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Primary adrenal insufficiency (PAI) results from destruction or dysfunction of the adrenal cortex; 50% to 70% of cases presenting in infancy or childhood represent specific enzymatic defects in corticosteroid biosynthesis, collectively termed congenital adrenal hyperplasia (CAH; see Chapter 29). CAH occurs in 1:16,000 newborns in most populations, corresponding to an incidence of ~1/300,000 if counting all children younger than 18 years. Therefore the incidence of other causes of adrenal insufficiency must be similar to or slightly less than this. Approximately half of the remaining non-CAH cases are caused by autoimmune adrenalitis (Table 28-1). We begin this section with a general discussion of primary adrenal insufficiency, and then consider specific etiologies.

TABLE 28-1Comorbidities of the Autoimmune Polyglandular Syndromes



Each adrenal gland is located above the upper pole of each kidney and consists of the adrenal cortex and adrenal medulla. The adrenal cortex (which forms about 90% of the adrenal gland’s total mass) consists of three anatomical zones: the outer zona glomerulosa (approximately 15% of the cortex), the intermediate zona fasciculata (75%), and the inner zona reticularis (10%). These zones are where the three main types of hormones are produced, respectively: mineralocorticoids (aldosterone), glucocorticoids (eg, cortisol and corticosterone) and sex steroids (mainly the androgen precursors dehydroepiandrosterone and androstenedione). Many other steroid precursors and side products are secreted by the cortex and in some cases are biologically active, but they are normally of limited importance compared to cortisol or aldosterone. Internal to the zona reticularis is the adrenal medulla, which comprises approximately 10% of the adrenal gland’s mass and secretes catecholamines.


The adrenal cortex and medulla develop independently, with the cortex deriving from mesodermal cells and the medulla from neuroectoderm. Mesodermal cells also play a role in the developing gonad; both the adrenals and gonads have common enzymes involved in steroidogenesis. At approximately 5 to 6 weeks of gestation, the gonadal ridge develops into separate steroidogenic cells of the gonads and adrenal cortex; specifically, mesothelial cells migrate into the underlying mesenchyme (close to the developing gonad) and become the fetal zone of the adrenal cortex. A second migration of mesothelial cells forms the adult (definitive) zone. Neural crest ...

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