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Congenital adrenal hyperplasia is a group of genetic disorders, each characterized by inadequate synthesis of cortisol, aldosterone, or both. In the most common forms, accumulated hormone precursors are shunted into androgen production, causing androgen excess; in rarer forms, synthesis of androgens is also inadequate.
In the various forms of congenital adrenal hyperplasia, production of cortisol (a glucocorticoid), aldosterone (a mineralocorticoid), or both is impaired because of an autosomal recessive genetic defect in one of the adrenal enzymes involved in synthesizing adrenal steroid hormones from cholesterol. The enzyme may be absent or deficient, completely or partially disabling synthesis of cortisol, aldosterone, or both. In the forms in which cortisol synthesis is absent or decreased, ACTH (corticotropin) release, normally suppressed by cortisol, is excessive. In the most common forms, 21-hydroxylase deficiency and 11β-hydroxylase deficiency, precursors proximal to the enzyme block accumulate and are shunted into adrenal androgens. The consequent excess androgen secretion causes varying degrees of virilization in external genitals of affected female fetuses; no defects are discernible in external genitals of male fetuses. In some less common forms affecting enzymes other than 21-hydroxylase and 11β-hydroxylase, the enzyme block impairs androgen synthesis (dehydoepiandrosterone [DHEAS] or androstenedione). As a result, virilization of male fetuses is inadequate, but no defect is discernible in female fetuses.
21-Hydroxylase Deficiency
21-Hydroxylase (CYP21A2) deficiency causes defective conversion of adrenal precursors to cortisol and, in some cases, to aldosterone, resulting in virilization and sometimes severe hyponatremia and hyperkalemia. Diagnosis is by measurement of cortisol, its precursors, and adrenal androgens, sometimes after ACTH administration. Treatment is with a glucocorticoid plus, if needed, a mineralocorticoid and, for some female neonates with genital ambiguity, surgical reconstruction.
21-Hydroxylase deficiency causes 90% of all cases of congenital adrenal hyperplasia. Incidence ranges from 1/10,000 to 1/15,000 live births. The deficiency completely or partially blocks conversion of adrenal precursors into cortisol and aldosterone, resulting in increased levels of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone (DHEA, a weak androgen that masculinizes affected female infants), and androstenedione. Plasma deoxycorticosterone, deoxycortisol, cortisol, and aldosterone levels are low or absent.
Complete 21-hydroxylase deficiency, the salt-wasting form, accounts for 70% of 21-hydroxylase deficiency cases. The salt-wasting form (sometimes called the classic form of congenital adrenal hyperplasia) is the most severe form of 21-hydroxylase deficiency; aldosterone is not secreted and salt is lost, leading to hyponatremia, hyperkalemia, and increased plasma renin activity.
Partial 21-hydroxylase deficiency causes a less severe, non–salt-losing form, in which aldosterone levels are normal or only slightly decreased.
Symptoms and Signs
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.
Very young female infants with the salt-wasting form 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 sexual development. When the enzyme deficiency is much milder, neonates have little or no virilization, but androgen excess manifests later with 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.
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 have Leydig cell dysfunction, decreased testosterone, and impaired spermatogenesis. Most affected males with the non–salt-losing form, even if untreated, are fertile, but in some, spermatogenesis is impaired. Patients with the non–salt-losing form are normotensive.
Diagnosis
Routine neonatal screening typically includes measuring serum levels of 17-hydroxyprogesterone. If levels are elevated, the diagnosis is confirmed by identifying low blood levels of deoxycortisol, cortisol, deoxycorticosterone, corticosterone, progesterone, and 17-hydroxyprogesterone and by identifying high blood levels of DHEA and androstenedione. Rarely, the diagnosis is uncertain, and levels of these hormones must be measured before and 60 min 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. In children with the salt-wasting form, deoxycorticosterone, corticosterone, and aldosterone levels are low, and renin levels are high. Levels of urinary metabolites of cortisol precursors (eg, pregnanetriol) and androgen precursors (eg, 17-ketosteroids) are also high but rarely necessary for the diagnosis.
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.
Treatment
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; the dose is reduced over several weeks to a more physiologic replacement dose. Stress doses of hydrocortisone are also given to prevent adrenal crisis if the salt-wasting form is suspected.
Maintenance treatment is corticosteroids as replacement for deficient steroids (typically, oral hydrocortisone 5 to 8 mg/m2 tid or prednisone 1.5 to 2 mg/m2 bid). Dexamethasone is used only in postpubertal adolescents and adults. Cortisone acetate 18 to 36 mg/m2 IM q 3 days may be used in infants when oral therapy is unreliable. Response to therapy is monitored in infants every 3 mo and in children aged > 12 mo every 3 to 4 mo. Overtreatment with a corticosteroid results in iatrogenic Cushing's disease, 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 and DHEA or androstenedione, 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 Na and K homeostasis. Oral fludrocortisone (usually 0.1 mg once/day, range 0.05 to 0.3 mg) is given if salt loss occurs. Infants often require supplemental oral salt for about 1 yr. Close monitoring during therapy is critical.
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 pregnant 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.
11β-Hydroxylase Deficiency
11β-Hydroxylase (CYP11B1) deficiency involves defective conversion of adrenal precursors to cortisol, resulting in virilization, hypernatremia, hypokalemia, and hypertension. Diagnosis is by measurement of cortisol, its precursors, and adrenal androgens and sometimes by measuring 11-deoxycortisol and 11-deoxycorticosterone after ACTH administration. Treatment is with a corticosteroid.
11β-Hydroxylase deficiency causes about 5% of all cases of congenital adrenal hyperplasia. Conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone is partially blocked, leading to increased levels of ACTH and overproduction of 11-deoxycortisol, 11-deoxycorticosterone (which has mineralocorticoid activity), and adrenal androgens.
Symptoms and Signs
Female neonates may present with genital ambiguity, including clitoral enlargement, labial fusion, and a urogenital sinus. Male neonates usually appear normal, but some present with penile enlargement. Some children present later, with sexual precocity or, in females, menstrual irregularities and hirsutism. Salt retention with hypernatremia, hypertension, and hypokalemic alkalosis may result from increased mineralocorticoid activity.
Diagnosis
Prenatal diagnosis is not available. Plasma levels in neonates are determined for 11-deoxycortisol, 11-deoxycorticosterone, adrenal androgens, and renin. Diagnosis is established by increased levels. If the diagnosis is uncertain, levels of 11-deoxycortisol and 11-deoxycorticosterone are measured before and 60 min after ACTH stimulation. In affected adolescents, basal plasma levels may be normal, so ACTH stimulation is recommended.
Treatment
Treatment is cortisol replacement, typically with hydrocortisone 5 to 8 mg/m2 tid, which reduces ACTH secretion and reduces levels of 11-deoxycorticosterone and adrenal androgens to normal. Mineralocorticoid replacement is usually not necessary for restoration of Na and K homeostasis but may be required in the neonate or during severe stress. Response to treatment should be monitored, typically by measuring serum 11-deoxycortisol, DHEA, and androstenedione and by assessing growth velocity and skeletal maturation. BP should be monitored in patients who presented with hypertension.
Affected female infants may require surgical reconstruction with reduction clitoroplasty and construction of a vaginal opening. Often, further surgery is required in adulthood, but with appropriate care and attention to psychosexual issues, a normal sex life and fertility may be expected.
Last full review/revision May 2009 by Nicholas Jospe, MD
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