SUN-690 HNF4A Mutation in Siblings with Diazoxide Responsive Congenital Hyperinsulinism

Background: Congenital hyperinsulinism (HI) is the leading cause of severe, persistent hypoglycemia in infants. Transient HI seen at risk neonates due to prenatal stress and some of the congenital HI cases due to mutations in K-ATPase channel are responsive to diazoxide. It is not a common practice to obtain genetic evaluation for diazoxide responsive HI. However, children with dominant inactivating variants in HNF4A gene may present with diazoxide-responsive HI and mimic transient HI in infancy. Objective: To describe two siblings with diazoxide responsive HI with HNF4A mutation associated with maturity onset diabetes of youth type 1 (MODY1). Clinical Case: Case 1, term female with macrosomia and Case 2, preterm male appropriate for gestational age were born to same mother without gestational diabetes and with no perinatal stress. Siblings were non-dysmorphic and both presented with hypoglycemia during first week of life. Diagnosis of HI is confirmed based on inappropriately suppressed β-hydroxybutyrate at the time of hypoglycemia and inappropriate glycemic response to glucagon consistent with increased insulin action. Both siblings responded to diazoxide therapy. Family history was significant for late-onset diabetes in paternal extended family. Case 1 required very low dose diazoxide (2 mg/kg/day) during first year of life to sustain normoglycemia. She came off of diazoxide at 19 months of age. Case 2 is normoglycemic on 5mg/kg/day diazoxide at 4 months of age. Genetic evaluation through whole exome sequencing pursued upon diagnosis of Case 2 revealed paternally inherited heterozygous pathogenic start loss variant in HNF4A gene (c.3G>T) in both siblings. Father was completely asymptomatic without any history of hypo- or hyperglycemia. Conclusion: HNF4A gene encodes hepatocyte nuclear factor-4-alpha that regulates hepatic gluconeogenesis and lipid metabolism. Dominant inactivating variants in HNF4A gene associated with familial HI, are typically associated with increased size for gestational age, mild diazoxide-responsive hypoglycemia (which may be transient) and monogenic diabetes during adolescence. HNF4A mutations were described as one of the most common genetic cause of diazoxide-responsive congenital hyperinsulinism and are associated with MODY1. It is important to consider genetic evaluation in diazoxide responsive HI cases. Identifying children with HNF4A variant early on will impact their long-term follow-up leading to earlier diagnosis and treatment of MODY-1 and potentially improve long-term outcomes.