Pathogenesis
This condition results from mutations in the STAR and CYP11A1 genes. The steroidogenic acute regulatory protein (StAR) is responsible for transporting cholesterol from the cytoplasm to the mitochondrial inner membrane, where it is then converted to pregnenolone under the action of cholesterol side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene. This process represents the initial and rate-limiting step in steroid hormone biosynthesis. Deficiencies in either StAR or P450scc lead to disruptions in the synthesis of glucocorticoids, mineralocorticoids, and sex hormones. Additionally, the accumulation of large amounts of cholesterol and lipids in the adrenal cortical cells results in a visibly lipid-laden, hyperplastic appearance.
Clinical Manifestations
The clinical symptoms of P450scc and StAR deficiencies are highly similar. These include significant adrenal cortical insufficiency, hypogonadism, severe salt-wasting, and skin hyperpigmentation. Males present with underdeveloped external genitalia and fail to undergo puberty. Females exhibit variable presentations depending on the degree of disruption in sex steroid synthesis, ranging from underdeveloped genitalia to the presence of pubertal development. Compared to StAR deficiency, P450scc deficiency typically manifests later, with milder early symptoms.
Diagnosis
Affected newborns show early-onset symptoms of adrenal cortical insufficiency accompanied by abnormalities in external genitalia, including male pseudohermaphroditism and sexual infantilism in females. Laboratory findings show reduced levels of all types of steroid hormones in blood and urine, along with elevated plasma ACTH and renin activity.
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.