Laboratory Studies
The diagnosis of congenital adrenal hyperplasia depends on the demonstration of inadequate production of cortisol, aldosterone, or both in the presence of accumulation of excess concentrations of precursor hormones. [2] For example, the distinguishing characteristic of 21-hydroxylase deficiency is a high serum concentration of 17-hydroxyprogesterone (usually >1000 ng/dL) and urinary pregnanetriol (metabolite of 17-hydroxyprogesterone) in the presence of clinical features suggestive of the disease (eg, salt wasting, clitoromegaly or ambiguous genitalia, precocious pubic hair, excessive growth, premature phallic enlargement in the absence of testicular enlargement, hirsutism, oligomenorrhea, female infertility).
Likewise, 11-beta-hydroxylase deficiency is indicated by excess concentrations of 11-deoxycortisol and deoxycorticosterone or by an elevation in the ratio of 24-hour urinary tetrahydrocompound S (metabolite of 11-deoxycortisol) to tetrahydrocompound F (metabolite of cortisol).
Both forms of adrenal hyperplasia are accompanied by elevated levels of 24-hour urinary 17-ketosteroids, the urinary metabolites of adrenal androgens.
3-beta-hydroxysteroid dehydrogenase deficiency is indicated by an abnormal ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and dehydroepiandrosterone to androstenedione.
Salt-wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone concentrations, hyponatremia (see Serum Sodium), hyperkalemia (see Potassium), and elevated plasma renin activity (PRA), indicating hypovolemia. In contrast, hypertensive forms of adrenal hyperplasia (ie, 11-beta-hydroxylase deficiency and 17-alpha-hydroxylase deficiency) are associated with suppressed PRA and, often, hypokalemia.
Subtle forms of adrenal hyperplasia (as in nonclassic forms of 21-hydroxylase deficiency and nonclassic 3-beta-hydroxysteroid dehydrogenase deficiency) often require a synthetic corticotropin (Cortrosyn) stimulation test to demonstrate the abnormal accumulation of precursor steroids. Nomograms are available for interpreting the results. [5]
Imaging Studies
Imaging studies of the adrenal gland are generally not useful in the evaluation of patients with suspected adrenal hyperplasia. However, CT scanning of the adrenal gland can be useful in excluding bilateral adrenal hemorrhage in patients with signs of acute adrenal failure without ambiguous genitalia or other clues of adrenal hyperplasia. [6]
Pelvic ultrasonography may be performed in an infant with ambiguous genitalia to demonstrate a uterus or associated renal anomalies, which are sometimes found in other conditions that may result in ambiguous genitalia (eg, mixed gonadal dysgenesis, Denys-Drash syndrome).
Urogenitography is often helpful in defining the anatomy of the internal genitalia.
A bone-age study is useful in evaluating a child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth. Patients who have these symptoms because of adrenal hyperplasia have advanced skeletal maturation.
Other Tests
A karyotype is essential in the evaluation of an infant with ambiguous genitalia to establish the patient's chromosomal sex.
Genetic testing is rarely necessary to diagnose classic forms of adrenal hyperplasia but is essential for genetic counseling and prenatal diagnosis of adrenal hyperplasia. [2]
Newborn screening programs for 21-hydroxylase deficiency should be encouraged as they may be lifesaving in an affected male infant who would otherwise be undetected until presentation with a salt-wasting crisis. [7]
Histologic Findings
Histologic features of congenital adrenal hyperplasia include hyperplasia of the adrenal cortex and disorganized architecture of both the adrenal cortices and medullae.
Lipoid deposits in the adrenal cortical cells characterize lipoid adrenal hyperplasia due to a deficiency of StAR. Lipoid deposits are thought to represent cholesterol esters that have accumulated from the inability of the cell to transport cholesterol into the mitochondria.
With salt wasting, hypertrophy of the juxtaglomerular apparatus of the kidney occurs due to hypovolemia stimulating enhanced renin activity.
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Enzymes and genes involved in adrenal steroidogenesis.
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Steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis. A mutation or deletion of any of the genes that code for enzymes involved in cortisol or aldosterone synthesis results in congenital adrenal hyperplasia. The particular phenotype that results depends on the sex of the individual, the location of the block in synthesis, and the severity of the genetic deletion or mutation.
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A female patient with the 46,XX karyotype with mild virilization due to congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency. Despite the mild clitoromegaly, this patient has fusion of the labial-scrotal folds and salt wasting.
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Severe virilization in a female patient with the 46,XX karyotype with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. This patient also has salt wasting.
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Short stature in a male patient with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. His compliance with medical therapy was poor, and early growth and skeletal maturation was advanced, resulting in early puberty and completion of growth. This 12-year-old boy has reached final adult height, which is well below that of his mother.
