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SCOPE

DISEASE/CONDITION(S)

Congenital adrenal hyperplasia in the neonate.

GUIDELINE OBJECTIVE(S)

Describe the etiology, pathophysiology, and management of congenital adrenal hyperplasia in the neonate.

BRIEF BACKGROUND

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders in which impaired cortisol biosynthesis by the adrenal glands leads to overproduction of hypothalamic corticotrophin-releasing hormone (CRH) and the secretion of pituitary adrenocorticotrophic hormone (ACTH), with consequent hyperplasia of adrenal tissue. In addition, diversion of precursor products into alternate pathways causes elevated levels of other classes of corticosteroid, particularly gonadal steroid hormones.

Cortisol is produced by the adrenal cortex under the regulation of ACTH from the anterior pituitary, which in turn is regulated by CRH from the hypothalamus—the hypothalamic−pituitary−adrenal (HPA) axis. Cortisol concentration in the serum modulates the resting activity of the HPA axis via negative feedback on ACTH and CRH secretion (Figure 49.1).

FIGURE 49.1

The hypothalamic−pituitary−adrenal (HPA) axis.

Steroid hormone biosynthesis commences with cholesterol translocation from the cytoplasm to the inner membrane of the mitochondrion, a rate-limiting step mediated by the steroidogenic acute regulatory (StAR) protein. Catalyzed by side-chain cleavage (P450scc), cholesterol is converted into pregnenolone, the common precursor for all other steroids. Glucocorticoid (cortisol), mineralocorticoid (aldosterone), and adrenal androgen are all synthesized from pregnenolone, after sequential processing by the appropriate steroidogenic enzymes.

Deficiency in one of the critical steroidogenic enzymes leads to impaired production of cortisol, which leads to increased secretion of both CRH and ACTH. Excessive ACTH causes hyperplasia of the adrenal cortex and also stimulates melanocytes, with an excess of ACTH potentially leading to hyperpigmentation.

With the block in the biosynthesis of cortisol, common precursors at supraphysiologic concentrations are shunted into an alternative pathway, which can lead to either increased or decreased androgen production. As a result, the target organ is subject to either undesired, long-term exposure or deprivation of the sex steroid hormones. Overvirilization in females (such as in 21-hydroxylase deficiency [21-OHD]), and undervirilization in males (from 3β-hydroxysteroid dehydrogenase deficiency [3B-HSD]), can be seen during gestation or at birth, presenting as atypical genitalia, or occasionally diagnosed at a later time.

The regulation of aldosterone secretion is via plasma renin. Depending on where the enzyme blockage is, mineralocorticoid levels may be low (due to enzyme block) or high (due to excessive synthesis through alternative pathways). The neonate might present with features of mineralocorticoid disturbances and manifest hyponatremia and shock in the context of 21-OHD, or with hypertension when 11β-hydroxylase is deficient.

There are several different forms of CAH depending on the defective enzyme involved (Table 49.1 and Figure 49.2). These include StAR protein deficiency, 21-OHD, 3B-HSD, 17α-hydroxylase deficiency, and 11β-hydroxylase deficiency. Though this group of disorders shares ...

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