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Congenital Adrenal Hyperplasia Caused by 11Beta-Hydroxylase Deficiency

By Andrew Calabria, MD, Assistant Professor of Pediatrics;Attending Physician, Division of Endocrinology & Diabetes, Perelman School of Medicine at The University of Pennsylvania;The Children's Hospital of Philadelphia

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11Beta-hydroxylase (CYP11B1) deficiency involves defective production of cortisol, with accumulation of mineralocorticoid precursors, resulting in hypernatremia, hypokalemia, and hypertension and increased production of adrenal androgens, leading to virilization. Diagnosis is by measurement of cortisol, its precursors, and adrenal androgens and sometimes by measuring 11-deoxycortisol after ACTH administration. Treatment is with a corticosteroid.

11Beta-hydroxylase deficiency causes about 5 to 8% of all cases of congenital adrenal hyperplasia. Conversion of 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone is partially blocked, leading to

  • Increased levels of ACTH

  • Accumulation of 11-deoxycortisol (which has limited biological activity) and deoxycorticosterone (which has mineralocorticoid activity)

  • Overproduction of adrenal androgens (DHEA, androstenedione, and testosterone)

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 due to increased deoxycorticosterone levels.

Diagnosis

  • Plasma levels of 11-deoxycortisol and adrenal androgens

Prenatal diagnosis is not available. Diagnosis of 11beta-hydroxylase deficiency in neonates is established by increased plasma levels of 11-deoxycortisol and adrenal androgens (DHEA, androstenedione, and testosterone). Plasma renin activity is often suppressed because of increased mineralocorticoid activity; this test may be useful in older children but is less reliable in neonates. If the diagnosis is uncertain, levels of 11-deoxycortisol and adrenal androgens are measured before and 60 min after ACTH stimulation. In affected adolescents, basal plasma levels may be normal, so ACTH stimulation is recommended.

Hypertension occurs in about two thirds of patients with CYP11B1 deficiency and distinguishes it from CYP21A2 deficiency, which causes hypotension. Because both CYP11B1 deficiency and CYP21A2 deficiency can cause increased levels of 17-hydroxyprogesterone, which is measured during routine newborn screening, patients with mild to moderately increased levels of 17-hydroxyprogesterone should have 11-deoxycortisol levels measured. Hypokalemia may occur but not in all patients.

Pearls & Pitfalls

  • 11Beta-hydroxylase deficiency causes hypertension and sometimes hypokalemia, in contrast to 21-hydroxylase deficiency, which causes hypotension and hyperkalemia.

Treatment

  • Corticosteroid replacement

  • Possibly antihypertensive therapy

  • Possibly reconstructive surgery

Treatment is cortisol replacement, typically with hydrocortisone 3.5 to 5 mg/m2 tid, with total daily dose typically ≤ 20 mg/m2, which prevents further virilization and ameliorates hypertension by reducing levels of 11-deoxycortisol, deoxycorticosterone, and adrenal androgens that are stimulated by ACTH. Unlike CYP21A2 deficiency, mineralocorticoid replacement is not required, because sodium and potassium homeostasis is maintained from mineralocorticoid effects of deoxycorticosterone.

Response to treatment should be monitored, typically by measuring serum 11-deoxycortisol and adrenal androgens and by assessing growth velocity and skeletal maturation. BP should be monitored closely in patients who presented with hypertension. Antihypertensives, such as potassium-sparing diuretics or calcium channel blockers, may be required.

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.

Key Points

  • Children with 11beta-hydroxylase deficiency have excess mineralocorticoid activity and increased adrenal androgens, which cause hypertension, hypokalemia, and virilization.

  • 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.

  • Male infants usually appear normal but may later have sexual precocity.

  • Diagnose by steroid hormone levels and sometimes ACTH stimulation.

  • Treat with corticosteroid replacement and sometimes antihypertensives; females may require reconstructive surgery.

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