Pathogenesis
17α-hydroxylase deficiency (17α-OHD) is caused by mutations in the CYP17A1 gene, which encodes the enzymes 17α-hydroxylase and 17,20-lyase. These enzymes catalyze the conversion of pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively, followed by their conversion to dehydroepiandrosterone (DHEA) and androstenedione by 17,20-lyase. Deficiencies in one or both of these enzymatic activities result in varying degrees of impaired synthesis of adrenal glucocorticoids and sex hormones, while an increased conversion of pregnenolone into mineralocorticoid precursors occurs.
Clinical Manifestations
With impaired synthesis of cortisol and sex hormones, along with increased levels of deoxycorticosterone (DOC) and corticosterone, clinical symptoms include increased blood volume, hypertension, hypokalemia, metabolic alkalosis, and abnormal sexual development. Corticosterone has some glucocorticoid activity, which makes symptoms of adrenal insufficiency mild and precludes adrenal crises. Male patients may present with male pseudohermaphroditism, showing female-like underdeveloped external genitalia, a blind vaginal pouch, hypospadias, absence of a uterus and ovaries, cryptorchidism, and gynecomastia. Female patients typically present with sexual infantilism, failure of secondary sexual characteristics to develop during puberty, primary amenorrhea, and absence of pubic and axillary hair. The lack of sex hormones results in inadequate negative feedback regulation, leading to significantly elevated gonadotropins (FSH and LH) and features of hypergonadotropic hypogonadism, along with delayed bone age. Non-classical 17α-OHD cases in women may present with irregular menstruation or infertility, with increased progesterone and decreased estradiol levels during the follicular phase, while potassium levels, blood pressure, and external genitalia appear normal.
Diagnosis
Suspected cases arise when male pseudohermaphroditism or sexual infantilism in females, absence of secondary sexual development during puberty, or primary amenorrhea is observed alongside hypokalemia, metabolic alkalosis, and low-renin hypertension. Laboratory findings show decreased plasma renin activity, aldosterone, 11-deoxycortisol, 17α-hydroxyprogesterone, androgens, estrogens, and cortisol levels. Increased levels of pregnenolone, progesterone, DOC, corticosterone, FSH, LH, and ACTH confirm the diagnosis. In atypical cases presenting with ambiguous clinical features and biochemical changes, ACTH and hCG stimulation tests aid in diagnostic clarification.
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.