A number of abnormal karyotypes involving the sex chromosomes, ranging from 45,X to 49,XXXXY, are compatible with life. Indeed, phenotypically normal males with two and even three Y chromosomes have been identified. Such extreme karyotypic deviations are not encountered with the autosomes. In large part, this latitude relates to two factors: lyonization of X chromosomes and the small amount of genetic information carried by the Y chromosome. The consideration of lyonization must begin with Mary Lyon, who in 1962 proposed that in females, only one X chromosome is genetically active. X inactivation occurs early in fetal life, about 16 days after conception. Either the paternal or the maternal X chromosome is randomly inactivated in each cell of the developing embryo. Once inactivated, the same X chromosome remains inactive in all of the progeny of these cells. Moreover, all but one X chromosome is inactivated, and so a 48,XXXX female has only one active X chromosome. This phenomenon explains why normal females do not have a double dose (compared with males) of phenotypic attributes encoded on the X chromosome. The Lyon hypothesis also explains why normal females are in reality mosaics, containing two cell populations: one with an active maternal X, the other with an active paternal X. The molecular basis of X inactivation involves a long non–coding RNA that is encoded by the XIST gene. This non–coding RNA is retained in the nucleus, where it “coats” the X chromosome that it is transcribed from and silences the genes on that chromosome. The other XIST allele is switched off in the active X, allowing genes encoded one one X chromosome to be expressed.
Although essentially accurate, the Lyon hypothesis subsequently has been somewhat modified. Most important, the initial presumption that all of the genes on the inactive X are “switched off” has been revised, as roughly 21% of genes on Xp, and a smaller number (3%) on Xq, escape X inactivation. This observation has implications for monosomic X chromosome disorders, or Turner syndrome, as discussed later.
Extra Y chromosomes are readily tolerated because the only information known to be carried on the Y chromosome seems to relate to male differentiation. Of note, whatever the number of X chromosomes, the presence of a Y invariably dictates the male phenotype. The gene for male differentiation (SRY, sex-determining region of Y chromosome) is located on the short arm of the Y.
Described briefly next are two disorders, Klinefelter syndrome and Turner syndrome, that result from aberrations of sex chromosomes.
Klinefelter syndrome is defined as male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes. It is the most common cause of hypogonadism in males. Most affected patients have a 47,XXY karyotype. This karyotype results from non-disjunction of sex chromosomes during meiosis. The extra X chromosome may be of either maternal or paternal origin. Advanced maternal age and a history of irradiation in either parent may contribute to the meiotic error resulting in this condition. Approximately 15% of the patients show mosaic patterns, including 46,XY/47,XXY, 47,XXY/48,XXXY, and variations on this theme. The presence of a 46,XY line in mosaics usually is associated with a milder clinical condition.
Klinefelter syndrome is associated with a wide range of clinical manifestations. In some persons it may be expressed only as hypogonadism, but most patients have a distinctive body habitus with an increase in length between the soles and the pubic bone, which creates the appearance of an elongated body. Also characteristic is eunuchoid body habitus. Reduced facial, body, and pubic hair and gynecomastia also are frequently seen. The testes are markedly reduced in size, sometimes to only 2 cm in greatest dimension. In keeping with the testicular atrophy, the serum testosterone levels are lower than normal, and urinary gonadotropin levels are elevated.