Atypical Sexual Differentiation: Not Always Just X and Y

Prenatal development depends on carefully orchestrated developmental stages. At any stage, sex hormone irregularities, genetic abnormalities, or exposure of the fetus to in­appropriate maternal hormones can result in atypical sexual differentiation. The result can be a child born with ambiguous genitals or with the external genitals of one sex and the genetic makeup of the other sex.

Sex Chromosome Disorders

Sometimes a person’s sex chromosomes will include an extra X or Y chromosome or will be missing one. Though medical researchers have identified over 70 such abnormalities of the sex chromosomes, we will discuss the three most common.

Klinefelter’s syndrome, which occurs in about 1 in 700 live male births, occurs when an ovum containing an extra X chromosome is fertilized by a Y sperm (designated XXY), giving a child 47 chromosomes altogether. The Y chromosome triggers the de­velopment of male genitalia, but the extra X prevents them from developing fully. Men with Klinefelter’s syndrome are tall, with feminized body contours, small testicles, low levels of testosterone, gynecomastia, and are infertile. In fact, Klinefelter’s syndrome is

the most common genetic cause of male infertility (Lanfranco et al., 2004). These men often show low levels of sexual desire, probably due to the lack of testosterone. Testosterone therapy, especially if it is begun during adolescence, can enhance the de­velopment of secondary sexual characteristics.

Turner’s syndrome is another chromosomal disorder. It is among the most common of the chromosomal disorders, occurring in 1 of every 2,500 live female births. Turner’s syn­drome results from an ovum without any sex chromosome being fertilized by an X sperm (designated XO), which gives the child only 45 chromosomes altogether (if an ovum with­out a chromosome is fertilized by a Y sperm and so contains no X sex chromosome, it will not survive). Though the external genitalia develop to look like a normal female’s, the woman’s ovaries do not develop fully, causing amenorrhea (aye-men-uh-REE-uh) and in­fertility. In addition, Turner’s syndrome is characterized by short stature, immature breast de­velopment, and abnormalities of certain internal organs (Moreno-Garcia et al., 2005). Therapeutic administration of estrogen and progesterone, especially during puberty, can help enhance some sexual characteristics and slightly increase height (Turner’s Syndrome Society, 2002).

XYY syndrome and triple X syndrome are very rare disorders. As the names imply, these syndromes occur when a normal ovum is fertilized by a sperm that has two Y chro­mosomes or two X chromosomes or when an ovum with two X chromosomes is fertilized by a normal X sperm. The XYY individual may grow up as a normal male and the XXX as a normal female, and so often their unusual genetic status is not detected. However, many do suffer from some genital abnormalities, fertility problems, and possible learning difficulties later in life. There is no effective treatment for XYY or XXX syndrome.

The median age at which a young girl is diagnosed with Turner’s syndrome is 6.6 years old, although some are not diagnosed until much later (Massa et al., 2005). Research has shown that there are many advantages to an early diagnosis.

XYY syndrome A genetic abnormality in which a male has an extra X sex chromosome; characterized by de­creased fertility, some genital abnormality, and slight mental retardation.

I triple X syndrome A genetic abnormality in which a female has an extra X sex chromosome; characterized by de­creased fertility, some genital abnormality, and slight mental retardation.

hermaphrodite Person born with fully formed ovaries and fully formed testes.

pseudohermaphrodite A person who has the gonads of one sex and the genitalia of the other or is born with am­biguous genitalia; also referred to as intersexed.

congenital adrenal hyperplasia (CAH) A disorder involving an overproduction of an­drogen in the adrenal glands that can affect males and females. Females born with this con­dition frequently have masculinized genitals be­cause of excess prenatal androgen exposure, whereas males typically experience early puber­tal changes.

Genitalia of fetally androgenizedfe­male and androgen-insensitive male with feminized genitals.

Female with Turners syndrome.

form female genitalia, and drugs can be prescribed to control adrenal output (Warne et al., 2005). Because the internal organs are unaffected, even pregnancy is possible in many CAH females. Overall, research has shown that CAH females have good long­term psychological health and social functioning (Morgan et al., 2005). Interestingly, some research has found that CAH girls choose more male-typical toys than girls with­out CAH (Pasterski et al., 2005).

CAH may also appear in newborn boys, although it is less common. No obvious ab — normalitis are often present, but 2 to 3 years prior to the onset of typical puberty, a CAH boy often experiences increased muscular strength, penile growth, an increase in pubic hair, and a deepening in the voice. The testicles, however, remain small.

Androgen-insensitivity syndrome (AIS) is, in some ways, the opposite of CAH. It is often first detected when a seemingly normal teenage girl fails to menstruate and chro­mosomal analysis discovers that she is XY, a genetic male. It is estimated that 1 in 20,000 boys are born each year with AIS (Medline Plus, 2004a). In this syndrome, although the gonads develop into testes and produce testosterone normally, for some reason the AIS individual’s cells cannot absorb it; in other words, the testosterone is there but has no ef­fect on the body. Because the Wolffian ducts did not respond to testosterone during the sexual differentiation phase, no male genitalia developed; but because the gonads, which are male, did produce Mullerian inhibiting factor, the Mullerian ducts did not develop into normal female internal organs either. The AIS individual ends up with no internal reproductive organs except two testes, which remain in the abdomen producing testos­terone that the body cannot use.

The AIS infant has the “default” female genitals, but because the Mullerian ducts also form the last third of the vagina, the infant has only a very shallow vagina. Usually the syndrome is undetected at birth, and the baby is brought up female. Because males do produce a small amount of estrogen, the breasts do develop, so it is only when the teen fails to menstruate that AIS is usually diagnosed. Surgery can then be initiated to lengthen the vagina to accommodate a penis for intercourse, though without any female internal organs, the individual remains infertile. Even though they are genetically male, most AIS individuals seem fully feminized and live as females.

Now that we have discussed the various chromosomal and hormonal conditions that may affect gender, the important question becomes, what can a parent do after a child is born with ambiguous genitals or the genitals of one sex and the genetic makeup of the other? Today’s experts recommend that no surgery be performed until the child can con­sent to it (Neergaard, 2005) because there is too much uncertainty in infancy about in­tersex conditions (Lorio, 2004; Thyen et al., 2005). This would mean waiting until a child is perhaps 3-5 years old or even older to determine whether to proceed with gen­der reassignment.