Evaluation and management of the newborn with ambiguous genitalia should be immediately evaluated for potential life-threatening, salt-wasting form of congenital adrenal hyperplasia (CAH). Due to the complexity of the medical, emotional, and psychosocial dilemma, early intervention is essential.

Two main disorders are seen with ambiguous genitalia: disorders of gonadal differentiation (gonadal dysgenesis and true hermaphroditism) and disorders of steroidogenesis (CAH, 5α-reductase deficiency, and androgen insensitivity). Other causes include androgen insensitivity, maternal hyperandrogenism, and environmental or drug exposure.

The newborn with gonadal dysgenesis is a phenotypic male infant with a 46, XX karyotype who can present at birth with abnormal genitalia ranging from cryptorchidism to significant genital ambiguity, or a phenotypic female with 46, XY karyotype who may not be diagnosed at birth. The usual diagnosis is made when the patient presents with delayed puberty or primary amenorrhea. These patients usually have Müllerian structures due to the absence of anti-Müllerian hormone. Both of these diagnoses are usually associated with infertility. They may also have phenotypic characteristics of Turner syndrome (webbed neck, short stature, shield chest) due to the 45, X cell lines. Patients with streak gonads are at increase risk for neoplastic transformation.

True hermaphroditism may present with a spectrum of genital ambiguity. They have both ovarian tissue with mature Graafian follicles and testicular tissue with seminiferous tubules present on histologic evaluation. Both Müllerian and Wolffian ductal structures may be present. Fertility is variable.

Steroidogenesis begins with the conversion of cholesterol to pregnenolone. The adrenal gland produces enzymes related to the production of cortisol and aldosterone, and the gonads express enzymes related to the production of androgens and sex steroids. One of the most frequently encountered mutations is the 21-hydroxylase gene. The female infant will present with variable degrees of virilization. The male infant will be diagnosed when signs of mineralocorticoid insufficiency are observed (electrolyte disturbance, dehydration) as in the classical salt-losing CAH, or early pubic hair development as in nonclassical CAH. Other forms of CAH with ambiguous genitalia includes 11β-hydroxylase deficiency (female virilization, glucocorticoid insufficiency, and hypertension), 3β-hydroxysteroid dehydrogenase (HSD) deficiency (female virilization, male external undervirilization, with corticosteroid, and possibly mineralocorticoid, insufficiency), and more rare conditions include 17α-hydroxylase/17,20-lyase deficiency and 17β-HSD deficiency.