Planning for Children months following discharge and despite careful follow-
with Hyperinsulinism Include an Assessment of Fasting up, intermittent hypoglycemia is common [116]. The side
Tolerance [GRADE 2⊕⊕○○] effects of the HI medications [111, 128, 169] should be
Prior to discharge from the hospital, a fasting study to monitored, and support should be provided from the
determine the control of HI is suggested for all children, multidisciplinary feeding team in the hospital as well as in
regardless of whether they are on medical therapy or have the community. In some children with certain forms of
undergone pancreatic resection. The fasting duration HI (e.g., defects in ABCC8, KCNJ11, HNF-1A, and HNF-
should be predetermined for each patient to ensure that 4A), severity may decrease over time [170–172], allowing
they will be safe in their home environment and to guide the dose adjustments to medications.
child’s sleeping, feeding, and glucose monitoring regimen. For patients who have undergone a pancreatectomy and
For those with ongoing hypoglycemia, we suggest gastro- are no longer on treatment for hypoglycemia, screening for
stomy tube placement prior to discharge home for use in diabetes should include hemoglobin A1c every 6–12
emergency situations or for continuous overnight feeds/ months and monitoring for symptoms of hyperglycemia.
dextrose when fasting tolerance is too short for safe Transition to diabetes may be slow, and some patients may
overnight glucose control. Contingency plans should be have both fasting hypoglycemia and postprandial hyper-
considered for accidental disconnection of overnight con- glycemia. The need for diabetes medications should be
tinuous intragastric infusions; these may include the use of a evaluated on an individual basis, taking into account the
continuous glucose monitoring system and nocturnal en- current HbA1c, ability to fast without hypoglycemia, and
uresis alarm pad (to identify fluid leaks). Individuals with presence or absence of symptoms of diabetes.
ongoing hypoglycemia should also have access to glucagon In patients with postsurgical diabetes mellitus, insulin
therapy for emergency rescue. treatment by conventional or pump therapy similar to
An individualized approach should be taken for de- children with type 1 diabetes mellitus is necessary to
cision-making regarding child and family readiness for achieve optimal glycemic control [173]. Pancreatic en-
safe discharge home. Upon discharge, any required zyme replacement therapy should be initiated when there
medications, supplies for glucose monitoring, discharge is evidence of pancreatic insufficiency [166].
summary letter/emergency management plans for hy-
poglycemia/hyperglycemia, and follow-up plans should 5.2 We Recommend that, due to the Increased Risk of
be provided to the family both in their language and the Neurocognitive Deficits and Feeding Difficulties, All
primary language of the country in which they reside. Children with Hyperinsulinism Should Undergo a
Other medical and psychological co-morbidities should Referral for Developmental Surveillance, Feeding
also be addressed before discharge. In a recent study, Assessment, and Early Intervention [GRADE 1⊕⊕⊕○]
caregivers have reported that the ongoing worry asso- Neurodevelopment delays and neurological disorders,
ciated with managing the complexity of their child’s HI including epilepsy and microcephaly, due to hypoglycemic
can impact their physical and mental health. Therefore, brain injury occur frequently in patients with HI [163, 164,

Hyperinsulinism Guidelines Horm Res Paediatr 2024;97:279–298 291

DOI: 10.1159/000531766
172]. Infantile spasms [174]; an increase in motor and Conclusions
speech delay during early childhood [175]; or deficits in
attention, memory, visual, and sensorimotor functions Scientific and clinical advances over the last three
have also been reported. Children with transient HI are decades have improved our understanding of the path-
also at risk of developing neurodevelopmental deficits with ophysiology of HI in children and have led to treatment
reported incidence rates ranging between 26 and 44% [170, approaches that take into account the many differences in
176, 177, 178]. Abnormal neurodevelopment and seizures their genotype and phenotype. Despite these advances,
are particularly high in HI associated with GLUD1 treatment options are still limited for most children with
pathogenic variants [25]. HI. Affected children continue to experience high rates of
Children with HI should have regular neuro- neurological sequelae due to hypoglycemia-induced brain
developmental follow-up and monitoring that should damage. To improve neurological outcomes, prompt
include formal neurodevelopmental testing during early recognition of hypoglycemia and its etiology leading to
childhood for appropriate educational and rehabilitative rapid and effective treatment are essential.
placement. The care of children with HI may need to Currently, pancreatectomy may be required for the
involve neurodevelopmental pediatricians, physiothera- surgical treatment of diffuse HI. New medical therapies
pists, occupational therapists, and speech and language are urgently needed to prevent the need for pancrea-

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therapists [26]. tectomy and the resultant hypoglycemia and diabetes in
Feeding problems that may be associated with HI are the postoperative period. In addition, alternative medical
complex, multifactorial, and often iatrogenic [151]. therapy choices are needed to replace those current
Feeding issues have been reported in 68.6% of all patients medications that may cause significant side effects.
[116]. Vomiting, sucking and swallowing difficulties, and Centers caring for infants and children with HI should
food aversion can occur either in isolation or combina- consider developing multidisciplinary teams to provide
tion. The use of medications that cause nausea and an- all aspects of care, including social and psychological
orexia and have unpleasant taste, and the use of intra- support not only for the children but also the families. An
venous glucose support and tube feedings with high individualized approach to each child would be preferred
carbohydrate content that impair appetite, can interrupt to ensure optimal patient experience and outcomes. It is
the development of normal feeding milestones and put also important to offer long-term peer support to patients
infants with HI at risk of feeding problems. Although the and families. There are a host of national and interna-
goal of preventing hypoglycemia is the primary goal in tional family support organizations that can be found
the newborn period, we suggest encouraging oral feeding online (https://congenitalhi.org/links/).
over tube feeding especially when intravenous glucose These guidelines provide a systematic approach to the
support is being used to control hypoglycemia [28]. diagnosis and management of children with persistent
Prompt management of medical problems, such as hypoglycemia due to hyperinsulinism while at the same
vomiting and gastroesophageal reflux, may help prevent time recognizing that access to diagnostic tools, medi-
long-term feeding problems. In addition, in children with cations, and medical and surgical expertise is limited in
ongoing hypoglycemia, insertion of a gastrostomy tube many areas of the world and that good-quality evidence is
should be considered for prompt correction of hypo- often lacking. This further illustrates the urgent need for
glycemia, and parents should be advised of the possibility collaborative research efforts to generate this evidence
of tube dependency and how to avoid this complication. and revise our recommendations in the future.

5.3 We Suggest that Programs Be Established for the

Transition to Adult Care for Children and Adolescents Acknowledgments
with Hyperinsulinism and Ongoing Medical Needs, and
The authors would like to acknowledge the great contributions to
for the Development of Adult Programs for Adults with science in the field of hyperinsulinism by Prof. Mark Dunne. His
Hyperinsulinism [Grade 2⊕⊕○○] premature death during the preparation of this manuscript left us all
Adults with HI who continue to have complex needs saddened, and we dedicate this manuscript to his memory in honor
require transition of care to appropriately trained adult of his leadership in the field of Hyperinsulinism. The authors would
specialists to address all ongoing issues, including HI like to thank the patient and caregiver representatives of the
Congenital Hyperinsulinism Collaborative Research Network for
treatment, neurodevelopmental delays and memory is- providing the patient perspective. The authors thank the members
sues, hypoglycemia unawareness, risk of developing di- of the societies of the ICPE for reviewing this manuscript and for
abetes, and implications of genetic diagnosis. their thoughtful feedback. This paper has been endorsed by the

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DOI: 10.1159/000531766
societies of the International Consortium of Pediatric Endocri- Hyperinsulinism International. A.V. received an investigator-initiated
nology: Australasian Paediatric Endocrine Group (APEG), Asia grant from Novo Nordisk and has consulted for vTv Therapeutics,
Pacific Paediatric Endocrine Society (APPES), Pediatric Endocrine Zeeland Pharmaceuticals, Crinetics, and Rezolute. P.S.T. has received
Society (PES), European Society for Paediatric Endocrinology research payments from Ascendis, Novo Nordisk, OPKO, Rezolute,
(ESPE), Latin American Society for Pediatric Endocrinology (SLEP), and Zealand and was a member of the Board of the PES at the time of
Japanese Society for Pediatric Endocrinology (JSPE), International writing. The following report to have no COI: I.B., T.B., J.F.F., S.E.F.,
Society for Pediatric and Adolescent Diabetes (ISPAD), African D.G., K.M., P.S., C.A.S., and T.Y.
Society for Pediatric and Adolescent Endocrinology (ASPAE), Arab
Society for Pediatric Endocrinology and Diabetes (ASPED), Indian
Society for Pediatric and Adolescent Endocrinology (ISPAE), Global
Pediatric Endocrinology and Diabetes (GPED), and the Chinese Funding Sources
Society for Pediatric Endocrinology and Metabolism.
D.D.L. is funded by grants from the NIH-NIDDK: R01-
DK056268, R01-DK098517. T.B. is supported by NIH/NIDDK
DK056268-22. S.E.F. is a Wellcome Trust Senior Research Fellow
Conflict of Interest Statement (Grant No. 223187/Z/21/Z). T.M. is funded by Ilse-Bagel Foun-
dation, Düsseldorf, Germany. K.M. received funding from Metab
D.D.L. has received research funding from Zealand Pharma, ERN. A.V. is supported by NIH/NIDDk DK78646, DK116231, and
Tiburio Therapeutics, Twist Bioscience, and Crinetics Pharmaceu- DK126206. P.S.T. is partially funded by the Cook Children’s

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ticals and consulting fees from Zealand Pharma, Crinetics Phar- Health Care System Endowed Chair for Hyperinsulinism.
maceuticals, Hanmi Pharmaceutical, and Eiger Biopharmaceuticals
and is named inventor inventor in patents # USA Patent Number
9,616,108, 2017, USA Patent Number 9,821,031, 2017, Europe Patent
Number EP 2120994, 2018, Europe Patent Number EP2818181, Author Contributions
2019. J.B.A. has received consulting fees from Alexion, Immedica,
Zealand Pharma, Sobi, Pierre Fabre, and BioMari and speaker D.D.L. and P.S.T. jointly formulated the plan to write the
honorarium from Sanofi, Genzyme, Recordati, Pierre Fabre, and manuscript, selected the co-authors, coordinated the societies,
Vitaflo. I.B. has received funding support from Merck, Crinetics, wrote sections of the first draft, edited the subsequent drafts,
Zealand, and Diurnal. He is also the Chair of the ESPE Commu- reviewed the references for accuracy, and approved the final draft.
nications Committee and BSPED-NIHR Clinical Studies Group. He J.B.A., I.B., I.Ber., T.B., L.S.C., J.F.F., S.E.F., D.G., T.M., K.M.,
is a co-opted member of NICE guidelines. L.S.C. is an advisory Board T.L.S.P., P.S., C.A.S., A.V., and T.Y. each wrote first drafts of their
member and consultant to Zealand Pharma. T.M. received research sections, edited subsequent drafts, reviewed the manuscript, and
payments from Zealand Pharma. T.L.S.P. is an employee of Congenital approved the manuscript.

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