The term congenital adrenal hyperplasia encompasses a group of autosomal recessive disorders, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both and androgens (testosterone). Congenital adrenal hyperplasia is a family of genetic conditions affecting the adrenal glands. It can interfere with normal growth and development in children ? including normal development of the genitals.

 

Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency.

Approximately 50% of patients with classic congenital adrenal hyperplasia due to CYP21A mutations or deletions have salt wasting due to inadequate aldosterone synthesis.

Types of congenital adrenal hyperplasia

• Classic congenital adrenal hyperplasia
• Nonclassic congenital adrenal hyperplasia

Classic congenital hyperplasia

• This more severe form of the disease affects very young children and newborns.
• In girls, signs and symptoms of this condition reflect the influence of being exposed to elevated levels of male sex hormones (androgens) while in the womb.
• The most obvious sign of classic congenital adrenal hyperplasia in girls is often abnormal-appearing genitals that look more male than female, which may include an enlarged clitoris — a condition called ambiguous external genitalia.
• The condition is not typically as visually evident in baby boys; although some affected male infants have an enlarged penis.

Clinical presentation in females

Classic virilizing adrenal hyperplasia

• Females with severe forms of adrenal hyperplasia due to deficiencies of 21-hydroxylase, 11-beta-hydroxylase or 3-beta-hydroxysteroid dehydrogenase have ambiguous genitalia at birth due to excess adrenal androgen production in utero.
• This more severe form of the disease affects very young children and newborns.
• In girls, signs and symptoms of this condition reflect the influence of being exposed to elevated levels of male sex hormones (androgens) while in the womb.
• The most obvious sign of classic congenital adrenal hyperplasia in girls is often abnormal-appearing genitals that look more male than female, which may include an enlarged clitoris — a condition called ambiguous external genitalia.
• The condition is not typically as visually evident in baby boys; although some affected male infants have an enlarged penis.

Signs and symptoms of classic CAH

• Ambiguous genitalia in girls
• Enlarged penis in boys
• Failure to regain birth weight
• Weight loss
• Dehydration
• Vomiting
• Very early puberty
• Rapid growth during childhood, but shorter than average final height
• Irregular menstrual cycles in women
• Infertility in women and men

Simple virilizing adrenal hyperplasia

Mild forms of 21-hydroxylase deficiency in females are identified later in childhood because of precocious pubic hair, clitoromegaly, or both, often accompanied by accelerated growth and skeletal maturation due to excess postnatal exposure to adrenal androgens.

Non classic adrenal hyperplasia

Milder deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility.

 

Females with 17-hydroxylase deficiency appear phenotypically female at birth but do not develop breasts or menstruate in adolescence because of inadequate estradiol production. They may present with hypertension.

Clinical presentation in males

• 21-hydroxylase deficiency in males is generally not identified in the neonatal period because the genitalia are normal.
• If the defect is severe and results in salt wasting, these male neonates present at age 1-4 weeks with failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock (classic salt-wasting adrenal hyperplasia).
• Patients with less severe deficiencies of 21-hydroxylase present later in childhood because of the early development of pubic hair, phallic enlargement, or both, accompanied by accelerated linear growth and advancement of skeletal maturation (simple virilizing adrenal hyperplasia).
• In male infants, the disease may be misdiagnosed as gastroenteritis or pyloric stenosis, with potentially disastrous consequences due to delayed treatment with glucocorticoids.
• Males with steroidogenic acute regulatory (StAR) deficiency, classic 3-beta-hydroxysteroid dehydrogenase deficiency, or 17-hydroxylase deficiency generally have ambiguous genitalia or female genitalia because of inadequate testosterone production in the first trimester of fetal life.

Other finding

• Hyponatremia
• Hypokalemia
• Hypoglycemia
• Hypotension
• Two forms of adrenal hyperplasia (ie, 11-hydroxylase [CYP11B1] and 17-hydroxylase [CYP17] deficiency) result in hypertension due to the accumulation of supraphysiologic concentrations of deoxycorticosterone.
• Infants with StAR deficiency (lipoid adrenal hyperplasia) usually have signs of adrenal insufficiency (eg, poor feeding, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia).

Causes

The defects that cause congenital adrenal hyperplasia are autosomal recessive disorders due to deficient activity of a protein involved in cortisol synthesis, aldosterone synthesis, or both.

In most cases, this disorder is due to a mutation or deletion of the gene that codes for the involved protein.

Enzyme defects

• 21-hydroxylase CAH
• 11β-hydroxylase CAH
• 17α-hydroxylase CAH
• Lipoid CAH
• 3β-HSD CAH

Tests and diagnosis

Blood and urine tests measure levels of hormones manufactured by the adrenal glands — cortisol, aldosterone and androgens.

Prenatal testing- amniocentesis, chorionic villous sampling.

Treatment and drugs

• Supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids
• Providing replacement mineralocorticoid and extra salt if the person is deficient
• Providing replacement testosterone or estrogen at puberty if the person is deficient
• Additional treatment of aromatase inhibitors to optimize growth by delaying puberty or delaying bone maturation

 

Patients with dehydration, hyponatremia, or hyperkalemia and a possible salt-wasting form of adrenal hyperplasia should receive an intravenous (IV) bolus of isotonic sodium chloride solution (20 mL/kg or 450 mL/m²) over the first hour, as needed, to restore their intravascular volume and blood pressure.

Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropic-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone may partially improve the patient's height.

 Surgical care

• The traditional approach to the female patient with ambiguous genitalia due to adrenal hyperplasia is clitoral recession early in life followed by vaginoplasty after puberty.
• Some female infants with adrenal hyperplasia have only mild virilization and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization (flutamide (an androgen blocker to reduce virilization).
• Bilateral adrenalectomies have been suggested in the management of virilizing forms of adrenal hyperplasia in order to prevent further virilization and advancement of skeletal maturation.