Pathogenesis
11β-hydroxylase plays a critical role in the biosynthesis of both glucocorticoids and mineralocorticoids in the adrenal cortex. There are two isoenzymes of 11β-hydroxylase in humans, CYP11B1 and CYP11B2, which are involved in the biosynthesis of cortisol and aldosterone, respectively. Genetic defects in these enzymes obstruct the conversion of 11-deoxycortisol to cortisol due to impaired 11β-hydroxylation, while the conversion of deoxycorticosterone (DOC) to aldosterone through 11β, 18β-hydroxylation, and 18β-oxidation is also disrupted. A reduction in cortisol synthesis causes compensatory increases in ACTH secretion via feedback mechanisms, leading to the excess production of cortisol and aldosterone precursors, which are diverted into the adrenal androgen synthesis pathway. Concurrently, DOC acts as a weak mineralocorticoid and suppresses renin activity, further lowering aldosterone levels. Mutations in the CYP11B1 gene result in defects in cortisol synthesis, while mutations in the CYP11B2 gene lead to deficiencies in aldosterone synthesis.
Clinical Manifestations
In classical 11β-hydroxylase deficiency (11β-OHD), elevated levels of DOC may result in hypernatremia, hypokalemia, metabolic alkalosis, and increased blood volume. Approximately 2/3 of affected individuals experience hypertension. Additionally, excessive adrenal androgen secretion leads to a phenotype of isolated virilization similar to that observed in 21-hydroxylase deficiency (21-OHD). In non-classical cases, blood pressure is typically normal or mildly elevated, and external genitalia at birth are usually normal. However, females may develop mild clitoromegaly, hirsutism, or oligomenorrhea associated with hyperandrogenism during or after puberty. Males may exhibit signs of precocious puberty.
Diagnosis
Elevated plasma DOC levels suppress plasma renin activity in 11β-OHD, distinguishing it from 21-OHD, where hypertension is absent. However, features of hyperandrogenism and associated signs are similar in both conditions. In non-classical cases, significant elevations in 11-deoxycortisol and DOC levels following ACTH stimulation aid in confirming the diagnosis.
Treatment
Glucocorticoid Replacement Therapy
Glucocorticoid replacement therapy is the primary treatment for all types of congenital adrenal hyperplasia (CAH). Administration of appropriate doses of exogenous glucocorticoids serves to both compensate for the deficiency of endogenous glucocorticoids and suppress excessive ACTH secretion via feedback mechanisms. This suppression reduces the overproduction of precursor substances and androgens, thereby improving symptoms, preventing accelerated skeletal maturation, and delaying premature gonadal development. For pediatric patients, hydrocortisone is recommended at a daily dose of 10–20 mg/m2 in 2–3 divided doses. After reaching adult height, the typical dose is 15–25 mg/day in two divided doses. The dosage varies among individuals and requires lifelong administration. During periods of stress, dosage adjustments are necessary.
Mineralocorticoid Replacement Therapy
For CAH patients with salt-wasting symptoms, it is essential to provide mineralocorticoid replacement therapy along with glucocorticoid supplementation. In addition to increasing dietary salt intake, fludrocortisone (commonly used dose: 0.05–0.15 mg/day for infants and young children, 0.15–0.30 mg/day for older children and adults) is administered daily. However, in most cases of salt-wasting CAH, adults may eventually discontinue mineralocorticoid replacement therapy.
Hormone replacement therapy for this condition remains lifelong. Regular monitoring of steroid hormone levels, biochemical markers, bone age, and growth rates is essential. Clinical symptoms and physical signs should be observed continuously to allow for timely dose adjustments. Correction of abnormal sexual differentiation should be performed depending on the CAH subtype and results of chromosomal karyotyping, thus confirming the patient’s genetic sex. Clinical presentation should guide any necessary reconstructive surgery. Additional symptomatic treatments include management of hypertension, potassium supplementation, and correction of electrolyte and acid–base imbalances. Early diagnosis of the condition, particularly prenatal diagnosis, is critical for improving the prognosis of certain CAH subtypes.