Pathogenesis
21-hydroxylase deficiency (21-OHD) results from mutations in the CYP21A2 gene. The deficiency of 21-hydroxylase impairs the conversion of progesterone and 17-hydroxyprogesterone into deoxycorticosterone (DOC) and 11-deoxycortisol, leading to disrupted synthesis of cortisol and aldosterone. The resulting decrease in cortisol weakens the negative feedback on the hypothalamus-pituitary axis, leading to overproduction of the precursors of 21-hydroxylase substrates (including 17-hydroxyprogesterone, pregnenolone, 17-hydroxypregnenolone, and progesterone), with subsequent excessive conversion into adrenal androgens (such as dehydroepiandrosterone [DHEA], androstenedione, and testosterone). Clinically, the disease is categorized into three types: simple virilizing, salt-wasting, and non-classical.
Clinical Manifestations
Simple Virilizing Type
Partial 21-hydroxylase deficiency allows for limited synthesis of cortisol and aldosterone, resulting in manifestations primarily related to androgen excess. Female infants may exhibit varying degrees of ambiguous genitalia at birth, including clitoromegaly, labial fusion, and urogenital sinus formation, making this the most common cause of female pseudohermaphroditism. Females often present with primary amenorrhea or irregular menstruation, along with infertility and hirsutism. Male individuals typically present with isosexual precocious puberty—generally asymptomatic at birth but showing accelerated growth and signs of early puberty by six months of age, with pronounced symptoms by ages 4–6, such as penile enlargement, pubic and axillary hair growth, acne, and voice deepening. Physically, these individuals may appear tall and muscular during childhood, but early closure of the epiphyseal plates often leads to final adult stature being shorter than expected. Males may also exhibit small testicles and azoospermia.
Salt-Wasting Type
Complete 21-hydroxylase deficiency leads not only to androgen excess but also to symptoms associated with aldosterone deficiency and increased renin activity. These manifestations include hyponatremia, hyperkalemia, natriuresis, hypovolemia, hypotension, dehydration, and metabolic acidosis. Severe cases may present with a life-threatening "salt-wasting crisis" within the first two weeks of life, characterized by adrenal crisis involving hypovolemia and hypoglycemia. Without timely diagnosis and treatment, these cases rapidly progress to shock or even death.
Non-Classical Type
Also referred to as late-onset 21-OHD, this form involves milder enzyme deficiency compared to the classical types, resulting in less severe clinical symptoms. Female infants generally do not present with significant ambiguous genitalia. The age of onset varies, and symptoms typically emerge during adrenarche. Clinical manifestations are highly variable. In males, early signs include acne, premature facial and pubic hair growth, precocious puberty, accelerated growth, and advanced bone age. Females may also display signs of androgen excess, with delayed menarche, primary amenorrhea, or polycystic ovary syndrome (PCOS). Both male and female adults may experience reduced fertility.
Diagnosis
The diagnosis primarily depends on clinical findings, biochemical and hormonal measurements, and genetic mutation analysis. Infants with ambiguous genitalia accompanied by salt wasting, hypotension, or hypoglycemia should be evaluated for 21-hydroxylase deficiency. Elevated blood levels of 17-hydroxyprogesterone are a key diagnostic marker. Values of 17-hydroxyprogesterone greater than 300 nmol/L typically indicate the classical form of 21-OHD, while levels below 6 nmol/L effectively exclude the non-classical form. In cases of mild non-classical 21-OHD where baseline 17-hydroxyprogesterone levels are inconclusive, an ACTH stimulation test aids in confirming the diagnosis. After intravenous administration of 250 μg synthetic ACTH, a 17-hydroxyprogesterone level exceeding 30 nmol/L at 60 minutes suggests non-classical 21-OHD.
Other steroid biosynthesis enzyme deficiencies can also cause elevated 17-hydroxyprogesterone levels after ACTH stimulation. To differentiate 21-OHD from other conditions, simultaneous measurements of cortisol, DOC, 11-deoxycortisol, 17-hydroxypregnenolone, DHEA, and androstenedione can be helpful. In cases where a definitive clinical diagnosis is not possible, or differentiation from related disorders is necessary, genetic testing is essential. There is often a strong correlation between the genotype and phenotype in patients with 21-OHD.
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.