An eight-year-old girl presented with abnormal secondary sexual development. The patient had no notable medical history and was taking no medication.
On examination, her breast development was classified as Tanner stage 1 and her pubic hair development as Tanner stage 3. She had an enlarged clitoris (see accompanying figure) and mild acne on her face. Her height was 4 ft, 6 in (138 cm), and her weight was 70.5 lb (32 kg).
Laboratory studies showed a basal 17-hydroxyprogesterone (17-OHP) level of 5,860 ng per dL (the normal reference range for prepubescent girls is less than 110 ng per dL); a total testosterone level of 56 ng per dL (1.94 nmol per L; reference range is less than 32 ng per dL [1.11 nmol per L]); and a dehydroepiandrosterone sulfate level of 87 mcg per dL (2.35 μmol per L; reference range is 3 to 85 mcg per dL [0.08 to 2.29 μmol per L]).
The answer is B: nonclassic congenital adrenal hyperplasia. In contrast to the classic form, patients with nonclassic congenital adrenal hyperplasia have no symptoms or signs at birth. Congenital adrenal hyperplasia is a disorder of cortisol biosynthesis, commonly triggered by 21-hydroxylase deficiency.1,2 Because of 21-hydroxylase deficiency, overproduced cortisol precursors shunt onto the adrenal production of androgens. Thus, congenital adrenal hyperplasia related to 21-hydroxylase deficiency is characterized by impaired cortisol biosynthesis and androgen excess, with or without aldosterone deficiency.
Different degrees of enzyme function loss are caused by CYP21 gene mutation, which has two clinical phenotypes: classic and nonclassic congenital adrenal hyperplasia. Female infants with the classic form have ambiguous genitalia at birth, with or without salt loss.2 Because of hyperandrogenemia, patients with the nonclassic form develop a broad spectrum of clinical manifestations later in childhood or early adulthood.1,3 The symptoms may include precocious puberty, clitoromegaly, and acne in children; or hirsutism, acne, alopecia, infertility, oligomenorrhea/amenorrhea, clitoromegaly, and polycystic ovaries in early adulthood. Studies suggest that patients with congenital adrenal hyperplasia are at increased risk of metabolic syndrome.1 Nonclassic congenital adrenal hyperplasia may be misdiagnosed as polycystic ovary syndrome because their clinical manifestations overlap.
The corticotropin stimulation test may be needed for diagnosis of nonclassic congenital adrenal hyperplasia. The test relies on the measurement of 17-OHP before and one hour after intravenous administration of 0.25 mg of cosyntropin (Cortrosyn), a synthetic version of adrenocorticotropic hormone. If 17-OHP is within the normal range, a corticotropin stimulation test should be performed. Elevated basal 17-OHP levels are diagnostic.
Patients with symptomatic nonclassic congenital adrenal hyperplasia should be treated with glucocorticoids to suppress androgen excess. Hydrocortisone is the glucocorticoid of choice for children.1 Unlike with the classic form, patients with nonclassic congenital adrenal hyperplasia do not need stress doses of hydrocortisone.
Adrenocortical carcinomas are more common in children than adults. Generally, these tumors are functional, or hormone-producing. Because of secretion of androgens (dehydroepiandrosterone sulfate), virilization is the most common clinical manifestation in girls. Adrenocortical carcinoma can be diagnosed with computed tomography of the adrenal glands.4
Premature adrenarche is the precocious activation of zona reticularis for unknown reasons. In girls, the condition leads to the development of pubic hair before eight years of age without other signs of puberty. However, premature adrenarche does not lead to clitoromegaly, and androgen levels are normal for the stage of pubic hair development. Many girls with premature adrenarche develop clinical features of polycystic ovary syndrome in adulthood.5,6
|Adrenocortical carcinoma||Generally functional (hormone-producing); virilization common in girls; diagnosed with computed tomography of adrenal glands|
|Nonclassic congenital adrenal hyperplasia||No signs or symptoms at birth, unlike classic form; hyperandrogenemia leads to symptoms in childhood or early adulthood; elevated basal 17-OHP levels are diagnostic, but corticotropin stimulation test warranted if 17-OHP levels are normal|
|Premature adrenarche||Precocious activation of zona reticularis for unknown reasons; pubic hair before eight years of age without other signs of puberty; normal androgen levels|
|Sex cord-stromal tumors||Arise from gonadal nongerminative component; often functional; may produce androgens leading to clinical manifestations of hyperandrogenism; ovarian imaging findings abnormal|
Sex cord-stromal tumors arise from the gonadal nongerminative component, have low malignant potential, and are often functional. Some of these tumors, such as Sertoli-Leydig cell tumor and Leydig cell tumor, can produce androgens, mainly testosterone. Accordingly, patients develop clinical manifestations of hyperandrogenism, and findings on ovarian imaging studies are abnormal. Surgical resection is the mainstay of treatment for ovarian and adrenocortical tumors.4