Endocrine Abstracts

JOINT799

Background: Congenital Hyperinsulinemic Hypoglycemia (CHI) is a rare disorder of insulin dysregulation caused by genetic mutations that impair the function of pancreatic β-cells. Accurate genotype-phenotype correlations and understanding of therapeutic responses, including to diazoxide, are crucial for effective diagnosis and management. This review examines molecular findings, diazoxide response rates, and alternative therapies for CHI, focusing on phenotype and genotype relationships.

Methods: A systematic review of studies published from 2013 to 2025 was conducted, analyzing genetic variants, clinical phenotypes, and diazoxide response rates. Data were extracted from verified studies on key genotypes (e.g., ABCC8, KCNJ11, GLUD1, HNF4α, GCK, and INSR) and phenotypes (e.g., diffuse, focal, atypical, and transient CHI).

Results: Data from 546 patients across 14 studies revealed distinct patterns in diazoxide response by genotype and phenotype.

• Genotype-based responses:

• ABCC8 and KCNJ11 mutations, the most common genetic causes of CHI, showed low response rates to diazoxide (40% and 50%, respectively).

• GLUD1 mutations had high response rates (81%), while GCK mutations were moderately responsive (71%).

• HNF4α mutations exhibited the highest response rates (90%), whereas INSR mutations were poorly responsive (30%).

• Phenotype-based responses:

• Diffuse CHI, often associated with severe neonatal presentations, had a low response rate (35%).

• Focal CHI, typically caused by paternal ABCC8 mutations with somatic loss of heterozygosity, showed the highest response rate (90%) after surgical resection.

• Atypical CHI demonstrated variable diazoxide responsiveness (50%), reflecting its heterogeneous etiology.

• Transient CHI, common in mild and perinatal cases, had a high response rate (80%) with medical therapy.

• Therapeutic insights:

• Long-acting somatostatin analogs, such as octreotide and lanreotide, provided effective alternatives for diazoxide-unresponsive diffuse and atypical CHI cases.

• Emerging therapies, including GLP-1 receptor antagonists, showed promise in preclinical studies for severe CHI unresponsive to standard treatments.

Conclusions: The genotype and phenotype of CHI strongly influence therapeutic outcomes, particularly diazoxide responsiveness. Diffuse and severe forms often require alternative therapies or surgery, while milder forms respond well to medical management. Comprehensive molecular and phenotypic analysis is essential for tailoring treatment and improving long-term outcomes in CHI. Further research into personalized therapeutic approaches and emerging treatment options is warranted.

Keywords: Congenital hyperinsulinism, ABCC8, KCNJ11, diazoxide, somatostatin analogs, GLP-1 receptor antagonists, genotype-phenotype correlation.