Congenital adrenal hyperplasia (CAH), also known as the “adrenogenital syndrome,” is an uncommon condition caused by a congenital defect in one of several enzymes that take part in the chain of reactions whereby cortisol is manufactured from its precursors. There are at least six fairly well-defined variants of CAH that result from the various enzyme defects. The most common of these are types I and II, which are due to C21-hydroxylase enzyme deficiency. All CAH variants are inherited as autosomal recessive traits. The clinical and laboratory findings depend on which metabolic pathway—and which precursor in the metabolic pathway— is affected. All variants affect the glucocorticoid (cortisol) pathway in some manner. In CAH due to 21-hydroxylase defect (types I and II) and in CAH type III, although formation of cortisone and cortisol is blocked, the precursors of these glucocorticoids are still being manufactured. Most of the early precursors of cortisone are estrogenic compounds, which also are intermediates in the production of androgens by the adrenal cortex. Normally, the quantitative production of adrenal androgen is small; however, if the steroid precursors pile up (due to block in normal formation of cortisone), some of this excess may be used to form more androgens.

Three things result from these metabolic pathway abnormalities. First, due to abnormally high production of androgen, secondary sexual characteristics are affected. If the condition is manifest in utero, pseudohermaphroditism (masculinization of external genitalia) or ambiguous genitalia occur in girls and macrogenitosomia praecox (accentuation of male genitalia) occurs in boys. If the condition does not become clinically manifest until after birth, virilism (masculinization) develops in girls and precocious puberty in boys. In CAH variants IV, V, and VI there is some degree of interruption of the adrenal androgen pathway, so that the external appearance of the female genitalia is not significantly affected and subsequent virilization is minimal or absent. External genitalia in genotypic boys appear to be female or ambiguous.

Second, the adrenal glands themselves increase in size due to hyperplasia of the steroid-producing adrenal cortex. This results because normal pituitary production of ACTH is controlled by the amount of cortisone and hydrocortisone produced by the adrenal. In all variants of congenital adrenal hyperplasia, cortisone production is partially or completely blocked, the pituitary produces more and more ACTH in attempts to increase cortisone production, and the adrenal cortex tissue becomes hyperplastic under continually increased ACTH stimulation.

Third, when the mineralocorticoid pathway leading to aldosterone is blocked, there are salt-losing crises similar to those of Addison’s disease. This occurs in CAH types II, IV, and VI. On the other hand, hypertension may develop if there is accumulation of a salt-retaining precursor (CAH type III) in the mineralocorticoid pathway or a mineralocorticoid production increase due to block in the other adrenal pathways (CAH type V).

Since 21-hydroxylase deficiency is responsible for more than 90% of the CAH variants and the others are rare, only laboratory data referable to this enzyme defect (CAH types I and II) will be discussed.

The CAH 21-hydroxylase deficiency is brought to the attention of the physician by either abnormalities in newborn external genitalia (CAH types I and II, the most common cause of female pseudohermaphroditism) or salt-losing crises (type II, constituting one third to two thirds of 21-hydroxylase deficiency cases). In later childhood, virilization is the most likely clinical problem. In patients with ambiguous genitalia, a buccal smear and chromosome karyotype establish the correct (genotypic) sex of the infant. In salt-losing crises, the infant is severely dehydrated and may develop shock. The serum sodium level is low and the serum potassium level is high-normal or elevated. For a number of years, the diagnosis was made through elevated urine 17-KS levels (metabolites of androgens) and increased urinary pregnanetriol levels (metabolite of 17-OH-progesterone). However, 17-KS values may normally be 4-5 times as high in the first 2 weeks of life as they are after 4 weeks, and pregnanetriol values may be normal in some neonates with CAH in the first 24-48 hours of life. At present, plasma 17-OH-progesterone is considered the best screening test for neonatal 21-hydroxylase deficiency. After the first 24 hours of life, plasma 17-OH-progesterone is markedly elevated in most patients with CAH type I or II. Also, plasma specimens are easier to obtain in neonates or infants than 24-hour urine collections. However, plasma 17-OH-progesterone may be elevated to some extent by pulmonary and other severe illnesses. Also, because there is diurnal variation, the blood specimen should be drawn in the morning.