63: Disorders of Sexual Differentiation

Key Points

• Disease summary:

  • Genetic sex is determined by the paternally inherited X or Y chromosome. Once established sexual determination, the commitment of the primordial gonads to becoming testes or ovaries, will follow and lead to the final phase of sexual differentiation which is the subsequent development of the internal and external genitalia. Sexual differentiation under normal circumstances is under the control of a 35 kb region of the Y chromosome known as the SRY gene. A defect anywhere in this process can cause disorders of sexual differentiation and can be classified as one of the following:

  • 46,XY disorders of gonadal determination

  • 46,XX disorders of gonadal determination

  • 46,XY disorders of androgen biosynthesis and action

  • Luteinizing hormone (LH) receptor defects

  • Disorders of antimüllerian hormone (AMH) or antimüllerian hormone receptor

  • Androgen excess

• Monogenic forms:

  • All enzymatic defects associated with the adrenals are monogenic.

• Family history:

  • A pedigree of at least three generations should be obtained to evaluate consanguinity.

• Environmental factors:

  • Fetal exposure to compounds with estrogenic effects (xenoestrogens) such as herbicides, pesticides, polychlorinated biphenyls (PCBs), polystyrenes, as well as antiandrogens such as the polyaromatic hydrocarbons, linuron, vinclozolin. Androgen exposure includes inadvertent contact by the mother with testosterone creams used by a family member or the mother taking progestin-containing oral contraceptives.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for Sexual Differentiation

Diagnostic criteria should include

All those being evaluated for a disorder of sexual differentiation will need a rapid and complete evaluation including

1. Serum hormone concentrations

2. Genotype

3. Extensive pedigree searching for abnormalities of sex development in family members including infertility

Clinical Characteristics

Clinical and Genetic Features of Sexual Differentiation

See Table 63-1.