Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2

Context Persistent hypoglycemia in the newborn period most commonly occurs as a result of hyperinsulinism. The phenotype of hypoketotic hypoglycemia can also result from pituitary hormone deficiencies, including growth hormone and adrenocorticotropic hormone deficiency. Forkhead box A2 (Foxa2) is a transcription factor shown in mouse models to influence insulin secretion by pancreatic β cells. In addition, Foxa2 is involved in regulation of pituitary development, and deletions of FOXA2 have been linked to panhypopituitarism. Objective To describe an infant with congenital hyperinsulinism and hypopituitarism as a result of a mutation in FOXA2 and to determine the functional impact of the identified mutation. Main Outcome Measure Difference in wild-type (WT) vs mutant Foxa2 transactivation of target genes that are critical for β cell function (ABCC8, KNCJ11, HADH) and pituitary development (GLI2, NKX2-2, SHH). Results Transactivation by mutant Foxa2 of all genes studied was substantially decreased compared with WT. Conclusions We report a mutation in FOXA2 leading to congenital hyperinsulinism and hypopituitarism and provide functional evidence of the molecular mechanism responsible for this phenotype.