Advice on the Management of Ambiguous Genitalia to a Young Endocrinologist From Experienced Clinicians

Jean D. Wilson, M.D.; Marco A. Rivarola, M.D.; Berenice B. Mendonca, M.D., Ph.D.; Garry L. Warne, A.M., M.B.B.S., F.R.A.C.P.; Nathalie Josso, M.D., Ph.D.; Stenvert L.S. Drop, M.D., Ph.D.; Melvin M. Grumbach, M.D.

Disclosures

Semin Reprod Med. 2012;30(5):339-350. 

In This Article

Differential Diagnosis

The most common causes of ambiguous genitalia are summarized in Table 1 , Table 2 , and Table 3 . Most result from inappropriate virilization of female infants or incomplete virilization of males. In bold are shown the disorders that in the experience of the author are responsible for most cases of ambiguous genitalia in the newborn—congenital adrenal hyperplasia (CAH) in girls and either 45,X/46,XY mixed gonadal dysgenesis or partial androgen insensitivity in boys. An essential component of the work-up is to obtain a detailed family history, including probing for consanguinity or a background suggesting that the parents came from an area with a high coefficient of inbreeding. The family history should also be explored for similarly affected cases, including formes fruste of the disorder in question (such as unexplained infertility in close relatives).

It follows from the potential complications of CAH that the initial diagnostic procedures should be assessment of the karyotype of blood leukocytes and measurement of the blood level of 17-hydroxyprogesterone (to determine whether female infants are in danger of developing adrenal crisis). If the karyotype is 46,XX and CAH is present, appropriate adrenal steroid replacement therapy should be initiated promptly. If CAH is ruled out, rare causes of female virilization such as placental aromatase deficiency, virilizing tumors of the mother, exposure to exogenous androgens, and 46,XX ovotesticular DSD should be looked for.

Regardless of whether CAH is present the sex assignment in 46,XX infants with ambiguous genitalia should be female because the vast majority of these girls have female urogenital tracts and female gender role behavior at the time of expected puberty, and many have the potential for fertility.

If the karyotype is 46,XY, then androgen and gonadotropin levels should be measured, the gonads should be explored, and the urethra and/or urogenital sinus should be characterized by urethrography. In my experience, the most frequent diagnosis in this situation is partial androgen insensitivity (although only 40% or so of individuals have an identifiable mutation in the androgen receptor or a history of X-linked inheritance of the phenotype) or 45,X/46,XY mixed gonadal dysgenesis. Rare causes of ambiguous genitalia include 46,XY ovotesticular DSD or defective androgen production. In males with partial androgen insensitivity, mixed gonadal dysgenesis, or ovotesticular DSD the decision as to sex assignment depends in large part on the nature of the anatomical defect, the potential for its correction by surgery, and the possibility for fertility. Individuals with these diagnoses appear to be content in later life with the social sex assigned at birth.

A special case can be made for male sex assignment in 46,XY DSD because of a few specific diagnoses, including deficiency of steroid 5α-reductase 2 (5αR2), 17β-hydroxysteroid dehydrogenase 3 (17βHSD3), or 3β-HSD 2 or in occasional instances of 45,X/46,XY mixed gonadal dysgenesis. Only the first two of these disorders (5αR2 and 17βHSD3 deficiencies) are common enough to have been studied in detail, but approximately half of 46,XY males with these autosomal recessive disorders who are raised as females undergo a change in social sex to male at the approximate time of expected puberty. In view of this change in gender role behavior and because fertility has occurred in several men with 5αR2 deficiency, my practice (after careful discussions with the parents) is to lean toward male sex assignment (provided that assignment as a male is anatomically practical) and to institute intermittent androgen therapy early to improve the chances for successful hypospadias repair and orchiopexy.

As to surgical interventions in children with ambiguous genitalia, the minimal amount of surgery should be performed in childhood in those raised as girls. This belief is based upon the fact that if the cause of the virilization is discovered and corrected (as by adequate glucocorticoid replacement in girls with CAH), the enlarged clitoris will either cease to grow or regress in size. In view of the fact that it is not known whether clitoral recession has a detrimental effect on sensation in the clitoris, it follows that surgery should be avoided unless it is absolutely necessary (as in the rare cases of a penile urethra in 21-hydroxylase deficiency or the unfortunate situation in which CAH is undertreated and phallic growth continues). Likewise, repair of short vaginas should be delayed until such time as the girl is ready for an active sex life and then should be accomplished by the McIndoe procedure rather than by surgical means.

The situation in boys is somewhat different in that severe hypospadias frequently causes spraying of urine and hence requires that the boy sit for urination. Consequently, hypospadias repair should be undertaken before the boy starts to school so that he can urinate standing up. At the same time any cryptorchidism should be corrected to enhance the likelihood of fertility. Many boys with sexual ambiguity have defects in androgen production, androgen metabolism, or androgen action and androgen therapy at the appropriate time may promote sexual virilization and maturation. However, in boys with partial androgen insensitivity androgen therapy may produce only limited effects. Nevertheless, many such boys have sperm production at the time of sexual maturity, and in others assisted fertilization by intracytoplasmic sperm injection (ICSI) is successful.

In addition to ambiguous genitalia, other forms of DSD that may be recognized at birth or in early childhood include gonadal dysgenesis (because of variable features of the Turner phenotype), complete androgen insensitivity (because of palpable testes in the labia majora or the presence of inguinal hernias), and the Klinefelter syndrome (because of the cognitive features). In all these disorders the sex assignment should not be influenced by the diagnosis.

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