Congenital Hyperinsulinism in the Era of Precision Medicine: Genetically Driven Diagnosis and Novel Therapies

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Abstract
Background/Objectives: Congenital hyperinsulinism (CHI) is the leading cause of persistent hypoglycaemia in infancy and childhood characterized by dysregulated insulin secretion despite low plasma glucose concentrations. Early recognition and treatment are essential to reduce the risk of neurological injury. Advances in molecular genetics have revealed substantial genetic and phenotypic heterogeneity beyond classical KATP-channel disorders. This review examines the expanding genetic landscape of CHI and the translation of molecular discoveries into precision clinical care. Methods: This narrative review, based on targeted literature searches of PubMed/MEDLINE, Scopus and Embase and expert selection of key publications, synthesizes current evidence on the genetic mechanisms, genotype–phenotype relationships, molecular diagnosis, and clinical management of CHI, with emphasis on established and emerging genetic subtypes and their implications for therapeutic decision-making. Results: More than 30 disease-associated genes have been identified, involving ion channels, metabolic enzymes, transcription factors, membrane transport proteins, mitochondrial pathways, and developmental mechanisms. Major genetic forms involving ABCC8, KCNJ11, GLUD1, GCK, HK1, HADH, SLC16A1, HNF4A, HNF1A, and FOXA2 illustrate diverse mechanisms of dysregulated β-cell insulin secretion. Recognition of non-coding regulatory variants has further expanded the molecular spectrum and provided new insights into tissue-specific gene regulation. Molecular diagnosis increasingly informs prediction of diazoxide responsiveness, selection for 18F-DOPA PET/CT, identification of patients at high risk of focal disease, surgical planning, genetic counselling, and long-term surveillance. Conclusions: Precision medicine is increasingly transforming CHI from a predominantly phenotype-based disorder into a genetically informed clinical entity. Integration of genomic testing with clinical phenotyping and functional assessment can improve diagnostic classification and individualize management. Continued genomic discovery, functional validation, and international collaboration will be important for patients who remain without a molecular diagnosis and for developing mechanism-based therapies.

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