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KEY POINTS
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Key Points

  • Incidence is 1 in 5,000 livebirths. Most common cause is congenital adrenal hyperplasia (CAH), resulting in a virilized genetic female. This autosomal recessive condition has an incidence of 1 in 14,000 livebirths.

  • Prenatal classification of ambiguous genitalia is based on cause. Fetuses can be virilized genetic females, undervirilized genetic males, or true hermaphrodites with both ovarian and testicular tissue present.

  • Sonographic prenatal diagnosis of ambiguous genitalia is more accurate in males. Clitoromegaly is associated with false-positive diagnosis in females. The presence of a normal fetal uterus after 19 weeks is strongly predictive of a virilized genetic female.

  • Differential diagnosis in a virilized female includes androgen exposure due to CAH or maternal tumors. An undervirilized male may be due to defects in the synthesis of testosterone or its precursor, androgen insensitivity, chromosome abnormalities, or true hermaphroditism. Single-gene disorders, such as Smith–Lemli–Opitz syndrome, should be considered.

  • Prenatal management should include fetal karyotype and testing of 7-dehydrocholesterol (7-DHC) levels in the amniotic fluid. Delivery should occur at a tertiary center.

  • Fetal treatment is available for CAH and Smith–Lemli–Opitz syndrome.

  • Infant sex assignment should occur after birth using a team approach.

  • The role of genital surgery in children with ambiguous genitalia is controversial.

  • Recurrence risk depends on the etiology of the ambiguous genitalia.

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CONDITION
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Although the genotype of a fetus is determined at conception, sexual differentiation does not occur until 6 to 7 weeks of gestation (McGillivray, 1992). Before that point, the embryo has bilateral undifferentiated gonads and both müllerian and wolffian duct systems. Fetuses with a Y chromosome containing the gene for the testis-determining factor (SRY) will convert the undifferentiated gonad to a testis, which involves the formation of seminiferous tubules that surround the primitive germ cells. As shown in Figure 84-1, Leydig cells begin to produce testosterone, which acts on the wolffian ducts to produce male internal genitalia. Sertoli cells produce anti-müllerian hormone (AMH), also known as müllerian duct inhibiting substance (MIS), which causes regression of the mullerian system (McGillivray, 1992).

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Figure 84-1

Development of genitalia in male and female fetuses. Normal sexual differentiation. SRY: sex determining region on Y chromosome; AMH: anti-Müllerian hormone; T: testosterone; DHT: dihydrotestosterone; Wnt4: Wnt = a group of secreted signaling molecules that regulate cell to cell interactions during embryogenesis; DAX1: DSS-AHC critical region of the X chromosome. (Reprinted with permission from, Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child. 2004;89:401-407.)

Graphic Jump Location
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At 6–7 weeks of gestation, the external genitalia are undifferentiated and consist of a genital tubercle, genital folds, and swellings. During male embryogenesis, masculinization of the common primordia is induced by the activity of dihydrotestosterone (DHT). DHT is formed from testosterone via the enzyme 5α-reductase. The urogenital tubercle then differentiates into the glans. The urogenital folds differentiate into the shaft ...

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