Endocrine Abstracts

JOINT953

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants, caused by dysregulated insulin secretion. The probability of response to diazoxide, first-line therapy, and other medical or surgical treatments varies based on genetic mutations and phenotypic presentations. Understanding these factors is crucial for optimizing treatment strategies.

Objective: To evaluate the probability of therapeutic response in CHI based on genetic mutations and phenotypic factors, highlighting genotype-phenotype correlations.

Methods: A literature review of studies between 2000 and 2024 was conducted, focusing on the influence of genetic mutations (ABCC8, KCNJ11, GLUD1, HNF4A, and HNF1A) and phenotypic factors (histological subtypes, age of onset) on diazoxide response and other treatment outcomes. Data were synthesized to calculate probabilities of therapeutic success.

Results: 1. Genetic Factors and Diazoxide Response:

• KATP Channel Mutations (ABCC8, KCNJ11):

• Dominant mutations: High probability of diazoxide response (>70%), as partial loss of function allows diazoxide to activate the KATP channel.

• Recessive mutations: Low response probability (<30%), associated with severe diffuse CHI due to complete channel dysfunction.

• Other Mutations:

• GLUD1: Very high response probability (>80%) due to effective suppression of insulin secretion with diazoxide.

• HNF4A/HNF1A: High probability (>80%), associated with mild forms of CHI.

2. Phenotypic Factors:

• Histological Subtype:

• Focal CHI: Response probability depends on mutation; lesions are often curable with lesionectomy.

• Diffuse CHI: Low diazoxide response probability (<20%); near-total pancreatectomy often required.

• Age of Onset:

• Neonatal CHI: Severe phenotype with low diazoxide response.

• Later-Onset CHI: Milder phenotype with higher diazoxide responsiveness.

3. Alternative Therapies:

• For diazoxide-unresponsive cases, therapies such as octreotide, lanreotide, and CGM-assisted glucose monitoring are effective, particularly in severe or diffuse CHI.

Conclusions: The probability of therapeutic response in CHI is highly dependent on genotype and phenotype. Diazoxide is effective in patients with dominant KATP mutations, GLUD1, and HNF4A mutations, while recessive KATP mutations and diffuse CHI predict poor response. Individualized treatment strategies based on genetic and phenotypic profiling are essential to optimize outcomes in CHI patients.