2.
A compensatory increase in ACTH levels.
3.
Hyperplasia of the zona reticularis of the adrenal cortex.
4.
An accumulation of the precursors of the affected enzyme in the bloodstream.
21-Hydroxylase Deficiency Deficiency of 21-hydroxylase is responsible for over 90% of all cases of adrenal hyperplasia due to adrenal synthetic enzyme deficiency. The disorder produces a spectrum of conditions; CAH, with or without salt wasting, and milder forms that are expressed as hyperandrogenism of pubertal onset (adult onset adrenal hyperplasia, AOAH). Salt-wasting CAH, the most severe form, affects 75% of patients with congenital manifestations during the first 2 weeks of life and results in a life-threatening hypovolemic salt-wasting crisis, accompanied by hyponatremia, hyperkalemia, and acidosis. The salt-wasting form results from a severity of enzyme deficiency sufficient to result in ineffective aldosterone synthesis. With or without salt-wasting and newborn adrenal crisis, the condition is usually diagnosed earlier in affected female newborns than in males as genital virilization (e.g., clitoromegaly, labioscrotal fusion, and abnormal urethral course) is apparent at birth.
In simple virilizing CAH, affected patients are diagnosed as virilized newborn females or as rapidly growing masculinized boys at 3 to 7 years of age. Diagnosis is based on basal levels of the substrate for 21-hydroxylase, 17-OHP; in cases of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and in milder forms of the disorder with manifestations later in life (acquired, late onset, or adult-onset adrenal hyperplasia), diagnosis depends on basal and ACTH-stimulated levels of 17-OHP.
Patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL, but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between 21-hydroxylase deficiency and other enzyme defects or to make the diagnosis in borderline cases. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.
The nonclassic type of 21-hydroxylase deficiency represents partial deficiency in 21hydroxylation, which produces a late-onset, milder hyperandrogenemia. Its occurrence depends on some degree of functional deficit resulting from mutations affecting both alleles for the 21-hydroxylase enzyme. Heterozygote carriers for mutations in the 21-hydroxylase enzyme will demonstrate normal basal and modestly elevated stimulated levels of 17-OHP, but no abnormalities in circulating androgens. Some women with mild gene defects in both alleles demonstrate modest elevations in circulating 17-OHP concentrations, but no clinical symptoms or signs.
The hyperandrogenic symptoms of AOAH are mild and typically present at or after puberty. The three phenotypic varieties are (174): 1.
Those with ovulatory abnormalities and features consistent with PCOS (39%) 2.
Those with hirsutism alone without oligomenorrhea (39%) 3.
Those with elevated circulating androgens but without symptoms (cryptic) (22%).
Precocious puberty reveals late-onset congenital adrenal hyperplasia in 5% to 20% of cases that mainly are caused by nonclassic 21-hydroxylase deficiency.