A REMARKABLE CHANGE has occurred in recent years in our concept of

Transcription

1 The Natural History of Klinefelter's Syndrome MURRAY L. BARR, M.D., F.R.C.P.(C) A REMARKABLE CHANGE has occurred in recent years in our concept of the cause of Klinefelter's syndrome. There have been several milestones as investigation of the syndrome progressed. Although isolated reports appeared in the earlier literature, a definitive syndrome was not recognized until 1942, when Klinefelter et al. published their much-quoted account of 9 adult males who had certain features in common. The features were: small testes with varying degrees of fibrosis of the seminiferous tubules but abundant Leydig cells, gynecomastia, increased urinary excretion of follicle-stimulating hormone (FSH)-approaching castrate levels, and normal or decreased excretion of 17 -ketosteroids. Those authors suggested that the syndrome was one of primary failure of testicular function, cause unknown. The increase in FSH excretion was attributed to failure of the seminiferous epithelium to secrete a hypothetical hormone, called the X hormone, which would normally have inhibited FSH secretion by the pituitary through one of the many endocrine feed-back mechanisms. The report of Klinefelter et al. led others, particularly Nelson and Heller, to search for similar males, and induction centers of the United States armed forces during World War II provided an opportunity to examine large numbers of adult males. As a result of clinical, endocrine, and testis biopsy studies, the delineation of the syndrome was modified. It became apparent that the only constant components of the syndrome were (1) small testes with fibrosis of the seminiferous tubules and intact Leydig cells, leading to azoospermia or severe oligospermia, and (2) an elevation of urinary excretion of FSH. The other clinical signs present in the 9 cases of Klinefelter et al., gynecomastia, eunuchoidism, tallness, high-pitched voice, etc., were variable in degree and not always evident. The disorder continued to be viewed as a primary failure of t~sticu]ar function, still of unknown etiology. From the Department of Anatomy, Health Sciences Centre, University of Western Ontario, and the Children's Psychiatric Research Institute, London, Canada. Based on the Ayerst Lecture, given at the 22nd Annual Meeting of the American Fertility Society, Chicago, Ill., Apr. 29-May 1,

2 430 BARR FERTILITY & STERILITY The next major development was made possible by the introduction of tests of nuclear sex, especially the buccal smear test. In 1956, Bunge and Bradbury, as well as Plunkett and Barr, found that the cell nuclei of males with the Klinefelter syndrome were indistinguishable from those of females-le., they were sex chromatin-positive. This finding made necessary an entirely new look at the cause of the syndrome. The precise origin of the sex chromatin was not known in 1956 and the era of chromosome analysis, although just around the corner, was not quite with us yet. It was reasonably clear, however, that the chromatin-positive Klinefelter patient must have two X chromosomes, whatever the precise sex chromosome complex might be. Technical improvements in cell culture and cytology soon made possible the objective analysis of the human chromosome complement. Ford et al., and Jacobs and Strong, were prompt in applying the techniques of chromosome analysis to the phenotypenuclear sex contradiction of Klinefelter's syndrome, showing in 1959 that the sex chromosome complex was XXY. Still other sex chromosome complexes are now known to cause the syndrome; they have in common the presence of at least two X chromosomes and at least one Y chromosome. From a strictly chromosomal point of view, the genetic guidance is intersexual since two X chromosomes appear to be a requirement for fully normal female development and the Y chromosome is definitely maledetermining. This much is now established, although a good deal remains in doubt about the pathogenesis of certain aspects of the syndrome, starting from the known chromosomal error as the etiological factor. TERMINOLOGY About one~fourth of males who qualify for a clinical diagnosis of Klinefelter's syndrome have a negative sex chromatin pattern and an XY sex chromosome complex. This is sometimes referred to as the "false" Klinefelter syndrome. Testicular histopathology tends to be less severe in the "false" than in the "true" or chromatin-positive form of the syndrome, but in fact they can only be distinguished with certainty by the buccal smear test. This paper is concerned with demonstrably chromatin-positive males, leaving for further investigation a judgment as to the basic relationship between the chromatin-positive male and the clinically similar male with a negative sex chromatin pattern. Because the term Klinefelter syndrome is eponymous, to which some are averse, and since criteria now accepted as a basis for diagnosis differ to some extent from those recorded in the original description of Klinefelter et al., several alternative names have been suggested. They include

3 VOL. 17, No.4, 1966 KLINEFELTER'S SYNDROME 431 seminiferous tubule dysgenesis, medullal'y gonadal dysgenesis, 3!ld primary mieroorchidism. Objections can be raised to all of them. The condition known for a century as mongolism is being referred to more and more frequently as the Langdon Down syndrome or, in view of its now-known chromosomal error, the trisomy-21 syndrome (or disease). I feel that the term trisomy-21 syndrome will eventually become well established and that the others, mongolism especially, will be of historical interest. Following the same pattern, it is suggested that the Klinefelter syndrome will come to be known as the XXY syndrome (or disease). It is true that complexes such as XXYY and XXXY are also involved to some extent, but this qualification can easily be taken for granted. THE SEX CHROMOSOME ABNORMALITIES The chromosome complement encountered most frequently in these patients is one of 47 chromosomes, made up of a normal set of 44 autosomes and an XXY sex chromosome complex. In 1960, Muldal and Ockey demonstrated an XXYY complex and Ferguson-Smith et al. found an XXXY complex in Klinefelter patients. A single instance of the XXXYY error was discovered later by Bray and Sr. Josephine. The developmental history of the individual is much the same for each of these complexes. Some 30 instances of the XXXXY complex have been recorded since it was first discovered in a complement of 49 chromosomes by Fraccaro et al. in The latter sex chromosome abnormality results in special developmental errors to produce a variant of the Klinefelter syndrome or perhaps a syndrome in its own right. It is hoped that it will eventually be possible to state in some detail just how the combinations of X and Y chromosomes noted above cause the testicular pathology and other signs of the syn-. drome. This may pose a difficult problem because the addition of so many gene loci is involved. Patients in whom there is a cellular mosaicism are encountered rather frequently. A proportion of their body cells have one of the sex chromosome complexes (usually XXY) known to cause the Klinefelter syndrome. Other cells have a different sex chromosome constitution (usually either XY or XX). The phenotypic manifestations mayor may not be those of the typical syndrome, depending on the proportion and location of the different kinds of cells. The sex chromosome abnormalities must originate in an error in the transmission of sex chromosomes to daughter cells during one or two meiotic cell divisions of gametogenesis, or especially in the case of mosaics, in a mitotic division of the zygote. In appropriate families, evidence of

4 432 BARR FERTILITY & STERILITY the parental source of the extra X chromosome can be obtained by studying the inheritance pattern of X-borne genes in the Klinefelter patient and his parents. For example, Race found, using the Xg" blood group, that both XS were of maternal origin in 63% of XXY males and that in the remainder one X was contributed from the mother and the other from the father. This would suggest that the fault underlying the XXY error is in oogenesis in about two-thirds of the cases, which is consistent with the finding of a slight increase in mean maternal age in relation to the Klinefelter syndrome. But in the few XXYY males whose families were suitable for Xga testing, both Race and Waterman et al. were able to show that the error occurred during spermatogenesis and that a normal ovum with one X chromosome was fertilized by an XYY sperm. Reliable information on the frequency of the syndrome is available. There have been several buccal smear surveys of newborns; those by Moore in Winnipeg, Bergemann in Berne, and Maclean and co-workers in Edinburgh are examples. There were 30 chromatin-positive male babies among 14,526 tested in the 3 series combined. The frequency of 1:480 makes this condition the commonest of diseases caused by abnormalities of the sex chromosome complex. Since there is no significant increase in mortality associated with the disorder, the frequency found among newborns probably applies to the adult male population. This is borne out by the results of buccal smear surveys of Paulsen et al. on adult males attending a clinic and by Baikie et al. on men admitted to a general hospital. THE SEX CHROMOSOMES OF MAN Consideration of the properties of the X and Y chromosomes is best approached in the context of evolution. Among the vertebrates, morphologically differentiated sex chromosomes are not present in other than the mammalian class. In the beginning of mammalian evolution, early in the Cenozoic era, one of the significant evolutionary changes was the modification of one pair of chromosomes to form the ma~e XY pair that prevails throughout mammals. The studies of Ohno indicate that the mammalian X differs little from its premammalian precursor and that it persists in its entirety in all placental mammals of today. The X chromosome was therefore the conservative member of the pair and one is perhaps justified, in some respects, in thinking of the human X chromosome as a forty-fifth autosome. It contains large numbers of gene loci that have nothing to do with sex determination or differentiation. Many such loci have been recognized from mutant alleles, usually disease-producing, of the normal or wild-type genes. Since the gonads of the adult XO female with Turner's

5 VOL. 17, No.4, 1966 KLINEFELTER'S SYNDROME 433 syndrome lack follicles, it would appear that a double dose of certain X-borne genes are necessary for normal development of the mature ovary. The major change occurred in the other member of the pair of premammalian chromosomes that was destined to become a sex chromosome pair, that is, the one we call the Y chromosome. Much of this chromosome was lost and male-determining gene loci (or, more accurately, testispromoting loci) were concentrated in what was left, probably along with other genes that have yet to be identified. The sex-orientated genes of the Y chromosome are sufficiently potent to overcome such contrary directives as there may be from two or more X chromosomes, to the extent that testes develop in the presence of an XXY or related complex. The unusual genetic directives inherent in an XXY or similar sex chromosome complex are probably responsible for the histopathological changes in the testis at puberty. After the initial stage of embryogenesis has passed successfully, the resting nucleus of each cell, regardless of the sex chromosome complement, contains only one X chromosome that is attenuated or uncoiled (euchromatic) like the autosomes and functioning at full genetic capacity. X chromosomes in excess of one are tightly coiled and compact (heterochromatic). Each such X chromosome can be identified in the resting or intermitotic nucleus as a mass of sex chromatin. There are reasons for believing that the compact X chromosome (or chromosomes) is inactive genetically, although perhaps not completely so. One may guess that this has a biological advantage in lessening undesirable genetic differences between the female with two large X chromosomes, carrying many important genes, and the male with only one, yet permissive of the advantages of an XXjXY sex-determining mechanism. Although the principle of having only one euchromatic X chromosome per cell evolved in the context of normal XY and XX complexes, it also applies to individuals with more than two X chromosomes. This bears on the Klinefelter problem in two ways. Judging from the effect of autosomal trisomies, it is probable that the XXXY and XXXXY errors would have very serious effects on development, were it not for the protection afforded by partial inactivation of X chromosomes in excess of one. It is even possible that without X-above-one inertness the large complexes would not enter into clinical consideration at all because of a lethal effect at the embryo stage. At the practical level, a buccal smear test gives a good indication of the nature of the sex chromosome complex. A singly chromatin-positive result in a male indicates that the complex is either XXY or XXYY. If doubly chromatin-positive nuclei are found, the complex is almost certain to be

6 434 BARR FERTILITY & STERILITY XXXY or the very rare XXXYY. Nuclei with triplicated sex chromatin point to an XXXXY complex. Chromosome studies should be done where possible because of the possibility of a cellular mosaicism-e.g., XXY in some cells and XY or XX in others-in an individual with the usual type of chromatin-positive smear. DEVELOPMENT OF PERTINENT SIGNS AND SYMPTOMS Conception to Puberty The sex chromosome complexes with which we are concerned were not seen in spontaneously aborted fetuses, in several series that have been reported. For example, Carr found no Klinefelter-producing complexes in examining the chromosomes of 200 spontaneously aborted fetuses. In contrast, the XO error occurred in 11 of the 200 abortuses, which illustrates the lethality of the error that causes Turner's syndrome in the few that survive. There is some evidence, not yet conclusive, that the Klinefelter complexes may be responsible for a somewhat higher than usual mortality late in gestation. In general, however, we are able to say that the chromosome errors under consideration interfere very little with the normal course of intrauterine development. This is in striking contrast to what happens when there is an extra autosome in the chromosome complement. The baby who will develop the signs of Klinefelter's syndrome at puberty is therefore normal at birth and the abnormality is undetected unless caught in the net of a buccal smear survey. It has been suggested by some that the test should be established as a routine in all hospital deliveries. One obstetrician has stated that babies need a sex chromatin test more than they need a bath. If the test should ever become routine, I would suggest that a bit of amnion from the placenta be examined rather than a buccal smear. There is no doubt that a sex chromatin test at birth should be obligatory if, as in phenylketonuria, the progress of the disorder could be checked by some therapeutic measure. It seems to me rather excessive to introduce a routine test, except in surveys for research purposes, that will disclose an occasional genetic abnormality for which there is no effective treatment. However, this attitude may be too conservative and much depends on improvements in management that may be introduced as a result of future research. There is no sure physical sign to alert the clinician that a boy will acquire the signs of Klinefelter's syndrome at puberty. However, about 1 in 4 chromatin-positive boys is mentally retarded in varying degree. Surveys of mentally retarded children in institutions and clinics show that 1 in about 100 male retardates is sex chromatin-positive. A good case can be

7 VOL. 17, No.4, 1966 KLINEFELTER'S SYNDROME 435 made for buccal smear testing of all mentally retarded children, especially if there is no obvious cause of retardation.. Although there is still much microscopy required for each positive result, the cause of the retardation would be detected in no other way before puberty; there would be some satisfaction to parents and physician in knowing the cause of the problem, as the area of specific diagnosis in mental retardation can be so frustrating. After Puberty The harmful effects of the chromosomal errors become fully manifest at the critical milestone of puberty. The Testes. Until puberty, the testes are of normal size and consistency for the age of the child. Histologically, the prepubertal testis is also normal, with one probably significant exception. Ferguson-Smith et al. reported a distinct reduction in the number of spermatogonia in the tubules of testis biopsy specimens from 8 chromatin-positive boys between the ages of 7 and 12 years. Apparently the conflicting genetic instructions, in spite of the potency of the testis-promoting genes on the Y chromosome, interfere sometime before midchildhood with the full population of the seminiferous tubules by germ cells. The full effect of the genetic error appears at puberty, when the testes are unable to respond normally to pituitary FSH-an abnormal end-organ response on a genetic basis. It is fortunate that the embryonic gonads function normally in spite of their cells' abnormal chromosomes, and elaborate the evocator substance that masculinizes the reproductive system. Were this not so, the genitalia would probably have some kind of intersexual morphology, leading to a form of male pseudohermaphroditism. The structure of the testis becomes pathological quite quickly at the onset of puberty, with excessive development of fibrous tissue as the main characteristic. The thin supporting wall of the seminiferous tubules undergoes hyperplasia and the important component of the tubules, the lining epithelium, fails to proliferate and usually consists only of Sertoli cells. The fibrotic process often continues, with conversion of the tubule into a structureless hyaline mass, devoid of epithelium. Since the tubules fail to enlarge on FSH stimulation, but instead shrink because of fibrosis, the postpubertal testis is notable for its small size, averaging 1 cm. in diameter, or about the size of a bean. In a section of normal testis, the Leydig cells are in small groups in the intervals between the large tubules. Tubular fibrosis and sclerosis seriously distorts this architectural pattern and Leydig cells become aggregated in clumps much larger than normal, in the spaces between shrunken tubules. Although the number of Leydig

8 436 BARR FERTILITY & STERILITY cells is considerably above normal in a section of a biopsy specimen, it is offset by the small size of the testis. The Leydig cells have a reasonably normal appearance, although degenerative signs have been described and apparently increase with the age of the patient. For example, a decrease in the number of cytoplasmic lipid droplets has been noted and interpreted as evidence of decreased secretory activity. The pathological changes in the testes are more variable than is suggested by the summary above. This is to be expected in view of the complicated biological factors involved. In a section of a biopsy specimen, tubules with only moderate thickening of the lamina propria, and an intact epithelium as far as Sertoli cells are concerned, are often adjacent to sclerosed tubules with a tiny lumen and no epithelium. There are wide variations in specimens obtained from different Klinefelter males. At one extreme, all of the tubules may have undergone severe sclerosis; we have seen such a specimen from a I5-year-old chromatin-positive boy. At the other extreme, a specimen may contain a few sections of tubules showing spermatogenesis to the stage of mature sperms. These more normal tubules occur as islands surrounded by tubules showing typical fibrosis. This accounts for the clinical finding of oligospermia, rather than azoospermia, in occasional patients. The rare occurrence of fertility cannot be ruled out, just as one instance is known of a woman with Turner's syndrome and an XO abnormality having borne a child. Nevertheless, reports of paternity are unlikely to stand up under close scrutiny and the utmost in diplomacy and discretion is required of the physician when dealing with this matter. Several of our Klinefelter patients gave accounts of sexual prowess with positive results. Their stories and their testicular histology were quite incompatible and we were forced to conclude that there was either psychological compensation or unrecognized collaboration, or (probably) both. Attempts to explain the changes that take place in the testes at puberty must be largely speculative. The cells of the various components of the testes certainly carry an abnormal genetic coding and it is perhaps reasonable to assume that this is reflected in changes in certain cytoplasmic enzyme systems. POSSibly, as a consequence, the cells making up the endorgan to FSH-the seminiferous tubules-react abnormally to the pituitary hormone. Fibroblasts are perhaps especially involved, in view of the excessive formation of connective-tissue fibers and interstitial substance in the process of tubular fibrosis and hyalinization. These changes may be accentuated by the high level of FSH production that is a nearly constant feature of the syndrome. Maddock and Nelson noted damage to the seminiferous tubules, similar to that seen in the Klinefelter syndrome, in

9 VOL. 17, No.4, 1966 KLINEFELTER'S SYNDROME 437 testis biopsy specimens of normal men to whom chorionic gonadotrophin had been administered. Thus the testicular pathology, like other features of the disorder, may be caused by a combination of genetic and hormonal influences, the former being the primary or basic etiological factor. Hormonal Changes. The urinary excretion of 17-ketosteroids is usually in the low-normal to definitely subnormal range. Since there is no evidence of adrenocortical dysfunction, the diminished 17 -ketosteroid excretion is probably a reflection of decreased secretion of testosterone and related androgenic hormones by the Leydig cells. The studies of Lipsett et al. indicate that the Leydig cells are synthesizing androgens at the maximum rate of which they are capable. The pubertal increase in 17-ketosteroid excretion is often delayed in Klinefelter patients and the middle-age fall may occur as early as the thirtieth year. The clinical picture frequently includes signs of androgen deficiency. Such evidence as is available suggests that the level of estrogen secretion is within normal limits. The most consistent abnormality in hormone assays is an elevated excretion of pituitary FSH from puberty onward, an excess that may be several times above normal. In the absence of evidence of pituitary pathology, the increase in FSH secretion must be attributed to a breakdown of the feedback from the testis, which normally plays such a large role in regulating the activity of the basophilic cells of the anterior pituitary. Further details are unclear. One still sees occasional reference to the hypothetical "X" hormone or "inhibin," which was postulated 20 years ago as a product of seminiferous epithelium and supposedly deficient in the Klinefelter syndrome. Johnsen recently put forward a modification of that hypothesis, to the effect that the cytoplasm which is split off from the spermatids immediately before liberation of the mature spermatozoa may be the source of the hypophyseal inhibitor. Another explanation for the elevated FSH secretion is that the basophils may not be normally inhibited because a qualitative abnormality is involved, in the sense that testosterone and related androgens may not be secreted in normal proportions to one another. Evidence of thyroid dysfunction in the Klinefelter syndrome has been reported by Plunkett et al. Although these patients are usually euthyroid clinically, 27 men with XXY and related complexes had decreased uptakes of radioactive iodine and poor responses to thyroid-stimulating hormone. This deficiency was also found in triple-x and tetra-x females. In view of this finding, the occasional occurrence of cretinism in XXY males may be more than a coincidence. It is tempting to implicate thyroid dysfunction

10 438 BARR FERTILITY & STERILITY in the mental retardation shown by a proportion of males and females with extra sex chromosomes. To venture in this direction, data are needed on thyroid function in young children with sex chromosome abnormalities, and even in intrauterine life (if it were not asking the impossible). Other Manifestations. Aside from the small size of the testes, the external genitalia are usually normal. The pubic hair is likely to have a gynecoid distribution. The growth of facial hair tends to be delayed to the age of 18 or 20 years, with scanty growth thereafter. The syndrome does not afford protection against premature baldness of the male type. The voice usually changes at the age of 13 or 14 years, although it may not become truly masculine. The inconstant signs just mentioned are eunuchoid traits. They are almost certainly attributable to androgen deficiency but some contribution by an abnormal tissue response to androgens, on a genetic basis, cannot be ruled out entirely. As for growth characteristics, one of the more consistent findings is that the legs are disproportionately long compared with the rest of the body. Tanner and colleagues state that chromatin-positive boys have longer legs than is normal, at all ages, though the trunk length is quite usual. They add that since this characteristic appears before puberty, it represents a fundamental difference in growth rate rather than a delay in epiphyseal fusion. This implies that the disproportionate leg length is caused by the genetic error and is not a sign of androgen-deficiency eunuchoidism. Klinefelter patients tend to be taller than average because of the unusual length of their legs. The physique is normally male in some patients but on the whole the musculature tends to be poorly developed and in the third decade there may be deposition of fat over the hips, buttocks, and breasts so that the contours become somewhat feminine. During the fourth decade, an early onset of osteoporosis is frequently evident because of androgen deficiency. Osteoporosis of the vertebrae may lead to kyphosis and bone pain, and there is often premature senility. It will be recalled that Klinefelter et al. included gynecomastia as a consistent component of the syndrome. We know now that less than half of chromatin-positive males have gynecomastia. Any attempt to explain the breast enlargement after puberty is beset with difficulties. Danowski lists six possible mechanisms and produces evidence against all of them. Perhaps the most plausible suggestion is that there is an imbalance between circulating androgens and estrogens, a predominance of the latter leading to feminizing signs, including breast enlargement. The cells of the breast tissue carry abnormal genetic information, of course, and this may predis-

11 VOL. 17, No.4, 1966 KLINEFELTER'S SYNDROME 439 pose to such feminization. This argument loses strength when it is recalled that gynecomastia occurs in chromosomally normal males. The apparently increased susceptibility of Klinefelter males to breast cancer, as compared with other males, is of special interest. In a recent study, Jackson and co-workers found evidence that the frequency of carcinoma of the breast in chromatin-positive males is over 60 times that of males generally and on a par with the frequency of breast cancer in females. Psychopathology. There is no doubt that the XXY error imposes an increased risk of mental retardation, and persons with XXYY or XXXY abnormalities fare somewhat worse. As a result, the frequency of chromatinpositive males in a population of mental retardates is of the order of 1 in 100-i.e., 4 or 5 times as numerous as in all male newborns. Nothing is known of abnormalities in brain chemistry or histology that might explain the mental retardation which afflicts about 1 in 4 Klinefelter patients. To keep this in perspective, it should be pointed out that instances of quite intelligent men with the syndrome have been encountered, men who are successful in the business world and in the professions. Some information is available on psychological aspects of the syndrome other than mental retardation. Sexual interest is directed toward the female. Although sexual drive is likely to be fairly strong in the young Klinefelter adult, it tends to diminish early and may progress to impotence. Lack of competence in the sexual sphere, aggravated by gynecomastia when present, may lead to neuroses, anxiety states, and reactive depressions. Transvestism has been described in several Klinefelter individuals; this is probably a coincidence because transvestites in general have a male nuclear sex. Some investigators feel that delinquency and antisocial acts are encountered more frequently in Klinefelter males, as compared with the general population. A recent report by Casey and collaborators suggests that the XXYY variant is of special significance in this context. Again, to maintain perspective, it must be borne in mind that descriptions of Klinefelter patients with psychopathology or behavioral deviations are often based on biased samples derived from mentally retarded, psychotic, or delinquent populations. As Pritchard noted, "most persons with Klinefelter's syndrome are probably stable law-abiding citizens." Although doubt has been expressed about the wisdom of introducing, at this time, routine sex chromatin testing of newborns, large-scale testing for research purposes, such as the survey that has been undertaken by Court Brown and colleagues in Edinburgh, is of great importance. Only in this

12 440 BABB FEBTILITY & STEHILITY way will fairly large numbers of children with sex chromosome anomalies be found. Periodical assessment of their physical and mental development will provide a more realistic picture of the Klinefelter syndrome than the one we now have, which is derived to a large extent from the study of biased samples. The XXXXY Sex Chromosome Abnormality. Some 30 individuals with the XXXXY error have been described in the literature since it was drawn to our attention by Fraccaro et al. This gross chromosomal abnormality causes mental retardation regularly, often of a severe degree. There is usually hypogenitalism, in the form of a small penis and delayed descent of the testes. Skeletal anomalies, including radio-ulnar synostosis, are common. The triad of severe mental retardation, hypogenitalism, and skeletal anomalies is sufficiently characteristic of the XXXXY error that some prefer to think of it as causing a distinct syndrome, separate from the Klinefelter syndrome. CONCLUSION Considerable progress has been made since Klinefelter et al. described a special form of hypogonadism in the male, leading to infertility. Cytogenetic studies have been crucial in establishing sex chromosome abnormalities as the cause of Klinefelter's syndrome. Much remains to be learned about specific aspects of pathogenesis. A deeper understanding of the basic biological factors involved is especially necessary if there are to be preventive measures directed toward the testicular changes at puberty, or the mental retardation which afflicts a considerable number with this disorder. Health Sciences Centre University of Western Ontario London, Canada REFERENCES 1. BAIKIE, A. G., GARSON, O. M., WESTE, S. M., and FERGUSON, J. Numerical abnormalities of the X chromosome. Frequency among inpatients of a general hospital and in a general population. Lancet 1 :398, BERGEMANN, E. Geschlechtschromatinbeststimmungen am Neuge borenen. Schweiz Med Wschr 91:292, BRAY, P., and JOSEPHINE, SB. A. An XXXYY sex chromosome anomaly. Report of a mentally deficient male. lama 184:179, BUNGE, R. G., and BRADBURY, J. T. Genetic sex: chromatin test versus gonadal histology. 1 Clin Endocr 16:1117, CARB, D. H. Chromosome studies in spontaneous abortions. Obstct Gynec 26: 308, CASEY, M. D., SEGALL, L. J., STREET, D. R. K., and BLANK, C. E. Sex chromosome abnormalities in two state hospitals for patients requiring special security. Nature (Land) 209:641, 1966,

13 VOL. 17, No.4, 1966 KLINEFELTEU'S SYNDUO~fE COUUT BROWN, W. M., HARNDEN, D. C., JACOBS, P. A., MACLEAN, N., and MANTLE, D. J. Abnormalities of the Sex Chromosome Complement in Man. Medical Research Council Special Report 305. Her Majesty's Stationery Office, London, DANOWSKI, T. Clinical Endocrinology. Williams & Wilkins, Baltimore, FERGUSON-SMITH, M. A. The prepubertal testicular lesion in chromatin-positive Klinefelter's syndrome (primary micro-orchidism) as seen in mentally handicapped children. Lancet 1 :219, FERGUSON-SMITH, M. A., JOHNSTON, A. \V., and HANDMAKER, S. D. Primary amentia and micro-orchidism associated with an XXXY sex-chromosome constitution. Lancet 2:184, FORD, C. E., POLANI, P. E., BRIGGS, J. H., and BISHOP, P. M. F. A presumptive human XXY/XX mosaic. Nature (Lon d) 183:1030, FRACCARO, M., KAIJSER, K., and LINDSTEN, J. A child with 49 chromosomes. Lancet 2:899, JACKSON, A. W., MULDAL, S., OCKEY, C. H., and O'CONNOR, P. J. Carcinoma of male breast in association with the Klinefelter syndrome. Brit Med J 1:223, JACOBS, P. A., and STRONG, J. A. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature (Lond) 183:302, JOHNSEN, S. C. Studies on the testicular-hypophyseal feed-back mechanism in man. Acta Endocl' (Khh) Suppl. 90:99, KLINEFELTER, JR., J. F., REIFENSTEIN, JR., E. C., and ALBRIGHT, F. Syndrome characterized by gynecomastia, aspermatogenesis without a-leydigism, and increased secretion of follicle-stimulating hormone. J Clin Endocr 2:615, LIPSETT, M. B., DAVIS, T. E., WILSON, H., and CANFIELD, C. J. Testosterone production in chromatin-positive Klinefelter's syndrome. J Clin Endocr 25: 1027, MACLEAN, N., HARNDEN, D. C., COURT BROWN, W. M., BOND, J., and MANTLE, D. J. Sex-chromosome abnormalities in newborn babies. Lancet 1 :286, MADDOCK, W.O., and NELSON, W. O. The effects of chorionic gonadotrophin in adult men: increased estrogen and 17-ketosteroid excretion, gynecomastia, Leydig cell stimulation and seminiferous tubule damage. J Clin Endocr 12:985, MOORE, K. L. Sex reversal in newborn babies. Lancet 1 :217, MULDAL, S., and OCKEY, C. H. The "double-male": a new chromosome constitution in Klinefelter's syndrome. Lancet 2:492, NELSON, W.O., and HELLER, C. C. Hyalinization of the seminiferous tubules associated with normal or failing Leydig cell function. Microscopic picture in the testis and associated changes in the breast. J Clin Endocr 5: 13, OHNO, S. A phylogenetic view of the X-chromosome in man. Ann Cenet (Par) 8: 3, PAULSEN, C. A., DE SONZA, A., YOSHIZUMI, T., and LEWIS, B. M. Results of a buccal smear survey in non institutionalized adult males. J Clin Endocr 24:1182, PLUNKETT, E. R, and BARR, M. L. Testicular dysgenesis, affecting the seminiferous tubules principally, with chromatin-positive nuclei. Lancet 2:853, PLUNKETT, E. R., RANGECROFT, C., and HEAGY, F. C. Thyroid function in patients with sex chromosome anomalies. J Ment Defic Res 8:25, PRITCHARD, M. Klinefelter's syndrome and behaviour. Lancet 2:762, RACE, R R Identification of the origin of the X chromosome(s) in sex chromosome aneuploidy. Callari J Genet Cytol 7:214, TANNER, J. ~1., PRADER, A., HABICH, H., and FERGUSON-SMITH, rvl A. Cenes on the Y chromosome influencing rate of maturation in man. Lancet 2:141, WATERMAN, D. F., LONDON, J., VALDMANIS, A., and MANN, J. D. The XXYY chromosome constitution. Amel' J Dis Child 111 :421, 1966.