A Novel Phenotype of GCK c.781G>A Variant Causing Neonatal Refractory Hyperinsulinaemic Hypoglycaemia

Glucokinase (GCK) mutations are well-known causes of maturity-onset diabetes of the young type 2 (MODY2) and hyperinsulinaemic hypoglycaemia type 3 (HH3). The GCK c.781G>A (p.Gly261Arg) variant has been exclusively reported in MODY2. We describe a term male infant with severe refractory neonatal hypoglycaemia and inappropriately elevated insulin. Genetic analysis identified a heterozygous GCK c.781G>A variant inherited from his father. Protein modelling supported a gain-of-function effect. The infant responded well to diazoxide and discontinued treatment two weeks after discharge. This is the first report of GCK c.781G>A presenting as neonatal HH3, expanding the known phenotypic spectrum of this variant.