Congenital Adrenal Hyperplasia

Background

• Congenital adrenal hyperplasia (CAH) is a genetic defect in one of the adrenal enzymes responsible for glucocorticoid production, resulting in glucocorticoid insufficiency, with or without changes in excess mineralocorticoid and/or adrenal sex steroid production.
• > 90% of CAH is due to 21-hydroxylase deficiency, which is caused by mutations in the CYP21A2 gene.
  • Classic salt-losing CAH involves severe 21-hydroxylase deficiency, resulting in glucocorticoid deficiency, mineralocorticoid deficiency leading to renal salt wasting and androgen excess which may lead to prenatal virilization in infant girls.
  • Classic non-salt-losing (simple virilizing) CAH can be seen in less severe 21-hydroxylase deficiency, resulting in virilization without renal salt wasting
  • Nonclassic (late-onset) CAH involves mild 21-hydroxylase deficiency, resulting in varying degrees of glucocorticoid deficiency and androgen excess, which may or may not be clinically significant, often presenting as early pubarche or sexual precocity in childhood.
• 5% of CAH is due to 11-beta-hydroxylase deficiency, which is caused by mutations in the CYP11B1 gene, and generally manifests as female ambiguous genitalia from virilization, male and female postnatal virilization, and hypertension due to mineralocorticoid excess.
• Rare forms of CAH involve deficiencies of 3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase, steroidogenic acute regulatory protein (StAR), or cytochrome P450 oxidoreductase, and may manifest as either salt wasting or hypertension, often with prenatal undervirilization in males.

Evaluation

• Suspect congenital adrenal hyperplasia (CAH) in:
  • newborns with ambiguous genitalia, salt-wasting symptoms, or hypotension that is unresponsive to fluids or inotropes
  • children with signs of androgen excess such as progressive penile or clitoral enlargement or premature pubarche
  • adolescents or adults with hirsutism, acne, alopecia, menstrual irregularities, or infertility
• Measure the baseline serum 17-hydroxyprogesterone (17OHP) level as a first-line test for routine newborn screening or for suspected CAH (Strong recommendation).
• In infants with confirmed or suspected CAH, measure electrolytes, plasma renin activity, and aldosterone level to identify salt wasting.
• If the baseline 17OHP is elevated or borderline, perform an adrenocorticotropin (ACTH) stimulation test (Strong recommendation).
  • An ACTH stimulation test may not be feasible in infants, and testing should not delay treatment in an infant with a positive newborn screen and electrolyte or circulatory instability.
  • A poststimulation 17OHP level < 30 nmol/L (1,000 ng/dL) suggests no congenital adrenal hyperplasia or heterozygote; a poststimulation 17OHP level > 30 nmol/L (1,000 ng/dL) indicates 21-hydroxylase deficiency of some type (with stimulated levels often reaching several thousand in classic CAH).
  • Poststimulation cortisol, deoxycorticosterone, 11-deoxycortisol, 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA), androstenedione, deoxycortisol, and aldosterone levels can help to identify and differentiate between other types of CAH.
• Consider genetic testing to identify disease-causing mutations for diagnostic confirmation if an ACTH stimulation test is not feasible or equivocal, for genetic counseling purposes, to predict disease severity, or for prenatal diagnosis (Weak recommendation).
• Consider ultrasonography to assess the adrenal glands in newborns, and to evaluate internal anatomy in infants with ambiguous external genitalia (Strong recommendation).

Management

• Provide maintenance glucocorticoid replacement therapy (such as hydrocortisone 15-25 mg/day [10-15 mg/m²/day in growing children] orally in 3 divided doses) for all patients with classic congenital adrenal hyperplasia (CAH), and for symptomatic patients with nonclassic CAH (Strong recommendation).
• Provide stress dosing of glucocorticoids for significant physical stressors (including fever, vomiting, other moderate to severe illness or injury, surgery requiring anesthesia, or labor and delivery) in all patients with classic CAH, and in patients with nonclassic CAH if adrenal function is iatrogenically suppressed or shown to be suboptimal on an adrenocorticotropin (ACTH) stimulation test (Strong recommendation).
  • For moderate stress that can be managed by oral stress dosing, the suggested oral regimen is hydrocortisone 30-50 mg/m²/day orally divided every 6-8 hours; in some cases, 3 times the usual daily dose can be used for stress dosing until recovery (usually 3-4 days).
  • For more severe stress, suggested parenteral regimen is 50 mg/m² initial dose, followed by 50 mg/m²/day in 3-4 divided doses given every 6-8 hours.
    • When body surface area is unknown, the following recommendations for initial parental administration: hydrocortisone 25 mg IV in infants and preschool children, 50 mg IV in school-aged children, and 100 mg IV in adults; successive parental hydrocortisone can be administered as one quarter the initial dose, given every 6 hours.
• Provide mineralocorticoid replacement therapy (fludrocortisone 0.05-0.2 mg orally once daily [or in 2 divided doses in growing children]) for all infants with classic CAH and patients with clinical or subclinical aldosterone deficiency (elevated plasma renin activity or decreased aldosterone to plasma renin activity ratio) (Strong recommendation).
• Provide sodium chloride supplementation (1-2 g/day [17-34 mEq/day] divided into several feedings) for all infants with classic CAH (may not be needed beyond infancy) (Strong recommendation).
• Pregnant women with CAH should continue glucocorticoid and mineralocorticoid replacement therapy, but should avoid glucocorticoids that cross the placenta (for example, dexamethasone) (Strong recommendation).
• Surgical procedures:
  • feminizing surgery may be considered in females with virilized genitalia, after extensive discussion of the risks and benefits).
  • bilateral adrenalectomy not recommended (Weak recommendation) .
  • testis-sparing surgery may be considered for adrenal rest tumors that do not decrease in size with increased glucocorticoid dose.
• Follow-up should include monitoring growth and treatment with:
  • regular physical exams (every 3-4 months in growing children) (Strong recommendation).
  • blood testing (including consistently timed hormone measurements) (Strong recommendation).
  • annual bone age suggested in growing children > 2 years old.
  • periodic testicular ultrasound beginning in adolescence for boys with classic CAH to screen for adrenal rest tumors (Strong recommendation).