Pathogenesis
3β-hydroxysteroid dehydrogenase (3β-HSD) is an essential enzyme that catalyzes the conversion of biologically weak Δ5-steroids into biologically potent Δ4-steroids. A deficiency in this enzyme prevents the conversion of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) to progesterone, 17-hydroxyprogesterone, and androstenedione, respectively, resulting in disruptions in the synthesis of cortisol, aldosterone, and androgens.
Clinical Manifestations
In classic cases, the activity of 3β-HSD in both the adrenal glands and gonads is significantly reduced. Male patients produce insufficient testosterone, leading to incomplete masculinization of the external genitalia and male pseudohermaphroditism, presenting as varying degrees of genital abnormalities such as micropenis and hypospadias. Female patients may exhibit female pseudohermaphroditism due to large amounts of DHEA being converted into testosterone in peripheral tissues, resulting in clitoromegaly and labial fusion. Severe deficiencies in glucocorticoid and mineralocorticoid synthesis can lead to symptoms of adrenal insufficiency shortly after birth, such as poor feeding, nausea, vomiting, dehydration, hyponatremia, and hyperkalemia. In severe cases, circulatory collapse may lead to death. Non-classical cases, similar to non-classical 21-hydroxylase deficiency (21-OHD), typically show no abnormalities at birth. During or after puberty, female patients may develop signs of androgen excess, such as hirsutism, acne, oligomenorrhea, and infertility, resembling polycystic ovary syndrome (PCOS).
Diagnosis
In classic cases, characteristic findings include salt-wasting, incomplete masculinization of the male external genitalia, and virilization in female patients. Elevated levels of plasma pregnenolone, 17-hydroxypregnenolone, and DHEA, alongside an increased Δ5-steroids to Δ4-steroids ratio, facilitate diagnosis. Non-classical cases, which exhibit milder symptoms and less obvious changes in these markers, often require ACTH stimulation testing to confirm the diagnosis. An elevated ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone, as well as an increased 17-hydroxypregnenolone to cortisol ratio after ACTH stimulation, are important diagnostic indicators. If adrenal or ovarian steroid-secreting tumors need to be ruled out, dexamethasone and norgestrel suppression testing may be performed, as 3β-HSD deficiency shows suppression, while steroid-secreting tumors do not. Imaging studies, such as ultrasound, CT, or MRI, may be required for further confirmation.
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.