Figure 1. Genetic defects in various steps along the hypothalamic-pituitary-adrenal (HPA) axis can result in either central or primary adrenal insufficiency depending on the location in the pathway. This figure displays the HPA axis and the location operative in the genetic defect, guiding the assessment of central or primary insufficiency. Genetic causes of central AI can include several genes involved in the development of the pituitary gland (e.g., PROP1, POU1F1 (formerly PIT1), GLI2, HESX1, LHX3, LHX4, SOX3, SOX2, OTX2), and result in multiple combined pituitary deficiencies. Central AI can result from an isolated ACTH deficiency caused by defects in the synthesis of pro-opiomelanocortin (POMC) or its cleavage. Defects of the melanocortin 2 receptor (MC2R) or its accessory protein MRAP result in ACTH-resistance (a.k.a. as Familial Glucocorticoid Deficiency). There are multiple genetic causes leading to primary AI (PAI). They range from genes that are involved in the development of the adrenal gland resulting in adrenal hypoplasia, defects in cortisol synthesis itself, or metabolic and autoimmune diseases (e.g. adrenoleukodystrophy, sphingolipidosis or autoimmune polyglandular syndrome), that result in destruction of the adrenal gland over time. Defects in steroidogenesis involve multiple genes along the pathway of cortisol synthesis and are the most frequent cause of PAI. Finally, PAI can be part of certain syndromes, such as Triple A Syndrome (AAAS) or disorders associated with oxidative stress.