Introduction: Congenital hyperinsulinism (CHI) is a heterogeneous disorder of insulin dysregulation, leading to hypoglycemia. This study describes the clinical characteristics, genetics, and management of CHI in Argentina. Methods: We retrospectively reviewed 70 probands diagnosed with CHI at multiple centres across Argentina. Clinical, biochemical, imaging, and treatment data were analyzed. Genetic testing was performed in 49 probands using Sanger and targeted next-generation sequencing of CHI-related genes. Results: Transient CHI was identified in 23/70 (33%) probands, with a median duration of 2 months. Risk factors for perinatal stress-induced hyperinsulinism (PSHI) were present in 85% of transient cases. Persistent CHI was diagnosed in 44/70 (63%) individuals, of whom 31 responded to diazoxide. Late-onset CHI (diagnosed >3 years) was identified in 3 children. A pathogenic variant was detected in 19/49 (39%) probands, all had persistent CHI. ABCC8 variants were most common accounting for 68% (13/19) of diagnoses. Imaging in 17 cases revealed focal disease in 8, diffuse disease in 8, and atypical disease in 1 individual. Seven individuals with focal disease underwent lesionectomy, which was curative in 5 (71%). Three children with diffuse disease required near-total pancreatectomy, with one developing postoperative diabetes. Conclusions: This study provides the largest CHI cohort reported from South America and highlights the clinical and genetic heterogeneity of the condition. Transient CHI was often associated with PSHI risk factors, while persistent CHI was predominantly linked to K-ATP channel variants. The findings underscore the importance of genetics and imaging for CHI management and emphasize the need for increased access to molecular diagnostics.

The authors have declared no competing interest.

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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the Wales Research Ethics Committee 5 (22/WA/0268), with participants recruited to the Genetic Beta Cell Research Bank (IRAS: 316050).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All available clinical data is provided in the manuscript. The raw sequencing data generated during the current study are not publicly available to preserve patient confidentiality. Variant call format (.vcf) files are available through collaboration to experienced teams working on approved studies examining the mechanisms, cause, diagnosis and treatment of diabetes and other beta cell disorders. Requests for collaboration will be considered by a steering committee following an application to the Genetic Beta Cell Research Bank (IRAS: 316050, https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/). Contact by email should be directed to Sarah Flanagan (s.flanagan@exeter.ac.uk).