Ambiguous genitalia are present when the sex of an infant is not readily apparent after examination of the external genitalia. If the appearance resembles neither a male with a normal phallus and palpable testes nor a female with an unfused vaginal orifice and absence of an enlarged phallic structure, the genitalia are ambiguous, and investigation before gender assignment is indicated. The recent trend has been to refer to these disorders as disorders of sex development (DSDs) because many of the other terms used are considered pejorative by some patients and professionals. Also, the term “atypical genitalia” instead of “ambiguous genitalia” has been suggested. New definitions and classifications are also being proposed in this already very complex area. For the purpose of this on-call manual, the embryology and pathophysiology are reviewed as relevant to the initial evaluation and treatment of patients in the neonatal period.
The quoted incidence of ambiguous genitalia varies according to the source and is likely somewhat variable for different ethnic groups; it appears to be ∼1 in 5000. Congenital adrenal hyperplasia is often considered the most common cause with an incidence quoted from 1 in 14,000 to 1 in 28,000, followed by androgen insensitivity and mixed gonadal dysgenesis. Hypospadias has a frequency of about 1 in 300 births, but only a minority of these patients has a disorder of sex development (usually presenting with hypospadias in combination with cryptorchidism).
The early fetus, regardless of the genetic sex (XX or XY), is bipotential and can undergo either male or female differentiation. The innate tendency of the embryo is to differentiate along female lines.
Development of the gonads. Gonadal development occurs during the embryonic period (the third through the seventh to eighth weeks of gestation).
Testicular differentiation. Gonadal differentiation is determined by the absence or presence of the Y chromosome. If the Y chromosome (more specifically, the sex-determining region of the Y or SRY gene) is present, the gonads differentiate as testes. The testes then produce and release testosterone, which is converted to dihydrotestosterone (DHT) in the target organ cells by 5α-reductase. DHT induces male differentiation of the external genitalia (see Section III.B.1). The testes descend behind the peritoneum and normally reach the scrotum by the eighth or ninth month.
Ovarian differentiation. In the female fetus, where the Y chromosome/SRY gene is absent, the gonads form ovaries (even in 45,X Turner syndrome, histologically normal ovaries are present at birth). As ovaries do not produce testosterone, female differentiation proceeds. Two X chromosomes are needed for differentiation of the primordial follicle. If part or all of the second X chromosome is missing, ovarian development fails, resulting in atrophic, whitish, streaky gonads by 1–2 years of age.
Development of external genitalia. This part of sexual differentiation occurs in the fetal period, beginning in the seventh week of gestation, ...