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III. Disorders of Sex Differentiation - A General Outline

Sex differentiation is a complex physiological process comprised of many steps. Problems associated with sex differentiation, or syndromes of intersexuality, occur when errors in development take place at any of these steps.

Genetic Sex

Problems can arise at fertilization when chromosomal sex is established. For example, girls with Turner Syndrome have a 45,XO karyotype and boys with Klinefelter Syndrome have a 47,XXY karyotype. It is also known that some women have a 46,XY or 47,XXX karyotype and some men a 46,XX or 47,XYY karyotype. Clearly then, when it is stated that 46,XY refers to male sex and 46,XX refers to female sex, this is a generalization which applies to most, but not all, individuals.

Gonadal Sex

Disorders of sex differentiation can occur when a bipotential gonad is incapable of developing into a testis or an ovary. The inability to develop testes may occur if a gene such as SRY is absent or deficient. When this is the case, a 46,XY fetus will not receive the SRY signal to develop testes despite the presence of a Y chromosome. Additionally, 46,XY fetuses may begin to develop testes, but this development can be thwarted, and subsequently MIS and androgen production may be absent or diminished.

Finally, the normal disappearance of germ cells associated with ovarian development in fetuses is so accelerated in Turner Syndrome that by birth these babies possess gonadal streaks as opposed to normal ovaries.

Mullerian and Wolffian Duct Development

Intersexuality can also result as a consequence of problems related to Mullerian or Wolffian duct development. For example, MIS secretion accompanied by the absence of androgens or the inability to respond to androgens can result in a fetus lacking both male and female internal duct structures. In contrast, the absence of MIS accompanied by androgen secretion can result in a fetus possessing both male and female internal duct structures to varying degrees.

External Genitalia

Babies born with sex differentiation syndromes possess external genitalia that can usually be classified as either:

  1. normal female
  2. ambiguous
  3. normal male but with a very small penis (micropenis)

Normal female external genitalia develop among 46,XY intersex patients when the genital tubercle, genital swellings, and genital folds either completely lack exposure to, or are totally incapable of responding to, male hormones. As a result, masculinization of the external genital structures is not possible. In such cases, the genital tubercle develops into a clitoris, the genital swellings develop into the labia majora and the genital folds develop into the labia minora.

Ambiguous external genitalia develop in female patients when the external genital structures are exposed to greater-than-normal amounts of male hormones (masculinized females) or in male patients when less-than-normal amounts of male hormones (under-masculinized males) occurs. Thus, in these patients, external genitalia develop in a manner that is neither female nor male, but rather is somewhere in between the two.

For instance, patients with ambiguous external genitalia may possess a phallus which ranges in size from resembling a large clitoris to a small penis. Additionally, these patients may possess a structure that resembles partially fused labia or a split scrotum. Finally, patients with ambiguous external genitalia often possess a urethral (urinary) opening that is not at the tip of the phallus (normal male position), but is instead located elsewhere on the phallus or perineum. The atypical positioning of the urethra in such instances is referred to as hypospadius.

Babies born with a penis that is much smaller than normal (micropenis) have a completely normal appearing external genitalia (i.e)., the urethra is properly located at the tip of the phallus and the scrotum is completely fused). However, the size of the phallus is closer to that of a normal clitoris than a normal penis.

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