Of Old and New Diseases: Genetics of Pituitary ACTH Excess (Cushing) and Deficiency

The pituitary gland orchestrates our endocrine environment: it produces hormones in response to hypothalamic factors that integrate neural inputs and its activity is balanced by the feedback action of peripheral hormones. Disruption of this equilibrium has severe consequences that affect multiple systems and may be fatal. Genetic analysis of pituitary function led to discovery of critical transcription factors that cause hormone deficiencies when mis-expressed. This review will summarize recent findings that led to the first complete clinical description of inherited, isolated corticotropin (ACTH) deficiency (IAD) and to the first molecular mechanism for excessive ACTH production in Cushing's disease. Indeed, mutations in TPIT, a positive or negative regulator of cell fates for different pituitary lineages, cause neonatal IAD, a condition considered anecdotic before discovery of this transcription factor. Cushing's disease is caused by corticotroph adenomas that produce excess ACTH as a result of resistance to glucocorticoids (Gc). Molecular investigation of the normal mechanism of Gc feedback led to identification of two essential proteins for pro-opiomelanocortin repression that are often mis-expressed in corticotroph adenomas thus providing a molecular explanation for Gc resistance. These two proteins, Brg1 and histone deacetylase 2 (HDAC2), are involved in chromatin remodeling and may also participate in the tumorigenic process, as Brg1 is a tumor suppressor. These recent advances have provided improved diagnosis and opened new perspectives for patient management and therapies.