Endocrine Abstracts

Background: Dominant inactivating mutations in the HNF4A gene have been associated with diazoxide-responsive hyperinsulinism (HI) during the neonatal period. However, there is limited literature reporting exceptional diazoxide sensitivity in neonates with HI due to novel HNF4A mutations. Objectives: To report on five neonates with HI due to HNF4A gene mutations who developed diazoxide-induced hyperglycemia and to explore phenotype-genotype correlations.

Methods: Retrospective data collection of five neonates (3 females, 2 males) diagnosed with HI due to a heterozygous pathogenic HNF4A variant, who developed diazoxide-induced hyperglycemia soon after starting diazoxide treatment. Two probands were siblings.

Results: All neonates presented immediately after birth with hypoglycemia and high glucose requirements (glucose infusion rate [GIR] range 17-20 mg/kg/min). Diagnosis of HI was confirmed by hypoglycemia screen. Subsequently, diazoxide was administered at doses ranging between 2–5 mg/kg/day during the second week of life, leading to marked hyperglycemia (maximum 15 mmol/l) within a few days in all five cases. Discontinuation of diazoxide was necessary for blood glucose normalization, but all infants exhibited persistent HI upon cessation. Therefore, a lower dose of diazoxide (1-2 mg/kg/day) was restarted, effectively controlling HI. Genetic testing confirmed heterozygosity for different pathogenic HNF4A variants, apart from the two siblings that were carrying the same variant, maternally inherited in four cases and paternally in one.

Conclusion: Diazoxide-induced hyperglycaemia is a rare adverse effect observed in neonates with HI due to HNF4Avariants, necessitating temporary cessation of treatment. Upon confirmation of persistent HI, restarting diazoxide at a lower dose can effectively manage the condition. Our cohort did not demonstrate mutation-specific predisposition to this complication, highlighting the importance of clinician and caregiver awareness regarding this risk.