Abstract
The pituitary gland produces hormones that regulate multiple functions including growth, metabolism, reproduction, and homeostasis. Thus, congenital hypopituitarism (CH) can have profound and widespread repercussions on physiological balance. Recent research identified the forkhead box A2 transcription factor (FOXA2) as a candidate gene responsible for CH. We sought to review the literature for mouse models and case reports describing FOXA2 mutations, to shed more light on the potential role of this gene in CH. Using a pretested search strategy, we searched the PubMed database, including in the review only original research articles reporting FOXA2 gene mutations in mouse models and human case reports. A total of 10 studies reporting different Foxa2 mutations in mouse models were included. These works described the involvement of Foxa2 in the regulation of murine organogenesis. Foxa2 was found to participate in the development of ventral midline structures and endodermal-derived organs. In addition, when mutated, it was found to determine defects in node, notochord and the neural tube, precursors of the pituitary gland. Foxa2 was also found to have important effects on glucose homeostasis and its deficiency is characterized by hyperinsulinemic hypoglycaemia. Regarding human case reports, a total of 5 cases describing nonsynonymous missense mutations of FOXA2 were identified. All mutations were localized in the DNA binding domain, which might regulate the expression of tissue-specific genes important for cell differentiation. Panhypopituitarism was a prominent feature among the cases as well as hypoglycaemia in infancy with abnormal glucose homeostasis later in life. Additional 6 cases describing patients with varying deletions of 20p11.2 that encompasses FOXA2 were selected. In addition to panhypopituitarism, the patients were found to have several other dysmorphic features, affecting the face as well as the cardiac, gastrointestinal and genital systems. Authors proposed a region of approximately 1.35 Mb that covers around 17 genes, among which FOXA2, as the critical region associated with hypopituitarism. However, the other genes also deleted from this region are associated with the development of the central nervous system and the pancreas and may be responsible of the observed phenotype of these patients. Considering this evidence, FOXA2 seems to be a strong candidate for CH. However, further research is required to elucidate its involvement in pituitary development, as well as the genetic cause that drive FOXA2 haploinsufficiency in determining CH.
Brain Dysfunction in LAMA2-Related Congenital Muscular Dystrophy: Lessons From Human Case Reports and Mouse Models