ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Hum Mol Genet. 2017 Nov 15;26(22):4315-4326

These two papers describe the association of heterozygous FOXA2 mutations with hypopituitarism and hyperinsulinism. The forkhead/winged helix transcription factor Foxa2 is a major upstream regulator of Pdx1, a transcription factor necessary for pancreatic development and also plays a role in the developmental biology of the pituitary gland. Heterozygous deletions in FOXA2 have been previously reported to associate with a complex syndrome consisting of situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features (1). Tissue specific deletion of FOXA2 leads to an imbalance in the beta to alpha cell ratio, profound hypoglucagonemia, inappropriate hyperinsulinemia, and hypoglycemia in mice.

First, Vajravelu et al. show that the FOXA2 mutation leads to changes in key FOXA2 transactivation genes (ABCC8, KNCJ11, HADH) in the beta cell and in the pituitary gland (GLI2, NKX2-2, SHH).

Second, Giri et al. demonstrate strong expression of FOXA2 in the developing hypothalamus, pituitary, pancreas, lungs and oesophagus of mouse embryos using in situ hybridization and transfection assays showed impaired reporter activity. Thus these studies are beginning to provide a link between the pancreatic beta cell dysfunction (hyperinsulinism) and the role of FOXA2 in the developing hypothalamus and pituitary. Thus other cases of unexplained hyperinsulinism and hypopituitarism should be screend for possible mutations in FOXA2. Further experiments to understand the mechanism of the unregulated insulin secretion (and possible low glucagon levels) and the underlying mechanism of the hypopituitarism will shed more insights into the role of FOXA2 in the pancreas and pituitary gland.

1. Tsai EA, Grochowski CM, Falsey AM, Rajagopalan R, Wendel D, Devoto M, Krantz ID, Loomes KM, Spinner NB. Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia. Hum Mutat.2015 Jun;36(6):631-7. doi: 10.1002/humu.22786. Epub 2015 Apr 21.