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Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders
Open accessAbstract
CONTEXT: Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25-50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including "idiopathic hypoglycemia of infancy," "leucine-sensitive hypoglycemia," or "nesidioblastosis." EVIDENCE ACQUISITION: In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic β-cell insulin secretion. EVIDENCE SYNTHESIS: There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother). Management of HI is one of the most difficult problems faced by pediatric endocrinologists and frequently requires difficult choices, such as near-total pancreatectomy and/or highly intensive care with continuous tube feedings. For 50 years, diazoxide, a KATP channel agonist, has been the primary drug for infants with HI; however, it is ineffective in most cases with mutations of ABCC8 or KCNJ11, which constitute the majority of infants with monogenic HI. CONCLUSIONS: Genetic mutation testing has become standard of care for infants with HI and has proven to be useful not only in projecting prognosis and family counseling, but also in diagnosing infants with surgically curable focal HI lesions. (18)F-fluoro-L-dihydroxyphenylalanine ((18)F-DOPA) PET scans have been found to be highly accurate for localizing such focal lesions preoperatively. New drugs under investigation provide hope for improving the outcomes of children with HI.
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“While the pathophysiology of persistent hyperinsulinemic hypoglycemia in childhood and infancy, which is morphologically similar to NIPHS, is well understood from a genetic and functional point of view, mechanistic data on adult-onset NIPHS is scarce [49].”
From An Uncommon Cause of Recurrent Presyncope, Dizziness, and Tachycardia: A Case Report of Diffuse, Adult-Onset Nesidioblastosis/Non-Insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS) (2023) · cites this paper as [49]
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“Loss-of-function mutations cause congenital hyperinsulinism because they result in permanent membrane depolarization and persistent insulin release (479, 644, 681).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [644]
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Citations
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Zani, A., & Pierro, A. (2017) · Springer eBooks · doi:10.1007/978-3-642-38482-0_65-1
“…such as GLUD1 (encoding the enzyme glutamate dehydrogenase), GCK (encoding the enzyme glucokinase), HADH (encoding the L-3-hydroxyacyl-coenzyme A dehydrogenase), UCP2 (encoding the uncoupling protein2), and SLC16A1 (encoding the monocarboxylate transporter 1) (Nessa et al. 2016; Stanley 2016).”
BackgroundClinical and genetic heterogeneity of congenital hyperinsulinism
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“Congenital hyperinsulinism may be associated with several syndromes, and Beckwith-Wiedemann syndrome is the most frequent comorbidity out of the overgrowth disorders.(4) In our series, 2 patients had polymalformative syndrome, of who 1 had a phenotype compatible with BeckwithWiedemann syndrome.”
Endokrine Erkrankungen des Pankreas bei Kindern und Jugendlichen
Barthlen, W., & von Schweinitz, D. (2018) · Springer Reference Medizin · doi:10.1007/978-3-662-53390-1_69-1
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Neonatal hyperinsulinism with an ABCC8 mutation: A case report
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AI-based discovery and cryoEM structural elucidation of a KATP channel pharmacochaperone
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Design and evaluation of fast-release glucose granules for self-management of hypoglycemiaPreprint
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Identification of an ABCC8 variant in a kindred with transient diazoxide responsive hyperinsulinism
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Abdulghfar, M. M., Alsagheir, A., Abdullah, I. A., & Alhuthil, R. T. (2025) · Journal of Medical Case Reports · doi:10.1186/s13256-025-05355-3
“[7], which suggests that all our cases will have exhibited genetic alterations during DNA testing.”
Widmer, A., Zumsteg, U., Szinnai, G., Filges, I., Meier, S., Geyter, J. D., Antwi, K., Wild, D., Nuoffer, J., & Christ, E. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf423
Chang, E. Y., Yang, M., Ahn, S. Y., Sung, S. I., Chang, Y. S., Jang, J., & Park, H. (2025) · Perinatology · doi:10.14734/pn.2025.36.4.107
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Pancreatectomy Outcomes in Pediatric Hyperinsulinism: A Retrospective Single-Center Experience
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“Mutation testing is the standard diagnostic modality for congenital hyperinsulinemia, and in some cases it may be necessary to use next-generation sequencing to rule out large genetic defects or recessive mutations [7].”
The impact of subtotal pancreatectomy on people with congenital hyperinsulinism and their caregivers
Rohli, K. E., Banerjee, I., Christesen, H. T., León, D. D. D., Lopez, L. N., Raskin, J., & Pasquini, T. L. S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1787064
Otaka, T., Kubo, M., & Koyama, S. (2026) · JCEM Case Reports · doi:10.1210/jcemcr/luag183
“Gain-of-function mutations in KCNJ11 lead to neonatal diabetes mellitus, whereas loss-of-function mutations result in CHI [5, 6].”
Kelay, A., Atiq, E. H., Dastamani, A., Stoyanov, D. V., Giuliani, S., & Coppi, P. D. (2026) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2026.163320
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Hyperinsulinism-hyperammonemia syndrome due to an autosomal dominant GLUD1 p.Ile497Met mutation
Anvaripour, A. S., Dhanabal, V., Blake, E. J., Dewey, A. F., Vetrini, F., & Felton, J. L. (2026) · JCEM Case Reports · doi:10.1210/jcemcr/luag227
“It is associated with several genetic mutations, most notably ABCC8 and KCNJ11 defects affecting the pancreatic β -cell K ATP channel [1, 2].”
InfluentialInsulin/C-peptide interpretation in infants with hypoglycaemia of unknown origin
Ismail, A. A., & Wilkinson‐Herbots, H. (2026) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/00045632261489517
Contractor, J. B., Bharti, L., Shah, I., Shah, S., Nimbalkar, S. M., Bajpai, A., Kumar, R., Mohan, V., Venkatesan, R., & Shah, P. (2026) · Children · doi:10.3390/children13101431
“Optimal surgical decision-making therefore requires multidisciplinary evaluation integrating genetic, radiological, biochemical, and histopathological findings [18,35].”
InfluentialParent experiences of infant feeding in congenital hyperinsulinism: a thematic analysis
Worthington, S., Ginbey, E., Otabor, O., Hall, C., Allchin, B., Auckburally, S. H., Salomon‐Estebanez, M., Banerjee, I., & Worth, C. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1955679
Metadata
- Authors
- Stanley, C. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Stanley, Charles A.
- ORCID
- Stanley, Charles A.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-03
- Volume
- 101
- Issue
- 3
- Pages
- 815-826
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4803157
- OpenAlex
- W2277559429
- Cited by
- 239
- References
- 104
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 13 · 2023: 13 · 2022: 24 · 2021: 25 · 2020: 36 · 2019: 24 · 2018: 39 · 2017: 25 · 2016: 13
- FWCI
- 6.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Children's Hospital of Philadelphia
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK056268)
- 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 › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital hyperinsulinism, pancreatic beta-cell insulin secretion, ABCC8, KCNJ11, genetic diagnosis, diazoxide, near-total pancreatectomy, 18F-DOPA PET, focal pancreatic lesions, Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, neonatal hypoglycemia
- MeSH terms
- Insulin Secretion, Humans, Infant, Newborn, Insulin, Congenital Hyperinsulinism, KATP Channels
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