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

Table 63–1   Hormonal and Genetic Aspects of Disorders of Sexual Differentiation 

46,XY Disorders of Sexual Determination (DSD)

The SRY gene, a 35-kb region located on Yp11.3, is a key genetic component of sex determination. A mutation or deletion in this region will cause maldevelopment of testicular tissue which affects both internal and external genitalia. Approximately 1:20,000 live births are affected with one of the following conditions:

  1. Complete gonadal dysgenesis (CGD): Also known as Swyer syndrome or 46,XY pure gonadal dysgenesis. Only 15% to 20% with CGD have been identified to have a defect in the SRY gene. Patients are born without normal testicular tissue (streak gonads) bilaterally and express phenotypic female external and internal genitalia. Subjects are assigned the female sex and go unrecognized at birth. Streak gonads may be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved.

    Diagnosis is made during adolescence or adulthood due to pubertal delay, lack of secondary sexual characteristics, or primary amenorrhea. In CGD, if breast tissue develops or menstruation occurs, an estrogen-secreting tumor should be suspected and must be investigated. Stature is normal to tall with eunuchoid habitus. A pelvic ultrasound reveals a normal vagina, uterus, and fallopian tubes with the absence of Wolffian structures and ovaries. Serum markers showing hypergonadotropic hypogonadism along with a karyotype and ultrasound of the internal organs can help make the proper diagnosis. Diagnosis is based on the appearance and histologic features of both gonads. The risk of gonadal tumors is 30% if testicular tissue is identified.

  2. Mixed or partial gonadal dysgenesis (GD):

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Jun 2, 2016 | Posted by in HUMAN BIOLOGY & GENETICS | Comments Off on 63: Disorders of Sexual Differentiation
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