21-Hydroxylase deficiency causes 90% of all cases of congenital adrenal hyperplasia. Incidence ranges from 1/10,000 to 1/15,000 live births. Disease severity depends on the specific CYP21A2 mutation and degree of enzyme deficiency. The deficiency completely or partially blocks conversion of 17-hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol, and conversion of progesterone to deoxycorticosterone, a precursor of aldosterone. Because cortisol synthesis is decreased, adrenocorticotropic hormone (ACTH) levels increase, which stimulates the adrenal cortex, causing accumulation of cortisol precursors (eg, 17-hydroxyprogesterone) and excessive production of the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione. Aldosterone deficiency can lead to salt wasting, hyponatremia, and hyperkalemia (1, 2).
Adrenal hormone synthesis
Classic 21-hydroxylase deficiency can be divided into 2 forms:
In both forms, adrenal androgen levels are elevated, causing virilization.
The salt-wasting form is the most severe and accounts for 70% of classic 21-hydroxylase deficiency cases; there is complete deficiency of enzyme activity that leads to very low levels of cortisol and aldosterone. Because minimal aldosterone is secreted, salt is lost, leading to hyponatremia, hyperkalemia, and increased plasma renin activity.
In the simple virilizing form, cortisol synthesis is impaired, leading to increased androgen activity, but there is sufficient enzyme activity to maintain normal, or only slightly decreased, aldosterone production.
Nonclassic 21-hydroxylase deficiency is more common than classic 21-hydroxylase deficiency. Incidence ranges from 1/1000 to 1/2000 live births in white populations (0.1 to 0.2%) to 1 to 2% in certain ethnic groups (eg, Ashkenazi Jews). Nonclassic 21-hydroxylase deficiency causes a less severe form of the disorder in which there is 20 to 50% of 21-hydroxylase activity (compared to 0 to 5% activity in classic 21-hydroxylase deficiency). Salt wasting is absent because aldosterone and cortisol levels are normal; however, adrenal androgen levels are slightly elevated, resulting in mild androgen excess in childhood or adulthood.
The salt-wasting form causes hyponatremia (sometimes severe), hyperkalemia, and hypotension as well as virilization. If undiagnosed and untreated, this form can lead to life-threatening adrenal crisis, with vomiting, diarrhea, hypoglycemia, hypovolemia, and shock.
With either form of classic 21-hydroxylase deficiency, female neonates have ambiguous external genitals, with clitoral enlargement, fusion of the labia majora, and a urogenital sinus rather than distinct urethral and vaginal openings. Male infants typically have normal genital development, which can delay the diagnosis of the salt-wasting form; affected boys are often identified only through routine newborn screening. Unless detected by newborn screening, boys with the simple virilizing form may not be diagnosed for several years, when they develop signs of androgen excess. Signs of androgen excess may include early appearance of pubic hair and increase in growth velocity in both sexes, clitoral enlargement in girls, and penile enlargement and earlier deepening of voice in boys.
Children with nonclassic 21-hydroxylase deficiency do not have symptoms at birth and usually do not present until childhood or adolescence. Affected females may have early pubic hair development, advanced bone age, hirsutism, oligomenorrhea, and/or acne; these symptoms may resemble the manifestations of polycystic ovary syndrome. Affected males may have early pubic hair development, growth acceleration, and advanced bone age.
In affected females, especially those with the salt-wasting form, reproductive function may be impaired as they reach adulthood; they may have labial fusion and anovulatory cycles or amenorrhea. Some males with the salt-wasting form are fertile as adults, but others may develop testicular adrenal rest tumors (benign intratesticular masses composed of adrenal tissue that hypertrophies under chronic ACTH stimulation), Leydig cell dysfunction, decreased testosterone, and impaired spermatogenesis. Most affected males with the non–salt-wasting form, even if untreated, are fertile, but in some, spermatogenesis is impaired.
Routine newborn screening typically includes measuring serum levels of 17-hydroxyprogesterone. If levels are elevated, the diagnosis of 21-hydroxylase deficiency is confirmed by identifying low blood levels of cortisol and by identifying high blood levels of DHEA, androstenedione, and testosterone. Rarely, the diagnosis is uncertain, and levels of these hormones must be measured before and 60 minutes after ACTH is given (ACTH or cosyntropin stimulation test). In patients who develop symptoms later, ACTH stimulation testing may help, but genotyping may be required.
Children with the salt-wasting form have hyponatremia and hyperkalemia; low levels of deoxycorticosterone, corticosterone, and aldosterone; and high levels of renin.
Prenatal screening and diagnosis (and experimental treatment) are possible; CYP21 genes are analyzed if risk is high (eg, the fetus has an affected sibling with the genetic defect). Carrier status (heterozygosity) can be determined in children and adults.
For adrenal crisis in infants, urgent therapy with IV fluids is needed. Stress doses of hydrocortisone (100 mg/m2/day) are given by continuous IV infusion to prevent adrenal crisis if the salt-wasting form is suspected; the dose is reduced over several weeks to a more physiologic replacement dose.
Maintenance treatment is corticosteroids as replacement for deficient steroids (typically, oral hydrocortisone 3.5 to 5 mg/m2 3 times a day, with total daily dose typically ≤ 20 mg/m2). Postpubertal adolescents and adults may be treated with prednisone 5 to 7.5 mg orally once a day or 2.5 to 3.75 mg 2 times a day, or dexamethasone 0.25 to 0.5 mg once a day or 0.125 to 0.25 mg 2 times a day.
Response to therapy is monitored in infants every 3 months and in children aged > 12 months every 3 to 4 months. Overtreatment with a corticosteroid results in iatrogenic Cushing syndrome, causing obesity, subnormal growth, and delayed skeletal maturation. Undertreatment results in inability to suppress ACTH with consequent hyperandrogenism, causing virilization and supranormal growth velocity in children and, eventually, premature termination of growth and short stature. Monitoring involves measuring serum 17-hydroxyprogesterone, androstenedione, and testosterone levels as well as assessing growth velocity and skeletal maturation each year.
Maintenance treatment for the salt-wasting form, in addition to corticosteroids, is mineralocorticoid replacement for restoration of sodium and potassium homeostasis. Oral fludrocortisone (usually 0.1 mg once a day, range 0.05 to 0.3 mg) is given if salt loss occurs. Infants often require supplemental oral salt for about 1 year. Close monitoring during therapy is critical.
With illness, corticosteroid dosages are increased (typically doubled or tripled) to prevent adrenal crisis. Mineralocorticoid replacement is not adjusted. When oral therapy is unreliable (eg, severe vomiting or life-threatening situations), a single IM injection of hydrocortisone (50 to 100 mg/m2) can be given. When the injection is given, children typically need to be evaluated in the emergency department to determine whether they require IV fluids, additional corticosteroids, or both.
Affected female infants may require surgical reconstruction with reduction clitoroplasty and construction of a vaginal opening. Often, further surgery is required during adulthood. With appropriate care and attention to psychosexual issues, a normal sex life and fertility may be expected.
For prenatal treatment, a corticosteroid (usually dexamethasone) is given to the mother to suppress fetal pituitary secretion of ACTH and thus reduce or prevent masculinization of affected female fetuses. Treatment, which is experimental, must begin in the first several weeks of gestation.
Treatment of nonclassic 21-hydroxylase deficiency depends on symptoms. If asymptomatic, no treatment is required. If symptomatic, corticosteroid treatment is similar to classic 21-hydroxylase deficiency, but lower doses are often effective. Mineralocorticoid replacement is not needed.
Children with 21-hydroxylase deficiency have varying degrees of androgen excess and about 70% have a salt-wasting form caused by aldosterone deficiency.
In females, androgen excess usually manifests at birth with ambiguous external genitals (eg, clitoral enlargement, fusion of the labia majora, a urogenital sinus rather than distinct urethral and vaginal openings); later in life they may have hirsutism, oligomenorrhea, and acne.
In males, androgen excess may not be apparent or may manifest in childhood with increased growth velocity and early signs of puberty.
In both sexes, salt wasting causes hyponatremia and hyperkalemia.
Diagnose by steroid hormone levels and sometimes adrenocorticotropic hormone (ACTH) stimulation and/or genotyping.
Treat with replacement of corticosteroids and sometimes mineralocorticoids; females may require reconstructive surgery.