Ambiguous Genitalia
Jennifer A. Danzig
Lorraine E. Levitt Katz
INTRODUCTION
Genitalia are defined as ambiguous when it is not possible to categorize the gender of the child based on outward appearances. Abnormalities in external genitalia that require endocrine evaluation occur in 1 out of every 4,500 births. Ambiguous genitalia may be associated with genotypic females who are virilized, genotypic males who are undermasculinized, problems of gonadal differentiation, and congenital embryopathy.
Sexual Differentiation
Management of patients with sexual ambiguity requires an understanding of normal sexual differentiation. The primitive gonad is bipotential, containing both ovarian (cortical) and testicular (medullary) components. Sexual differentiation is determined by the genetic information contained in the sex chromosomes, as well as by hormonal factors. Pseudohermaphroditism occurs when the external genitalia do not correspond to the chromosomal or gonadal sex (i.e., an XX female who is masculinized or an XY male who is inadequately masculinized). The internal genitalia develop normally.
Male Sexual Differentiation
The SRY gene (i.e., the sex-determining region) on the short arm of the Y chromosome is the primary testis-determining factor. Additional genetic factors important to sexual differentiation include DAX-1, SOX-9, and Wnt-4. The transcription factors WT1 and SF-1 are necessary for gonadal development. Testisdetermining factor induces the bipotential gonads to develop as testes by 6 to 7 weeks of gestation. At 7 to 8 weeks of gestation, Sertoli cells in the testes secrete anti-müllerian hormone (AMH), also called müllerian-inhibiting substance (MIS), which causes regression of the müllerian ducts in the male fetus.
Human chorionic gonadotropin (HCG) and fetal pituitary gonadotropin stimulate the Leydig cells in the fetal testes to secrete testosterone, which causes the wolffian structures to develop into the vas deferens, epididymis, and seminal vesicles. Testosterone is converted locally to dihydrotestosterone (DHT) by 5α-reductase. DHT is necessary for the development of the scrotum and phallus from the labial scrotal folds and the genital tubercle.
Female Sexual Differentiation
The differentiation of the bipotential gonad into an ovary by 10 weeks of gestation requires that two X chromosomes be present and that the Y chromosome (i.e., the SRY gene) be absent. Because MIS is not produced, the müllerian ducts develop into the uterus, the fallopian tubes, and the upper two-thirds of the vagina. In the absence of androgens, the wolffian ducts degenerate, the external genitalia differentiates as the clitoris and labia, and the urogenital sinus becomes the lower third of the vagina and urethra.
DIFFERENTIAL DIAGNOSIS LIST
HINT: The most common cause of virilization in a female is 21-hydroxylase deficiency. The most common cause of undervirilization in a male is androgen insensitivity syndrome (AIS).Virilized Genetic Female (Female Pseudohermaphroditism)
Congenital adrenal hyperplasia (CAH)—21-hydroxylase deficiency, 3 β-hydroxysteroid dehydrogenase deficiency, 11 β-hydroxylase deficiency
Exogenous androgen exposure—exogenous, excess androgen production
Aromatase Deficiency
Undervirilized Genetic Male (Male Pseudohermaphroditism)
Androgen Insensitivity Syndrome (AIS) and partial androgen receptor defects
CAH—Steroidogenic acute regulatory protein (StAR) deficiency, 17, 20-desmolase deficiency, 3 β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase deficiency
Other androgen synthesis defects—17-lyase deficiency, 17-ketosteroid reductase deficiency, 5α-reductase deficiency, Smith-Lemli-Opitz syndrome
Persistent müllerian duct syndrome Leydig cell hypoplasia
Gonadal Dysgenesis
Partial Gonadal Dysgenesis
Mixed Gonadal Dysgenesis—Chromosomal Aberrations (XO/XY, XX/XY)
True Hermaphroditism
Congenital Embryopathy
DIFFERENTIAL DIAGNOSIS DISCUSSION
Virilized Genetic Female
Etiology
Virilization of the genotypic female fetus is usually caused by androgens produced by the fetus or transferred across the placenta. Androgen exposure before 12 weeks of gestation results in interference of septation of the urogenital sinus and some
degree of labial scrotal fusion. After 12 weeks of gestation, androgen exposure can cause clitoral enlargement but not labial scrotal fusion. The following are sources of androgen exposure:
degree of labial scrotal fusion. After 12 weeks of gestation, androgen exposure can cause clitoral enlargement but not labial scrotal fusion. The following are sources of androgen exposure:
Congenital Adrenal Hyperplasia (CAH). This is the most common cause of virilization in genetic females and 21-hydroxylase deficiency represents 90% of cases of CAH. CAH is an autosomal recessive disorder caused by enzymatic defects in cortisol synthesis. Deficient cortisol causes a rise in corticotropin releasing hormone and adrenocorticotropic hormone (ACTH), which stimulates adrenal hyperplasia. As a result, adrenal androgen and steroid precursors prior to the enzyme defect accumulate. 21-Hydroxylase deficiency causes impaired production of cortisol and aldosterone and infants are susceptible to adrenal crisis. 11 β-Hydroxylase deficiency is the second most common cause of CAH and has similar clinical features except elevated 11-deoxycortisol and 11-deoxycorticosterone result in hypertension. 3 β-Hydroxysteroid dehydrogenase deficiency results in impaired cortisol, aldosterone, and testosterone biosynthesis. Affected females have mild virilization due to peripheral conversion of elevated DHEA to androgens.
Clinical Features
The external genitalia are virilized. Patients with 21-hydroxylase or 3 β-hydroxysteroid dehydrogenase deficiencies may present with salt-losing crises within a few weeks of birth.
Evaluation
The diagnosis of CAH can be made by obtaining baseline steroid measurements and steroid measurements following ACTH administration (Tables 12-1, 12-2 and 12-3). Baseline and stimulated steroid levels are elevated.
Treatment
Patients with CAH should receive cortisol and mineralocorticoid replacement as needed. Cosmetic surgical repair may be appropriate for all patients.
TABLE 12-1 Clinical and Biochemical Features of Congenital Adrenal Hyperplasia (CAH) | |||||||||||||||||||||||||||||||||||||
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TABLE 12-2 Normal Serum Adrenal Steroid Levels in Newborn Infants | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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