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Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism
Open accessAbstract
Background: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8,KCNJ11,GLUD1,GCK,HADH,SLC16A1,HNF4A and HNF1A) are known to cause CHI. Aim: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. Methodology: Three hundred patients were recruited and clinical information was collected before genotyping.ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1,HADH,GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). Results: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11(n=15),HNF4A(n=7),GLUD1(n=16) and HADH(n=3). Conclusions: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.
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“A rare pathogenic variant in ABCC8 that causes congenital hyperinsulinism was incorrectly genotyped as homozygous in 43% (9/21) of individuals.”
From Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation (2021) · cites this paper as [29]
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“A rare pathogenic variant in ABCC8 that causes congenital hyperinsulinism [29] is incorrectly genotyped in 43% (9/21) of individuals.”
From Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing (2019) · cites this paper as [29]
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“Typically, diazoxide-responsive dominant CHI was more common in this study (27% of P-CHI patients) compared with other cohorts (20% to 21%) (6, 32) due to the Finnish founder mutation ABCC8/p.”
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“HH can be congenital (known as congenital hyperinsulinaemic hypoglycaemia) or secondary to certain risk factors like birth asphyxia, intra-uterine growth retardation [4], maternal diabetes mellitus or associated with various developmental syndromes such as Beckwith-Wiedemann syndrome or metabolic conditions like conge…”
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“The majority of pathogenic variants (69, 70) affect the ATP-sensitive K + (KATP) channels in the pancreatic beta-cells, whilst others affect the intracellular proteins and enzymes involved in regulation of the insulin secretion pathway.”
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“6% of the 105 diazoxide-unresponsive patients (8).”
ResultClinical and genetic characterization of congenital hyperinsulinism in Spain
Martı́nez, R., Fernández-Ramos, C., Vela, A., Velayos, T., Aguayo, A., Urrutia, I., Rica, I., Castaño, L. A., & _, _. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0027 · Cited by 27
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Işık, E., Demirbilek, H., Houghton, J., Ellard, S., Flanagan, S. E., & Hussain, K. (2018) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2018.2018.0077 · Cited by 30
“Recessive inactivating mutations of the KATP channel genes (ABCC8 and KCNJ11) are the most common cause of severe, diazoxide unresponsive, diffuse CHI which usually requires pancreatectomy (1,10).”
BackgroundSelf-citationMaiorana, A., Barbetti, F., Boiani, A., Rufini, V., Pizzoferro, M., Francalanci, P., Faletra, F., Nichols, C. G., Grimaldi, C., de Goyet, J. D. V., et al. (2014) · Clinical Endocrinology · doi:10.1111/cen.12400 · Cited by 24
Weedon, M. N., Jackson, L., Harrison, J. W., Ruth, K. S., Tyrrell, J., Hattersley, A. T., & Wright, C. F. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/696799 · Cited by 19
Stimulus-Secretion Coupling in Beta-Cells: From Basic to Bedside
Islam, M. S. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12457-1_37 · Cited by 25
Arya, V. B., Aziz, Q. H., Nessa, A., Tinker, A., & Hussain, K. (2014) · International Journal of Pediatric Endocrinology · doi:10.1186/1687-9856-2014-24 · Cited by 23
“Although dominant acting ABCC8/KCNJ11 mutations have been reported, recessively inherited mutations are more common [4,5,9,10].”
BackgroundSelf-citationGuo, D., Liu, H., Ruzi, A., Gao, G., Abbas, N., Liu, Y., Yang, F., Wu, F., Xu, G., & Li, Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-03349-w · Cited by 22
Hyperinsulinemic hypoglycemia: clinical, molecular and therapeutical novelties
Maiorana, A., & Dionisi‐Vici, C. (2017) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-017-0059-x · Cited by 23
“…al 2011; Arya et al 2014a; Garg et al 2015 AKT3 Nellist et al 2015 PI3KCA De Leon and Stanley 2017 TRMT10A Gillis et al 2014 CACNA1D Flanagan et al 2017 Undiagnosed dysmorphisms Meissner et al 2001 (Touati et al 1998; Loechner et al 2011; Ismail et al 2012; Kapoor et al 2013; Maiorana et al 2014).”
BackgroundSaint‐Martin, C., Zhou, Q., Martin, G. M., Vaury, C., Leroy, G., Arnoux, J., de Lonlay, P., Shyng, S., & Bellanné‐Chantelot, C. (2014) · Clinical Genetics · doi:10.1111/cge.12428 · Cited by 23
Salisbury, R. J., Han, B., Jennings, R. E., Berry, A. A., Stevens, A., Mohamed, Z., Sugden, S. A., de Krijger, R. R., Cross, S. E., Johnson, P. P. V., et al. (2015) · Diabetes · doi:10.2337/db14-1202 · Cited by 23
“Inactivating mutations in either the ABCC8 or KCNJ11 genes, which encode subunits of the KATP channel, account for approximately 90% of those cases (3,4) where hypoglycemia necessitates partial or near-total pancreatectomy (1,2).”
BackgroundGenetic testing strategies in the newborn
Carroll, J. M., Wigby, K. M., & Murray, S. (2020) · Journal of Perinatology · doi:10.1038/s41372-020-0697-y · Cited by 21
Babiker, O., Flanagan, S. E., Ellard, S., Girim, H. A., Hussain, K., & Senniappan, S. (2015) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2015-0033 · Cited by 20
Self-citationÜnal, S., Gönülal, D., Uçaktürk, S. A., Bilgin, B. S., Flanagan, S. E., Gürbüz, F., Tayfun, M., Elmaoğulları, S., Yılmaz, A. A., Demirel, F., et al. (2016) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.2773 · Cited by 19
“5) result in focal pancreatic lesions (6,9,10,12,16).”
BackgroundSelf-citationMartı́nez, R., Gutierrez‐Nogués, Á., Fernández-Ramos, C., Velayos, T., Vela, A., Spanish Congenital Hyperinsulinism Group, Navas, M., & Castaño, L. A. (2017) · Clinical Endocrinology · doi:10.1111/cen.13318 · Cited by 19
Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes
Marucci, A., Rutigliano, I., Fini, G., Pezzilli, S., Menzaghi, C., Paola, R. D., & Trischitta, V. (2022) · Genes · doi:10.3390/genes13010117 · Cited by 22
“approximately 100 in KCNJ11) [49–52], are predominantly recessive inherited [53] and account for 36–70% cases of congenital hyperinsulinemic hypoglycemia (HH) [54,55], which is not the focus of this article and which has been discussed in details elsewhere [56,57].”
BackgroundNi, J., Ge, J., Zhang, M., Hussain, K., Guan, Y., Cheng, R., Xi, L., Zheng, Z., Ren, S., & Luo, F. (2019) · European Journal of Pediatrics · doi:10.1007/s00431-019-03408-6 · Cited by 18
Self-citationManaging congenital hyperinsulinism: improving outcomes with a multidisciplinary approach
Palladino, A., & Ackermann, A. M. (2015) · Research and Reports in Endocrine Disorders · doi:10.2147/rred.s56608 · Cited by 17
“Focal Hi As mentioned in previous sections, the most common gene mutations to cause CHI are in ABCC8 and KCNJ11, with most of these cases being diazoxide unresponsive.(23,24) A paternally inherited heterozygous recessive mutation in either of these genes is highly associated with focal HI.”
Comparative meta‐analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia
Hoermann, H., El‐Rifai, O., Schebek, M., Lodefalk, M., Brusgaard, K., Bachmann, N., Bergmann, C., Roeper, M., Welters, A., Dafsari, R. S., et al. (2020) · Clinical Endocrinology · doi:10.1111/cen.14267 · Cited by 18
Congenital Hyperinsulinism in China: A Review of Chinese Literature Over the Past 15 Years
Wang, W.-Y., Sun, Y., Zhao, W., Wu, T., Wang, L., Yuan, T., & Yu, H. (2017) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.3934 · Cited by 17
“Two HNF4A gene mutation cases were diazoxide-responsive in our study; Kapoor et al (37) also elucidated that CHI patients with HNF4A can exhibit mild, transient to severe, persistent hypoglycemia and are diazoxide-responsive.”
ResultInfluentialInsulinoma in childhood: a retrospective review of 22 patients from one referral centre
Melikyan, M. A., Gubaeva, D. N., Shadrina, A., Викторовна, Б. А., Kareva, M., Tiulpakov, A. N., Efremenkov, A. M., Sokolov, Y., Brusgaard, K., Christesen, H. T., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1127173 · Cited by 16
“While congenital hyperinsulinism is the most common cause for persistent and recurrent hypoglycemia in infancy (29), the possibility of insulinoma should be considered in those with HH presenting after the age of three years.”
BackgroundJahnavi, S., Varadarajan, P., Kanthimathi, S., Kandasamy, B., Bodhini, D., Yadav, J., Jain, V., Khadgawat, R., Sikdar, M., Bhavatharini, A., et al. (2014) · Annals of Human Genetics · doi:10.1111/ahg.12070 · Cited by 16
“Of note, a founder effect of the Gly111Arg mutation was reported recently in patients of Indian ethnic origin (Kapoor et al., 2013).”
BackgroundResultInfluentialPersistent hyperinsulinaemic hypoglycaemia in children with Rubinstein–Taybi syndrome
Welters, A., El‐Khairi, R., Dastamani, A., Bachmann, N., Bergmann, C., Gilbert, C., Clement, E. M., Hurst, J. A., Quercia, N. L., Wasserman, J. D., et al. (2019) · European Journal of Endocrinology · doi:10.1530/eje-19-0119 · Cited by 16
Çamtosun, E., Flanagan, S. E., Ellard, S., Şıklar, Z., Hussain, K., Kocaay, P., & Berberoğlu, M. (2015) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.1963 · Cited by 16
“So far, approximately 40 patients with CHH resulting from a mutation in the HADH gene have been reported (Table 1) (3,4,5,6,7,8,9,10,11,12, 13,14,15).”
Self-citationA syndrome of congenital hyperinsulinism and rhabdomyolysis is caused by KCNJ11 mutation
Albaqumi, M. N., Alhabib, F. A., Shamseldin, H. E., Mohammed, F., & Alkuraya, F. S. (2014) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2013-102085 · Cited by 15
Martino, M., Sartorelli, J., Gragnaniello, V., & Burlina, A. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.901338 · Cited by 15
“Symptoms of hypoglycemia can range from non-specific adrenergic symptoms (poor feeding, hunger, palpitations, sweating) to life-threatening, neuroglycopenic symptoms (seizures, unconsciousness, lethargy, coma and even death) (7).”
BackgroundCongenital hyperinsulinism: Global and Japanese perspectives
Yorifuji, T., Masue, M., & Nishibori, H. (2014) · Pediatrics International · doi:10.1111/ped.12390 · Cited by 15
Hyperinsulinemic Hypoglycaemia in a Turner Syndrome with Ring (X)
Cappella, M., Graziani, V., Pragliola, A., Sensi, A., Hussain, K., Muratori, C., & Marchetti, F. (2015) · Case Reports in Pediatrics · doi:10.1155/2015/561974 · Cited by 15
“The serum ammonia was normal sowe ruled out the hyperinsulinism-hyperammonaemia syndrome, the second common form of CHI (caused by mutation in the GLUD1 gene) [2, 3].”
BackgroundSelf-citationBendix, J., Laursen, M. G., Mortensen, M. B., Melikyan, M. A., Globa, E., Detlefsen, S., Rasmussen, L. M., Petersen, H., Brusgaard, K., & Christesen, H. T. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00478 · Cited by 15
“Furthermore, the laparoscopic approach is dependent on preoperative identification of the focal lesion as predicted by heterozygous paternal KATP-channel mutations and 18F-DOPA-PET/CT (29, 37, 38).”
BackgroundRasmussen, A. G., Melikyan, M. A., Globa, E., Detlefsen, S., Rasmussen, L. M., Petersen, H., Brusgaard, K., Rasmussen, A. H., Mortensen, M. B., & Christesen, H. T. (2020) · Pediatric Diabetes · doi:10.1111/pedi.12989 · Cited by 15
“Median (range), days 3 (1-270) 49 (1-270) 1 (1-120) .”
Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism
Chandran, S., Yap, F. K. P., Rajadurai, V. S., Lu, Y. T., Chang, K. T. E., Flanagan, S. E., Ellard, S., & Hussain, K. (2013) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-13-0041 · Cited by 15
Self-citationMatsutani, N., Furuta, H., Matsuno, S., Oku, Y., Morita, S., Uraki, S., Doi, A., Furuta, M., Iwakura, H., Ariyasu, H., et al. (2019) · Journal of Diabetes Investigation · doi:10.1111/jdi.13138 · Cited by 15
Possible New Strategies for the Treatment of Congenital Hyperinsulinism
Sikimic, J., Hoffmeister, T., Gresch, A., Kaiser, J., Barthlen, W., Wolke, C., Wieland, I., Lendeckel, U., Krippeit‐Drews, P., Düfer, M., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.545638 · Cited by 16
Sang, Y., Xu, Z., Liu, M., Yan, J., Wu, Y., Zhu, C., & Ni, G.-C. (2014) · Endocrine Journal · doi:10.1507/endocrj.ej13-0398 · Cited by 15
Velde, C. D., Molnes, J., Berland, S., Njølstad, P. R., & Molven, A. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae459 · Cited by 16
Lang, T., & Hussain, K. (2013) · Advances in clinical chemistry · doi:10.1016/b978-0-12-800094-6.00006-6 · Cited by 15
Self-citationCongenital hyperinsulinism: management and outcome, a single tertiary centre experience
Eltonbary, K., Robinson, P. N., Banerjee, I., & Shaikh, M. G. (2020) · European Journal of Pediatrics · doi:10.1007/s00431-020-03581-z · Cited by 14
Hyperinsulinemic Hypoglycemia Diagnosed in Childhood Can Be Monogenic
Hopkins, J. J., Childs, A. J., Houghton, J., Hewat, T. I., Atapattu, N., Johnson, M. B., Patel, K. A., Laver, T. W., & Flanagan, S. E. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac604 · Cited by 13
Self-citationLong-Term Follow-Up and Mutation Analysis of 27 Chinese Cases of Congenital Hyperinsulinism
Su, C., Gong, C., Saenger, P. H., Li, W., Wu, D., Gu, Y., & Cao, B. (2014) · Hormone Research in Paediatrics · doi:10.1159/000356911 · Cited by 13
Xu, A., Cheng, J., Sheng, H., Wen, Z., Lin, Y., Zhou, Z., Zeng, C., Shao, Y., Li, C., Liu, L., et al. (2019) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2019.2019.0046 · Cited by 13
“The mutation detection rates of ABCC8 and KCNJ11 genes reported by Kapoor et al (6) and by Snider et al (26) were 36.”
BackgroundResultInfluentialRefinement of the critical genomic region for hypoglycaemia in the Chromosome 9p deletion syndrome
Banerjee, I., Senniappan, S., Laver, T. W., Caswell, R. C., Zenker, M., Mohnike, K. L., Cheetham, T. D., Wakeling, M. N., Ismail, D., Lennerz, B. S., et al. (2019) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15465.1 · Cited by 12
Self-citationBanerjee, I., Senniappan, S., Laver, T. W., Caswell, R. C., Zenker, M., Mohnike, K. L., Cheetham, T. D., Wakeling, M. N., Ismail, D., Lennerz, B. S., et al. (2020) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15465.2 · Cited by 12
Self-citationLaimon, W. N., Aboelenin, H. M., & Tantawi, N. T. E. (2021) · Pediatric Diabetes · doi:10.1111/pedi.13186 · Cited by 12
Metadata
- Authors
- Kapoor, R. R., Flanagan, S. E., Arya, V. B., Shield, J. P., Ellard, S., & Hussain, K.
- Affiliations
- Great Ormond Street Hospital (GB)
- University of Exeter (GB)
- Corresponding author
- Hussain, Khalid
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04
- Volume
- 168
- Issue
- 4
- Pages
- 557-564
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- PMC
- PMC3599069
- OpenAlex
- W2111189973
- Semantic Scholar
- 1a21aa2a4c44a96603182b698464b7e013b7884f
- Cited by
- 243
- References
- 81
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 17 · 2023: 19 · 2022: 25 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 13 · 2017: 12 · 2016: 12 · 2015: 27 · 2014: 22 · 2013: 6
- FWCI
- 22.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Wellcome Trust (081188/A/06/Z)
- Society for Endocrinology
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- congenital hyperinsulinism, ABCC8, KCNJ11, HNF4α, GLUD1, hydroxyacyl-CoA dehydrogenase, glucokinase, MCT1, genetic diagnosis, recessive inheritance, paternal mutations, diffuse hyperinsulinism, hyperammonemia, consanguinity, genotype-phenotype correlation
- MeSH terms
- Kcnj11 Channel, Diazoxide, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Receptors, Drug, Cohort Studies, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, Congenital Hyperinsulinism, Sulfonylurea Receptors
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