bubble_chart Overview

Congenital adrenal hyperplasia, also known as adrenogenital syndrome or adrenal virilism, is primarily caused by defects in the enzymes necessary for the biosynthesis of adrenal cortical hormones, leading to abnormal corticosteroid production. In most cases, the adrenal glands secrete insufficient glucocorticoids and mineralocorticoids but excessive androgens. Clinically, this results in varying degrees of adrenal cortical insufficiency, accompanied by masculinization in girls and precocious puberty in boys. Additionally, it may present with various syndromes such as hyponatremia or hypertension.

bubble_chart Etiology

The synthesis of normal adrenocortical hormones is illustrated in the figure. Under the action of various enzymes, cholesterol, the precursor of cortisol and others, is converted into cortisol, aldosterone, sex hormones, etc. In patients with this disease, due to deficiencies of different enzymes in the synthesis process of the aforementioned hormones, the production of cortisol and corticosterone is reduced, leading to increased secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary. The adrenal cortex is stimulated by ACTH and undergoes hyperplasia, thereby maintaining the minimal level of cortisol synthesis necessary for survival. However, the zona reticularis also proliferates, producing large amounts of androgens, leading to masculinization. Depending on the specific enzyme deficiency, symptoms such as hyponatremia, hypertension, etc., may occur. Additionally, various intermediate metabolites before the blocked step, such as pregnanetriol, 17-hydroxypregnenolone, and tetrahydro compounds S, accumulate in the patient's body and can be detected in the urine.

This disease is an autosomal recessive genetic disorder. It manifests when two copies of the pathogenic gene are present (i.e., homozygous), while carriers with only one copy of the pathogenic gene (i.e., heterozygous) do not exhibit symptoms. Typically, only one type of enzyme deficiency occurs within a family. The most common clinical deficiencies are 21-hydroxylase (accounting for approximately 90% of patients) and 11-hydroxylase (accounting for about 5% of patients). Other deficiencies, such as 17-hydroxylase, 3β-hydroxysteroid dehydrogenase, 18-oxidase, 20,22-desmolase, etc., are very rare.

bubble_chart Clinical Manifestations

This disease is more common in girls, with a male-to-female ratio of approximately 1:4. A deficiency in any enzyme (except 3β-hydroxysteroid dehydrogenase) can lead to common symptoms caused by excessive adrenal androgen secretion.

Male infants may have a slightly larger penis at birth, but this often goes unnoticed. Symptoms of precocious puberty gradually appear after six months and become more pronounced by ages 4–5. The main manifestations include rapid penile enlargement, scrotal and prostate enlargement, but the testes remain relatively small for their age, with no sperm production, a condition known as macrogenitosomia praecox. The child develops pubic hair early, along with acne, an Adam's apple, a deeper voice, muscular development, accelerated physical growth, and height exceeding peers, with bone growth far surpassing their age. Without timely diagnosis and proper treatment, premature epiphyseal fusion can occur, leading to shorter stature in adulthood. Intellectual development is generally normal.

Female infants may have clitoral hypertrophy at birth, which gradually enlarges to resemble a boy's penis but is thicker than that of boys of the same age. The labia majora resemble a scrotum but lack testes (Figure 2). During embryonic development, excessive androgen can inhibit the normal development of female reproductive organs. By the 12th day of the day-night cycle, female external genitalia form, with the urethra and vaginal opening separate.

If the 21-hydroxylase deficiency is partial, the degree of masculinization is milder, presenting only as clitoral hypertrophy. If the deficiency is severe, androgen's impact on embryonic genital development is earlier and more severe, resulting in the urethra and vagina failing to separate, both opening into the urogenital sinus, sometimes extending to the base of the clitoris, resembling hypospadias in boys. Thus, the external genitalia may exhibit three types of malformations (see Figure 3), but the internal genitalia remain entirely female, a condition termed pseudohermaphroditism. Other masculinization symptoms and physical development resemble those described for male patients.

Additionally, due to increased ACTH and melanocyte-stimulating hormone, patients often exhibit hyperpigmentation of the skin and mucous membranes. Generally, the more severe the deficiency, the higher the likelihood of hyperpigmentation. In newborns, this may manifest as darkened areolae and external genitalia. Without treatment, hyperpigmentation can progress rapidly.

Depending on the specific enzyme deficiency, clinical manifestations can vary:

1. Simple virilizing type: Symptoms are as described above, caused by incomplete 21-hydroxylase deficiency. This is the most common type, accounting for over 50% of cases.
2. Salt-wasting type: Accounts for about one-third of cases. When 21-hydroxylase is deficient, precursors like progesterone and 17-hydroxyprogesterone are overproduced, while aldosterone synthesis decreases (see Figure 4), leading to excessive sodium excretion and reduced potassium excretion in the distal renal tubules. In addition to masculinization, infants soon develop vomiting, anorexia, restlessness, failure to thrive, severe dehydration, hyperkalemia, hyponatremia, and metabolic acidosis. Without timely treatment, circulatory failure can lead to death. Some believe this type results from a more severe 21-hydroxylase deficiency than the simple virilizing type, while others speculate there may be two isoenzymes of 21-hydroxylase. Girls with ambiguous genitalia at birth are easier to diagnose, whereas boys are often misdiagnosed with pyloric stenosis or infantile diarrhea, missing treatment opportunities and leading to early death. Some cases show no obvious dehydration or circulatory failure but result in sudden death, possibly due to cardiac arrest from hyperkalemia, warranting vigilance.
3. Hypertensive type: This type has a relatively low incidence rate, accounting for about 5% of the total patients with this disease. It is caused by excessive 11-deoxycorticosterone due to 11-hydroxylase deficiency. Patients exhibit milder masculinization and may develop hypertension, typically with moderate elevation of blood pressure, sometimes reaching 160–200/100–160 mmHg. A characteristic feature of this hypertension is that it can be reduced with corticosteroid treatment but rises again after discontinuation.

bubble_chart Diagnosis

If the disease can be diagnosed early and treatment is initiated promptly, the development of ambiguous genitalia or male precocious puberty can be prevented, allowing the child to maintain a normal life and growth.

The diagnosis is primarily based on clinical manifestations, with reference to family history. For suspected cases, the 24-hour urinary 17-ketosteroid excretion can be measured. 17-ketosteroids are the final metabolic products of androgens in the body. Normal infants have higher urinary 17-ketosteroid excretion within three weeks after birth, reaching up to 2.5 mg per day, which then decreases. Within one year of age, <1毫克， 1～4歲<2毫克，4～8歲<3毫克，青春期前<5毫克。患者可高達5～30毫克， 并隨年齡而增加。

when 21-hydroxylase deficiency is present, large amounts of pregnanetriol may appear in the urine; in cases of 11-hydroxylase deficiency, large amounts of tetrahydro compounds S may appear in the urine, while pregnanetriol only increases to grade I.

In cases of diagnostic difficulty, a low-dose dexamethasone suppression test can be performed. After medication, the urinary 17-ketosteroid excretion significantly decreases and rises again after discontinuation.

bubble_chart Treatment Measures

After diagnosis is confirmed, early administration of hydrocortisone or prednisone is essential. This serves a dual purpose: compensating for the deficiency in adrenal corticosteroid synthesis and inhibiting the release of pituitary adrenocorticotropic hormone, thereby suppressing excessive adrenal androgen production and halting the progression of virilization. With proper treatment, patients can maintain normal growth, development, and daily life. Initially, the dose should be relatively high. After 1–2 weeks, when urinary steroid excretion is controlled to a satisfactory level, the dose can be reduced to a physiological level: generally, oral prednisone doses are 2.5 mg daily for infants, 2.5–5 mg for children, and 7.5–10 mg for adolescents, adjusted based on urinary 17-ketosteroid excretion. The daily dose should be divided into two oral administrations, with the last dose taken in the evening.

Lifelong medication adherence is necessary. During stressful situations, the maintenance dose of hormones should be doubled. In cases of severe stress or acute adrenal insufficiency crisis, the hormone dose may even need to be increased 5–10 times, with intravenous infusion of water-soluble hydrocortisone and sodium chloride supplementation.

Patients with the salt-wasting type require prompt emergency treatment. Initially, hydrocortisone 25–100 mg/day should be administered intravenously, along with fluid and sodium chloride supplementation to correct dehydration and hyponatremia. Additionally, intramuscular injection of deoxycorticosterone acetate (DOCA) 0.5–1 mg/day or oral administration of the sodium-retaining hormone fludrocortisone 250–300 μg/m²/day in three divided doses can be used. For mild salt-wasting cases, oral prednisone with 2–5 g of added salt daily can maintain electrolyte balance.

For children with pseudohermaphroditism, clitoridectomy is best performed between 2–4 years of age. Surgery performed too early may be unsuccessful, while delaying it may have adverse psychological and social impacts. Patients with a common urogenital sinus opening for the urethra and vagina should undergo urethral and vaginal separation surgery after menstruation begins to prevent ascending urinary tract infections. If the diagnosis is confirmed only during adolescence and the external genitalia are already predominantly male in appearance, altering the original genital morphology is not advisable, as changing gender can be psychologically traumatic and socially complex. In such cases, hysterectomy and oophorectomy may be considered to allow continued development of male secondary sexual characteristics, with prednisone dosage adjusted based on urinary 17-ketosteroid excretion to maintain levels typical of normal adult males.

bubble_chart Differentiation

1. Female children should be differentiated from true hermaphroditism, which involves the presence of both ovarian and testicular tissues in the same individual, though underdeveloped. Consequently, the excretion of estrogen, androgen, and urinary 17-ketosteroids is lower than normal.
2. In girls where the urethra and vagina share a common opening into the urogenital sinus, particularly when the opening is located at the base of the clitoris, differentiation from male hypospadias and cryptorchidism is necessary. Iodized oil contrast imaging can be performed to check for the presence of a uterus, and chromosomal testing can be conducted. Patients with adrenal hyperplasia exhibit positive sex chromatin and female sex chromosomes.
3. For salt-wasting patients who present with symptoms such as vomiting and dehydration shortly after birth, differentiation from gastrointestinal disorders like pyloric stenosis and intestinal obstruction is essential, especially in male infants. If hyponatremia and hyperkalemia persist despite fluid therapy, this should be noted.