More rarely, but posing a clinically important problem, CS is caused by unregulated excessive production of ACTH by a pituitary tumor (Cushing’s disease) (142,143), by ectopic secretion of ACTH, by cortisol secreting adrenal cortical tumors, or by multiple hypersecreting nodules in both adrenal cortices (primary macronodular adrenocortical hyperplasia) (144,145). The gene discussed is POMC; the disease is Cowden syndrome 1.