Commentary - Heritable disorders of pituitary development

Basic and translational research achievements over the past 2 decades have disclosed the molecular mechanisms underlying several genetic forms of hypo pituitarism. Disorders that are limited to the hypothalamic, pituitary, GR axis are caused by mutations in individual components of that axis. Disorde rs involving GH and one or more additional pituitary hormones are caused by mutations in the homeodomain transcription factors that direct embryologic al development of the anterior pituitary gland. Pit-1 has a POU-specific an d a POU-homeo DNA-binding domain. The phenotype produced by mutations in th e PIT1 gene involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or normally sized. The PROP1 gene encodes a transcription fac tor with a Single paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have deficiencies of LH and FSH, as well as GPI, PRL, a nd TSH. Their pituitary glands may be small, normally sized, or extremely l arge and show suprasellar extension. Pituitary degeneration may produce acq uired deficiency of ACTH. Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread. The protein has a paired -like domain, and it competes with the product of PROP1 for DNA-binding. Ho mozygosity for inactivating mutations of HESX1 produces a complex phenotype that resembles septo-optic dysplasia. Much more needs to be learned about the role of HESX1 mutations in other forms of hypopituitarism.