Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

    45/328 (page 23)
    CHROMOSOMAL ABNORMALITIES II: SEX CHROMOSOME DEFECTS chance alone — four times or more the expected figure. It is possible, of course, in at least some of these conditions (XXY and XXX, for instance ) that the nor¬ mal-range individuals may be those with a better-than-average genetic en¬ dowment whose potential was stunted by the chromosome abnormality; stud¬ ies of such individuals in relation to their families' mental ability would be instructive but have not (so far as I know ) been made. Certainly most sex chromosome retardates are high- grade, and in no way comparable to the idiots and imbeciles produced by, say, untreated phenylketonuria or autosomal aberrations. Once again, the more extreme chromosomal devia¬ tions seem to produce more extreme and more consistent intellectual con¬ sequences; some of these deviations have been observed only in severely retarded individuals. With most of these rare disorders, however, the number of cases is still so small that any firm generalizations about them are dangerous. One should not close this section on mental consequences without men¬ tioning the so-called criminal efi^ects of the XYY condition. A surprisingly high frequency (about 4% ) of XYY's was first shown in a group of crimi¬ nals, and peculiarly violent and incor¬ rigible ones at that. Again, however, further studies have established that the XYY condition is by no means uncommon; in fact, its incidence is now estimated as about 1 in 700 males. If all these individuals — at least 50,000 in Great Britain alone — were violent criminals, the rest of us would not be very safe! Paralleling the case of mental retardation, the XYY condition does seem, for reasons at present unclear, to be more com¬ mon among violent criminals, but to consider it as some sort of automatic criminal stigma would be wildly at variance with the facts. Turning now to the mechanisms that produce numerical anomalies in the sex chromosomes, we find, unsur¬ prisingly, that they parallel those ob¬ served in the autosomal disorders. The two sex chromosomes of either the male or female gametocyte may in one way or another fail to separate prop¬ erly at meiosis, producing gametes with neither or with both sex chromo¬ somes. Alternatively, after fertiliza¬ tion a similar anomalous segregation may occur at mitosis, producing one cell line with excess chromosomes and another with a deficiency (i.e., XO or YO), the latter presumably dying off sooner or later. (See illustrations on pages 18 and 19.) When we come to the factors that engender these anomalous segrega¬ tions we are on less certain ground. Maternal age might be expected to play a part, as is known to be the case in many autosomal anomalies, but the data support this only in the case of the XXY anomaly. Here, in fact, we have been able to amass some very detailed and refined evidence. In fam¬ ilies possessing sex-linked traits (color blindness, the Xg blood group) it is sometimes possible to identify, through study of the inheritance of the trait, the parent in whom nondisjunc¬ tion of the sex chromosomes occurred. Thus if a couple of whom the mother is Xg (a-negative) and the father Xg ( a-positive ) produce an XXY son who is Xg ( a-positive ), he must have received the positive gene via an extra X chromosome from his father ( plus, of course, the Y ) ; if he is negative, he cannot have received the paternal X but must have got two X's from the /nother. And interestingly, though not surprisingly, in cases where the extra X is traceable to the mother, maternal age seems to be a potent influence, whereas when the father is at fault, parental age —either maternal or pa¬ ternal — plays no apparent role in the occurrence of anomalies. When we consider the sources of the XO anomaly, maternal age is found not to be a factor, which makes for a puzzling contradiction. The same processes that are deemed to produce XXY should with equal probability produce XO. To be sure, the actual relative incidence of the two condi¬ tions is heavily biased by the immense intrauterine mortality of the XO em¬ bryo, but even allowing for that one would expect a maternal age effect to manifest itself in both or neither. Even more puzzling is the fact that studies by the methods just described show that in some 72% of XO indi¬ viduals the single X was contributed by the mother, i.e., in nearly three out of four cases the condition was pro¬ duced by paternal nondisjunction. If nondisjunction occurred with equal frequency in both male and female meiosis, one would expect twice as many X^'O as Xi'O conceptions (YO conceptions are inviable). It is possi¬ ble that the greater than expected excess of Х^Ю conceptions is influ¬ enced by loss of the paternal X at fertilization. Furthermore, even in the minority of XO patients where ma¬ ternal nondisjunction can be demon¬ strated, the age of the mothers ap¬ pears to follow normal distribution patterns. More research is obviously needed here. It is perhaps worth noting that autoimmune mechanisms are sus¬ pected of playing a role in at least some sex chromosome disorders. Auto¬ antibodies to various tissues turn up relatively frequently in XO individuals and their parents. But we are again faced by the contradiction with XXY, where a normal incidence of autoanti¬ bodies has been demonstrated. This poses in another form the question of how a mechanism that produces chromosome deficiency in some gam¬ etes could fail at the same time to induce chromosome excess in an equal number ( or, of course, vice versa ). Where mitotic nondisjunction occurs at a later stage of development, when a normal cell line has already been established, the result may be a mo¬ saic. (Indeed certain types of mosaics — e.g., XX/XO —may be formed even at the first division, one chromosome being lost.) In fact, the clinical ma¬ terial now on record includes a comprehensive listing of the possibili¬ ties - XX/XO, XY/XO, XX/XXY, XY/XXY, etc. The actual phenotypic manifestation of mosaicism depends of course on the proportion of abnor¬ mal cells and their location within the body, and in fact a whole series of gradations have been described rang¬ ing from the classic Turner's or Klihefelter's syndrome to a physically normal male or female with lowered (or even normal) fertility. If the mosaic includes one cell line with a Y chromosome and another without it (e.g., XO/XY, XX/XXY) the result may well be an intersex. In XX/XY and XX/XXY mosaicism the individual may be that rare form of intersex, a true hermaphrodite, and have both testes and ovaries. Some¬ times the true hermaphrodite will be 23