Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

in European Journal of Endocrinology
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  • 1 Departments of Neonatology, Paediatric Endocrinology, Developmental Endocrinology Research Group, Departments of Paediatric Endocrinology, Departments of Paediatric Endocrinology, Departments of Paediatric Endocrinology, Departments of Paediatric Endocrinology, Institute of Biomedical and Clinical Science, Department of Medical Biology and Genetics, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK

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Objective

Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype–phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Design and methods

A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.

Results

Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype–phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).

Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.

Conclusions

This is the largest study to report genotype–phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

Abstract

Objective

Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype–phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Design and methods

A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.

Results

Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype–phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).

Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.

Conclusions

This is the largest study to report genotype–phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

Introduction

Hyperinsulinaemic hypoglycaemia (HH) is the commonest cause of hypoglycaemia in the neonatal, infancy and childhood periods (1, 2, 3). It occurs due to the unregulated secretion of insulin from pancreatic β-cells leading to severe and persistent hypoglycaemia. HH can be congenital (congenital hyperinsulinism, CHI) or transient due to risk factors such as perinatal asphyxia, intrauterine growth restriction (IUGR) and maternal diabetes mellitus (gestational or non-gestational) (1, 2, 3).

CHI refers to a group of conditions that are extremely heterogeneous in terms of clinical presentation, histological subgroups and underlying molecular biology. The molecular basis of CHI involves genetic defects in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A and UCP2) that are involved in regulating insulin secretion from β-cells (1, 3). Mutations in the ABCC8 and KCNJ11 genes that encode the two subunits (SUR1 and Kir6.2) of ATP-sensitive potassium (KATP) channel are the commonest cause of CHI (4, 5).

At a histological level, two major subtypes of CHI (diffuse and focal) have been described. The differentiation of these two histological subtypes is important from the management point of view (6). The diffuse form may require a near-total pancreatectomy (with the risk of diabetes mellitus and pancreatic exocrine insufficiency), whereas the focal form will only require a limited focal lesionectomy. The frequency of focal disease has been reported to be 30–40% of all CHI patients in different series (7, 8). Genetic analysis and specialised positron emission tomography scan using the isotope Fluorine 18 l-3,4-dihydroxyphenyalanine (18F-DOPA-PET) can be helpful in differentiating focal and diffuse diseases (9, 10). PET scan can also localise the focal lesions within the pancreas. Regarding their underlying genetic basis, the diffuse form is inherited in an autosomal recessive (or dominant) manner, whereas the focal form is sporadic in inheritance.

Besides differentiation of focal and diffuse diseases, documentation of protein sensitivity constitutes another important issue in the management of CHI. Mutations in GLUD1 and HADH are associated with protein-sensitive CHI (11, 12). Protein-restricted diet may increase the success of medical therapy (13).

Although the incidence of CHI in the general population is one in 35 000–40 000, it rises to one in 2500 in the communities with the high rates of consanguinity (14). Turkey also has a high rate of consanguineous marriage (15). Thus, interpretation of clinical characteristics, genetic basis and phenotype–genotype relation of Turkish patients with CHI could bring a new perspective in understanding genetic basis, genotype–phenotype correlation and management of CHI. However, to our knowledge, to date, except for two small studies reporting the clinical and genetic characteristics of five and 13 Turkish patients with CHI, there is no large-scale study reporting clinical and genetic characteristics of Turkish children with CHI (16, 17). In this study, we describe clinical characteristics, genetic results and treatment outcome of a large cohort of CHI patients from Turkey.

Subjects and methods

Patients

Patients presenting with CHI to four large paediatric endocrine centres in Turkey were included in this study. CHI was defined as a detectable insulin level (≥2 mU/l) during an episode of spontaneous or provoked hypoglycaemia (blood glucose <3.0 mmol/l). Patients with secondary HH due to IUGR, evidence of perinatal asphyxia and maternal diabetes mellitus were excluded. Detailed clinical and biochemical information was collected from the responsible clinician of these patients.

Written informed consent was obtained from parents of all participants for genetic mutation analysis. Diazoxide (5–15 mg/kg per day) was commenced as first line for the management of CHI. In diazoxide-unresponsive patients, octreotide (5–40 μg/kg per day) was tried. Patients unresponsive to medical therapy were managed with open near-total pancreatectomy. As 18F-DOPA-PET–CT is not currently available in Turkey, a near-total pancreatectomy was performed for all patients who required surgical therapy irrespective of the results of molecular genetic analysis.

Mutation analysis

Genomic DNA was extracted from peripheral leukocytes using standard procedures and the coding regions and intron/exon boundaries of the ABCC8 and KCNJ11 genes were amplified by PCR (primers available on request) in all patients. Amplicons were subsequently sequenced using the Big Dye Terminator Cycler Sequencing Kit v3.1 (Applied Biosystems) according to the manufacturer's instruction and reactions were analysed on an ABI 3730 Capillary sequencer (Applied Biosystems). Sequences were compared with the reference sequences (NM_000525.3 and NM_000352.3) using the Mutation Surveyor v3.24 software (SoftGenetics, State College, PA, USA). If no mutations in ABCC8 and KCNJ11 were identified, the coding regions of HADH (only in diazoxide-responsive patients and those with abnormal acylcarnitine and/or urine organic acid profile) and HNF4A were amplified and sequenced as described previously (18, 19).

Statistical analyses

IBM SPSS statistics 21.0 for Windows software package program was used for statistical analyses. The Kolmogorov–Smirnov test was used to test normality for distribution of data. The independent samples t-test was used to compare mean of normally distributed data and the Mann–Whitney U test for non-normally distributed data. The χ2-test was used to compare the ratios. A P value of <0.05 was considered statistically significant.

Results

A total of 35 patients presented with CHI between April 2002 and October 2013. The clinical and biochemical characteristics at presentation are summarised in Table 1. The median follow-up period for this cohort of patients was 2 years and 3 months (range: 1 month–10.5 years).

Table 1

Clinical characteristics of CHI patients.

Clinical characteristicsResults
Number of patients, n35
Males, n (%)20 (57.1)
Gestational age (weeks)a38 (29–40)
Birth weight (g)b3407±789
Large for gestational age (>90th percentile), n (%)14 (40)
Age at presentation (weeks)a1 (1–48)
Presentation within first week of life, n (%)19 (58)
Consanguinity, n (%)16 (45.7)
Family history of CHI, n (%)7 (20)
Hypoglycaemia screenb
 Blood glucose (mmol/l)1.7±0.5
 Serum insulin (mU/l)32.7±35.9
Hyperammonaemiac0

Median (range).

Mean±s.d.

Serum ammonia more than twice the normal upper limit.

Mutation analysis, genotype–phenotype relation and treatment outcome

Mutation analysis

Molecular genetic analysis identified pathogenic mutations in 51.4% of Turkish CHI patients (18/35; ABCC8 (14 patients), KCNJ11 (three patients) and HADH (one patient)) (Table 2). The KATP channel mutations included homozygous (13), compound heterozygous (2) and paternally inherited heterozygous (1) mutations. Maternal DNA was unavailable for testing to confirm the inheritance pattern in one patient with heterozygous ABCC8 mutation.

Table 2

Genetic analysis and treatment outcome of 18 patients with mutation-positive CHI.

GeneCurrent age (year)Exon/intronDNA descriptionProtein descriptionConsequenceTransmissionTreatmentFollow-upDevelopmental delayComments
Diazoxide responsiveOctreotide responsivePancreatectomy (histology)
ABCC8
 13.9Exon 28c.3554C>Ap.Ala1185GluMissenseHomozygous+Octreotide+++Novel mutation
 20.7Exon 28c.3554C>Ap.Ala1185GluMissenseHomozygous+OctreotideNovel mutation
 39.1Exon 28c.3554C>Ap.Ala1185GluMissenseHomozygousIrregular++++Novel mutation
 40.7Exon 28c.3554C>Ap.Ala1185GluMissenseHomozygous+Octreotide+Novel mutation
 50.2Exon 28c.3554C>Ap.Ala1185GluMissenseHomozygous+OctreotideNovel mutation
 60.7Exon 28c.3512delTp.Leu1171fsFrameshiftHomozygous+ (diffuse)Remission
 70.7Exon 28c.3512delTp.Leu1171fsFrameshiftHomozygous++ (diffuse)Octreotide
 8DiedExon 28c.3512delp.Leu1171fsFrameshiftHeterozygous paternal+ (diffuse)Died
 95.8Exon 28c.3512delTp.Leu1171fsFrameshiftHomozygous+Octreotide+++Ectodermal dysplasia
 109.6Exon 28c.3512delTp.Leu1171fsFrameshiftHomozygous+Octreotide+++
 110.7Exon 4c.502C>T c.563A>Gp.Arg168Cys/p.Asn188SerMissenseCompound heterozygous++ (diffuse)Octreotide
 12DiedExon 10c.1598T>Cp.Leu533ProMissenseHomozygous+DiedNovel mutation
 1310.6Exon 5/exon 21c.694T>G/c.2525G>Ap.Trp232Gly/p.Arg842GlnMissense/MissenseCompound heterozygous+Octreotide++
 145.5Exon 12c.1771T>Cp.Phe591LeuMissenseHeterozygous+Diazoxide
KCNJ11
 152.4Exon 1c.101G>A/c.376G>Ap.Arg34His/p.Glu126LysMissense/MissenseCompound heterozygous+Octreotide
 163.3Exon 1c.272G>Ap.Trp91XNonsenseHomozygous++ (diffuse)Octreotide++
 173.2Exon 1c.376G>Ap.Glu126LysMissenseHomozygous++ (diffuse)Octreotide++
HADH
 184.4Exon 6c.706C>Tp.Arg236XNonsenseHomozygous+Diazoxide+

While a mutation was identified in 14 out of 16 patients (87.5%) from consanguineous families, it was identified only in four out of 19 patients (21%) from non-consanguineous families (P<0.0001).

In 40% (14/35) of the CHI patients, eight different ABCC8 mutations were identified. One of the commonest mutations in our cohort was p.L1171fs (c.3512del), a frameshift mutation on exon 28 of ABCC8 gene (five patients). Four unrelated patients from consanguineous families were homozygous for this mutation and one was heterozygous (inherited from unaffected father). Another common mutation identified was c.3554C>A (p.Ala1185Glu). This was a novel mutation identified in the homozygous state in four first cousins and a second unrelated proband.

The remaining six ABCC8 mutations, p.R168C, p.N188S, p.L533P, p.W232G, p.R842Q and p.F591L were each identified in a single patient. Among these, p.L533P and p.W232G were novel mutations. These novel variants are not listed in various sequence variant databases (dbSNP, Exome Variant Server and 1000 Genomes) and the nucleotide at this position is conserved across all species. Additionally, in silico analysis by SIFT, PolyPhen2, AlignGVGD and Grantham distance predicts these novel variants to be likely pathogenic.

In 8.6% (3/35) of the CHI patients, three different KCNJ11 mutations were identified. These included two missense (p.E126K, and p.R34H) and one nonsense (p.W91X) mutation. Among these, p.E126K was a novel mutation. The p.E126K mutation was identified in two probands in our cohort. Conservation across species, in silico analysis and comparison with various sequence databases predict this variant to be likely pathogenic. The remaining two mutations in KCNJ11, p.W91X and p.R34H, were identified in trans in a single patient and have been reported previously (20).

A previously described homozygous nonsense mutation in exon 6 of HADH (p.R236X) was identified in one patient. A protein-loading test showed protein-sensitive HH in this patient.

Sequencing of ABCC8, KCNJ11, HNF4A and HADH did not identify a causative mutation in the remaining 15 patients.

Genotype–phenotype correlation

Comparison between KATP mutation-positive and KATP mutation-negative groups highlighted a statistically significant increased birth weight and younger age of presentation in KATP mutation-positive group as compared with KATP mutation-negative patients (Table 3).

Table 3

Clinical characteristics of CHI patients with and without mutation at presentation. Data are presented as mean±s.d.

CharacteristicsMutation positiveMutation negativeP value
Birth weight (g)3725±6643070±7880.012
Gestational age (weeks)38.6±1.637.6±3.10.532
Age of presentation (weeks)3.1±6.810.3±13.80.032
Serum insulin (mU/l)36.1±34.429.2±38.10.355
Blood glucose level (mmol/l)1.7±0.51.8±0.60.456

P<0.05 was considered statistically significant.

Rate of detection of a pathogenic mutation in diazoxide-unresponsive patients (16/17; 94.1%) was higher than that of diazoxide-responsive group (2/18, 11.1% (P<0.0001) (Fig. 1).

Figure 1
Figure 1

Mutation analysis results and treatment choices for patients with diazoxide-responsive CHI vs diazoxide-unresponsive CHI.

Citation: European Journal of Endocrinology 170, 6; 10.1530/EJE-14-0045

Treatment outcome

Of the total number of patients, 18 (51.4%; median age 22 months (range 3–128 months)) were responsive to diazoxide treatment (Fig. 1). Children were defined as being diazoxide responsive if they demonstrated age-appropriate fasting tolerance or evidence of appropriate hyperketonaemia before developing hypoglycaemia on diazoxide at doses <15 mg/kg per day. Administration of diazoxide could be successfully stopped in four of the diazoxide-responsive CHI patients at a median age of 3.5 months (range, 3–15 months). Of these, a pathogenic mutation was identified in only two patients (monoallelic ABCC8 – 1 and biallelic HADH – 1).

Of the diazoxide-unresponsive group (17), six patients underwent pancreatectomy (five subtotal and one near-total) and ten patients were managed with octreotide treatment. One patient was lost to follow-up and represented at a later age with severe learning disability due to uncontrolled severe hypoglycaemia. A pathogenic mutation was identified in 16 out of 17 patients (94.1%; biallelic KATP – 15 and paternally inherited KATP – 1).

The median age at pancreatectomy was 1.5 months (range 1–2 months). Histological examination identified typical diffuse disease (abnormal large β-cell nuclei in pancreatic islets and low nuclear crowding in the whole pancreas) in all of these patients. After pancreatectomy, one patient unfortunately died because of sepsis and four patients required octreotide treatment to maintain euglycaemia. In only one patient who underwent near-total pancreatectomy, normoglycaemia was achieved without the need for additional medical therapy. There was no correlation between the type of mutation and the severity of CHI.

Long-term neurological sequelae such as developmental delay, cerebral palsy and epilepsy were higher in diazoxide-unresponsive patients (9/17) as compared with diazoxide-responsive (3/18) patients (52.9 vs 16.6%; P=0.035). This is likely to be due to difficulties in controlling hypoglycaemia in the diazoxide-unresponsive group.

Discussion

In this study, 18 out of 35 patients (51.4%) had a genetically confirmed diagnosis of CHI (biallelic – 15 and monoallelic – 3). In two recent large studies of patients with CHI, genetic mutations were identified in 45.3 and 78.8% (21, 22). Mutations in the KATP channel genes were the commonest identifiable cause in our cohort (biallelic ABCC8 – 12, monoallelic ABCC8 – 2 and biallelic KCNJ11 – 3).

All patients with biallelic KATP channel mutations in our cohort (n=15; 43%) were unresponsive to diazoxide treatment. Despite high doses of diazoxide for an adequate period of time, these patients could not be weaned off high-concentration dextrose fluids and experienced random episodes of hypoglycaemia. Similar findings have been reported by other investigators (Table 4). In the studies by Kapoor et al. (21) and Snider et al. (22), all patients with biallelic KATP mutations (63/300 (21%) and 84/417 (20%)) were unresponsive to diazoxide. The prevalence of homozygous KATP mutations in these studies (15 and 3.6%) was less when compared with our study (42.8%), possibly due to high consanguinity in our cohort. The studies by Kapoor et al. (21) and Snider et al. (22) have not mentioned the percentage of patients born of consanguineous marriage in their cohorts.

Table 4

Summary of studies showing mutation detection rate, diazoxide responsiveness and histological subtype of CHI patients.

ReferenceYearnMutation detection rate n (%)KATPchannel mutations n (%)Other mutationsbHistologyaCountry
DZ responsiveDZ unresponsiveOverallMonoallelicBiallelicFocalDiffuse
This study2014352/18 (11)16/17 (94)18/35 (51)1 (6)15 (94)10 (0)6 (100)Turkey
(17)2002130/10 (0)3/3 (100)3/13 (23)0 (0)3 (100)0 (0)3 (100)Turkey
(20)2011174/5 (80)7/8 (87)14/17c (82)10/14 (71)4/14 (29)0 (0)6 (100)Korea
(23)201136NSNS24/36 (67)17/19 (84)2/19 (15)51 (10)9 (90%)Japan
(25)200926NSNS16/26 (58)6 (40)9 (60)13 (33)6 (67)Norway
(26)20133612/25 (48)9/11 (82)20/36 (55)12d (92)1 (8)83 (100)0 (0)Italy
(21)201330041/183 (22)92/105 (87.6)136/300e (45)46 (42)63 (58)27NSNSUK
(22)201341756/118 (47)272/292 (91)328/417 (79)200 (69)88 (31)40149 (53)122f (43)USA

n, number; DZ, diazoxide; NS, not specified.

Mutations detected in other genes (HADH, HNF4A, HNF1A, GCK, UCP2 and GLUD1).

Histology proven after surgery.

Diazoxide not tried in three patients.

One patient had monoallelic KATP as well as GCK mutation.

Diazoxide responsiveness not determined in 12 patients.

Histology normal in four patients and atypical diffuse disease in 11 patients.

Five patients with biallelic KATP mutations were treated with near-total pancreatectomy and the remaining patients were treated with s.c. octreotide injections and carbohydrate-rich feeds. All the patients with biallelic KATP channel mutations who were pancreatectomised had diffuse disease on histological examination of the pancreatic tissue.

Of the two patients with monoallelic ABCC8 mutations, the mutation was paternally inherited in one patient (p.Leu1171fs). This patient was medically unresponsive and was treated with near-total pancreatectomy. The histology of the resected pancreatic tissue showed diffuse disease, although it is likely that the focal lesion could have been missed. As this particular ABCC8 mutation was present in monoallelic state in clinically unaffected parents (although not biochemically evaluated) of four different patients in our cohort and it is a null mutation, it seems likely that this was a recessive ABCC8 mutation which has been unmasked by paternal uniparental disomy within the pancreas. Although there is no family history of hyperinsulinism or early-onset diabetes mellitus on the maternal side, the milder clinical phenotype (diazoxide responsiveness) of the second patient with monoallelic non-paternal ABCC8 mutation (maternal DNA unavailable for testing) was suggestive of dominant ABCC8 mutation.

The other interesting observation in our study was the low prevalence of monoallelic KATP mutation (2/35; 5.7%). This is in sharp contrast to observations from genetic analysis of patients from Korea and Japan, where the single mutation rate was between 50 and 60% (Table 4) (20, 23). In the study by Kapoor et al., monoallelic KATP mutation was present in 14.6% of patients, whereas 48% of patients had monoallelic KATP mutation in the study by Snider et al. (21, 22).

In our cohort, about half of the patients were diazoxide responsive (n=18). Only two patients from this group had a pathogenic mutation (monoallelic ABCC8 – 1 and biallelic HADH – 1). No mutation could be identified in the remaining 16 out of 18 (88.9%) diazoxide-responsive patients. The mutation detection rate in diazoxide-responsive category in our cohort is less when compared with other studies (21, 22). This may be due to the fact that sequencing of GLUD1, GCK and HADH genes was not performed in these patients unless indicated by the clinical phenotype. Novel genetic mechanisms might be responsible for CHI in these patients.

In our study, the majority of diazoxide-unresponsive patients (16/17; 94.1%) had a KATP channel mutation. This has been established in large cohort studies by Kapoor et al. (21) and Snider et al. (22) (87.6 and 91% respectively). Our results are in line with these larger studies.

This study identified a number of novel ABCC8 and KCNJ11 mutations (Table 2). One particular novel ABCC8 missense mutation (p.A1185E, c.3554C>A), co-segregating with disease in the family, was found in four affected cousins from one family and another unrelated patient. In addition to this mutation, another ABCC8 mutation (p.L1171fs, c.3512delT) was also detected in five patients from four different families, possibly suggesting a founder effect.

In this study, integration of the clinical findings and genetic results suggests the likelihood of KATP mutations in patients with CHI in the presence of increased birth weight and earlier age of presentation. It was striking that those patients with KATP channel mutations presented earlier and had a higher birth weight when compared with patients without a KATP channel mutation. Previous studies have shown that there may be an overlap between birth weight and age of presentation between patients with HNF4A and KATP channel mutations (21). However, our study clearly showed the difference in age of presentation and birth weight between KATP channel-positive and -negative groups. These observations can be very helpful in the clinical management of patients with CHI, especially if the clinicians do not have access to urgent molecular genetic analysis.

Lastly, in our cohort, 12 out of 35 (34%) patients had long-term neurological sequelae such as developmental delay, cerebral palsy and epilepsy. This is similar to what has been reported in the recent literature from Turkey (24). The likelihood of adverse neurological sequelae was significantly higher in the diazoxide-unresponsive group.

Conclusions

In conclusion, in this largest Turkish cohort with CHI, KATP channel mutations were detected in 48.6% (17/35) of the patients studied. The likelihood of long-term neurological sequelae was higher in the diazoxide-unresponsive group, highlighting the need for management of these complex patients in highly specialised centres. Additional research to identify novel genetic mechanisms for patients with diazoxide-responsive CHI is required.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

H Demirbilek was funded by the European Society for Paediatric Endocrinology (ESPE) and The Scientific and Technological Research Council of Turkey (TUBITAK) during his 1-year clinical fellowship at University College London (UCL) Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, Department of Paediatric Endocrinology.

Author contribution statement

H Demirbilek contributed to the conceptualisation of the manuscript, collection of data, data analysis and writing of the manuscript; V B Arya, collection of data, data analysis and writing of the manuscript; M N Ozbek, A Akinci, M Dogan, F Demirel, S Kaba, F Guzel, R T Baran, S Unal and S Tekkes, collection of data and review of the manuscript; J Houghton, S E Flanagan and S Ellard, genetic analysis and review of the manuscript and K Hussain, conceptualisation of the manuscript, review of the manuscript and guarantor of the manuscript.

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  • 13

    Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Reviews in Endocrine and Metabolic Disorders 2010 11 171178. (doi:10.1007/s11154-010-9146-0).

    • Search Google Scholar
    • Export Citation
  • 14

    Mathew PM, Young JM, Abu-Osba YK, Mulhern BD, Hammoudi S, Hamdan JA, Sa'di AR. Persistent neonatal hyperinsulinism. Clinical Pediatrics 1988 27 148151. (doi:10.1177/000992288802700307).

    • Search Google Scholar
    • Export Citation
  • 15

    Tuncbilek E, Ulusoy M. Consanguinity in Turkey in 1988. Turkish Journal of Population Studies 1989 11 3546.

  • 16

    Ocal G, Flanagan SE, Hacihamdioglu B, Berberoglu M, Siklar Z, Ellard S, Savas Erdeve S, Okulu E, Akin IM, Atasay B et al.. Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic β cell. Journal of Pediatric Endocrinology and Metabolism 2011 24 10191023. (doi:10.1515/JPEM.2011.347).

    • Search Google Scholar
    • Export Citation
  • 17

    Darendeliler F, Fournet JC, Bas F, Junien C, Gross MS, Bundak R, Saka N, Gunoz H. ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. Journal of Pediatric Endocrinology and Metabolism 2002 15 9931000. (doi:10.1515/JPEM.2002.15.7.993).

    • Search Google Scholar
    • Export Citation
  • 18

    Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O et al.. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. European Journal Endocrinology 2010 162 987992. (doi:10.1530/EJE-09-0861).

    • Search Google Scholar
    • Export Citation
  • 19

    Flanagan SE, Patch AM, Locke JM, Akcay T, Simsek E, Alaei M, Yekta Z, Desai M, Kapoor RR, Hussain K et al.. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. Journal of Clinical Endocrinology and Metabolism 2011 96 E498E502. (doi:10.1210/jc.2010-1906).

    • Search Google Scholar
    • Export Citation
  • 20

    Park SE, Flanagan SE, Hussain K, Ellard S, Shin CH, Yang SW. Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism. European Journal of Endocrinology 2011 164 919926. (doi:10.1530/EJE-11-0160).

    • Search Google Scholar
    • Export Citation
  • 21

    Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. European Journal of Endocrinology 2013 168 557564. (doi:10.1530/EJE-12-0673).

    • Search Google Scholar
    • Export Citation
  • 22

    Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. Journal of Clinical Endocrinology and Metabolism 2013 98 E355E363. (doi:10.1210/jc.2012-2169).

    • Search Google Scholar
    • Export Citation
  • 23

    Yorifuji T, Kawakita R, Nagai S, Sugimine A, Doi H, Nomura A, Masue M, Nishibori H, Yoshizawa A, Okamoto S et al.. Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. Journal of Clinical Endocrinology and Metabolism 2011 96 E141E145. (doi:10.1210/jc.2010-1281).

    • Search Google Scholar
    • Export Citation
  • 24

    Agladioglu SY, Savas Erdeve S, Cetinkaya S, Bas VN, Peltek Kendirci HN, Onder A, Aycan Z. Hyperinsulinemic hypoglycemia: experience in a series of 17 cases. Journal of Clinical Research in Pediatric Endocrinology 2013 5 150155. (doi:10.4274/Jcrpe.991).

    • Search Google Scholar
    • Export Citation
  • 25

    Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Søvik O, Njølstad PR, Molven A. The spectrum of ABCC8 mutations in Norwegian patients with congenitalhyperinsulinismof infancy. Clinical Genetics 2009 75 440448. (doi:10.1111/j.1399-0004.2009.01152.x).

    • Search Google Scholar
    • Export Citation
  • 26

    Faletra F, Athanasakis E, Morgan A, Biarnés X, Fornasier F, Parini R, Furlan F, Boiani A, Maiorana A, Dionisi-Vici C et al.. Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort. Gene 2013 521 160165. (doi:10.1016/j.gene.2013.03.021).

    • Search Google Scholar
    • Export Citation

 

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    Mutation analysis results and treatment choices for patients with diazoxide-responsive CHI vs diazoxide-unresponsive CHI.

  • 1

    Mohamed Z, Arya VB, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. Journal of Clinical Research in Pediatric Endocrinology 2012 4 169181. (doi:10.4274/Jcrpe.821).

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  • 2

    De Leon DD, Stanley CA. Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nature Clinical Practice. Endocrinology & Metabolism 2007 3 5768. (doi:10.1038/ncpendmet0368).

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  • 3

    Senniappan S, Arya VB, Hussain K. The molecular mechanisms, diagnosis and management of congenital hyperinsulinism. Indian Journal of Endocrinology and Metabolism 2013 17 1930. (doi:10.4103/2230-8210.107822).

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  • 4

    Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Human Molecular Genetics 1996 5 18091812. (doi:10.1093/hmg/5.11.1809).

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  • 5

    Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995 268 426429. (doi:10.1126/science.7716548).

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  • 6

    Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fekete C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ. Practical management of hyperinsulinism in infancy. Archives of Disease in Childhood. Fetal and Neonatal Edition 2000 82 F98F107. (doi:10.1136/fn.82.2.F98).

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  • 7

    Sempoux C, Guiot Y, Lefevre A, Nihoul-Fekete C, Jaubert F, Saudubray JM, Rahier J. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. Journal of Clinical Endocrinology and Metabolism 1998 83 14551461. (doi:10.1210/jcem.83.5.4768).

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  • 8

    Goossens A, Gepts W, Saudubray JM, Bonnefont JP, Nihoul F, Heitz PU, Kloppel G. Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. American Journal of Surgical Pathology 1989 13 766775. (doi:10.1097/00000478-198909000-00006).

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  • 9

    Hardy OT, Hernandez-Pampaloni M, Saffer JR, Scheuermann JS, Ernst LM, Freifelder R, Zhuang H, MacMullen C, Becker S, Adzick NS et al.. Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. Journal of Clinical Endocrinology and Metabolism 2007 92 47064711. (doi:10.1210/jc.2007-1637).

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    • Export Citation
  • 10

    Banerjee I, Skae M, Flanagan SE, Rigby L, Patel L, Didi M, Blair J, Ehtisham S, Ellard S, Cosgrove KE et al.. The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. European Journal of Endocrinology 2011 164 733740. (doi:10.1530/EJE-10-1136).

    • Search Google Scholar
    • Export Citation
  • 11

    Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K. 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. Journal of Clinical Endocrinology and Metabolism 2009 94 22212225. (doi:10.1210/jc.2009-0423).

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    • Export Citation
  • 12

    Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. New England Journal of Medicine 1998 338 13521357. (doi:10.1056/NEJM199805073381904).

    • Search Google Scholar
    • Export Citation
  • 13

    Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Reviews in Endocrine and Metabolic Disorders 2010 11 171178. (doi:10.1007/s11154-010-9146-0).

    • Search Google Scholar
    • Export Citation
  • 14

    Mathew PM, Young JM, Abu-Osba YK, Mulhern BD, Hammoudi S, Hamdan JA, Sa'di AR. Persistent neonatal hyperinsulinism. Clinical Pediatrics 1988 27 148151. (doi:10.1177/000992288802700307).

    • Search Google Scholar
    • Export Citation
  • 15

    Tuncbilek E, Ulusoy M. Consanguinity in Turkey in 1988. Turkish Journal of Population Studies 1989 11 3546.

  • 16

    Ocal G, Flanagan SE, Hacihamdioglu B, Berberoglu M, Siklar Z, Ellard S, Savas Erdeve S, Okulu E, Akin IM, Atasay B et al.. Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic β cell. Journal of Pediatric Endocrinology and Metabolism 2011 24 10191023. (doi:10.1515/JPEM.2011.347).

    • Search Google Scholar
    • Export Citation
  • 17

    Darendeliler F, Fournet JC, Bas F, Junien C, Gross MS, Bundak R, Saka N, Gunoz H. ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. Journal of Pediatric Endocrinology and Metabolism 2002 15 9931000. (doi:10.1515/JPEM.2002.15.7.993).

    • Search Google Scholar
    • Export Citation
  • 18

    Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O et al.. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. European Journal Endocrinology 2010 162 987992. (doi:10.1530/EJE-09-0861).

    • Search Google Scholar
    • Export Citation
  • 19

    Flanagan SE, Patch AM, Locke JM, Akcay T, Simsek E, Alaei M, Yekta Z, Desai M, Kapoor RR, Hussain K et al.. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. Journal of Clinical Endocrinology and Metabolism 2011 96 E498E502. (doi:10.1210/jc.2010-1906).

    • Search Google Scholar
    • Export Citation
  • 20

    Park SE, Flanagan SE, Hussain K, Ellard S, Shin CH, Yang SW. Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism. European Journal of Endocrinology 2011 164 919926. (doi:10.1530/EJE-11-0160).

    • Search Google Scholar
    • Export Citation
  • 21

    Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. European Journal of Endocrinology 2013 168 557564. (doi:10.1530/EJE-12-0673).

    • Search Google Scholar
    • Export Citation
  • 22

    Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. Journal of Clinical Endocrinology and Metabolism 2013 98 E355E363. (doi:10.1210/jc.2012-2169).

    • Search Google Scholar
    • Export Citation
  • 23

    Yorifuji T, Kawakita R, Nagai S, Sugimine A, Doi H, Nomura A, Masue M, Nishibori H, Yoshizawa A, Okamoto S et al.. Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. Journal of Clinical Endocrinology and Metabolism 2011 96 E141E145. (doi:10.1210/jc.2010-1281).

    • Search Google Scholar
    • Export Citation
  • 24

    Agladioglu SY, Savas Erdeve S, Cetinkaya S, Bas VN, Peltek Kendirci HN, Onder A, Aycan Z. Hyperinsulinemic hypoglycemia: experience in a series of 17 cases. Journal of Clinical Research in Pediatric Endocrinology 2013 5 150155. (doi:10.4274/Jcrpe.991).

    • Search Google Scholar
    • Export Citation
  • 25

    Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Søvik O, Njølstad PR, Molven A. The spectrum of ABCC8 mutations in Norwegian patients with congenitalhyperinsulinismof infancy. Clinical Genetics 2009 75 440448. (doi:10.1111/j.1399-0004.2009.01152.x).

    • Search Google Scholar
    • Export Citation
  • 26

    Faletra F, Athanasakis E, Morgan A, Biarnés X, Fornasier F, Parini R, Furlan F, Boiani A, Maiorana A, Dionisi-Vici C et al.. Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort. Gene 2013 521 160165. (doi:10.1016/j.gene.2013.03.021).

    • Search Google Scholar
    • Export Citation