ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2021, 106(10):e4142-e4154. doi: 10.1210/clinem/dgab352. PMID: 33999151.

Brief Summary: The authors show that patients with hypopituitarism and FOXA2 gene defects also need screening for dysfunction of the pancreas.

The Forkhead box A2 transcription factor (FOXA2) is important for normal development of the central nervous system, including the pituitary gland, and also for endoderm-derived organs in concert with e.g. Sonic Hedgehog (SHH). Previously, Giri et al. (1) reported a patient with a heterozygous FOXA2 mutation who had a complex congenital syndrome with hypopituitarism, hyperinsulinism, and endoderm-derived organ abnormalities. The mechanism of hyperinsulinemia remained unclear, although FOXA2 mutations may downregulate HADH and thus affect beta oxidation, downregulate GLUT2 and also KATP subunit expression.

The current study broadens the clinical FOXA2 -related pancreatic phenotype. Although it describes only 2 patients with hypopituitarism, their pancreatic hypoplasia or sulphonyl-urea responsive diabetes are new clinical findings. The first patient had a novel heterozygous nonsense FOXA2 variant, which encoded a truncated protein lacking part of the DNA-binding domain, and in vitro showed impaired transcriptional activation of GLUT2 -luciferase. Besides neonatal onset hypopituitarism, he had neonatal hyperinsulinism and later developed impaired glucose tolerance. Pancreatic hypoplasia was apparent on CT scan and exocrine function was mildly reduced. The second patient had a novel de novo 8.53 Mb deletion encompassing FOXA2. He presented with progressive hypopituitarism at age 20 months and at age 16 years he developed diabetes, which was responsive to sulphonylurea treatment.

Another recent study (2) showed that inactivation of FOXA2 in iPSCs downregulates key pancreatic development-specific transcription factors and explains the here detected pancreatic hypoplasia and dysfunction. Nevertheless, the mechanisms for neonatal hyperinsulinism and the progression to insulin-deficient diabetes remain open.

In conclusion, the authors propose that screening of FOXA2 should be considered as the first step in managing patients with hypopituitarism and multiple endodermal-derived organ anomalies, and regular follow-up is mandatory.

References: 1. Giri D, Vignola ML, Gualtieri A, Scagliotti V, McNamara P, Peak M, Didi M, Gaston-Massuet C, Senniappan S. Hum Mol Genet. 2017, 26:4315–4326. Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm-derived organ abnormalities. 2. Elsayed AK, Younis I, Ali G, Hussain K, Abdelalim EM. Cell Death Dis. 2021;12:103–120. Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency.