Thus, the real complete spectrum of different KS phenotypes remains still to be fully elucidated in detail Fig. Probably, the phenotype depends on the severity of the expression of genetic defect, androgen deficiency, and androgen receptor sensitivity i.
The more the genetic expression, androgen deficiency, and androgen receptor sensitivity are worse, the more the phenotype will be severe [ 13 ] Fig.
Less severe forms of genetic abnormalities, such as mosaicism, generally result in both less severe clinical symptoms and endocrine abnormalities [ 14 ], while the phenotype progressively worsens with the severity of polysomy e.
Language and speech disabilities increases with the increase of supernumerary X chromosome and seem to contribute decreasing of 15—16 points of intelligence quotient IQ per each extra X chromosome [ 15 ]. The broad spectrum of phenotypes in KS depends on the severity of all its components number of supernumerary X chromosome, genetic impact of supernumerary X, severity of hypogonadism as well as on the time duration of the disease, the delay in the diagnosis of testosterone deficiency, and advancing age coupled with increasing other comorbidities.
The high frequency of mild phenotypes explains, at least in part, why most of the patients with KS remain undiagnosed [ 6 ] and claims for efforts in improving our ability to promptly reach a diagnosis.
Since symptoms rarely present simultaneously, the disease remains often overlooked and the diagnosis is missed or delayed. Furthermore, the phenotype tends to worsen with advancing age Fig. The timing of the clinical features appearance allows identifying both androgen-dependent and supernumerary X-dependent signs and symptoms Table 1.
Distinguishing symptoms related to androgen deficiency from that due to chromosomal abnormalities is crucial in order to improve the outcome of testosterone replacement therapy, to establish how the disease should be monitored during the follow-up, and to inform the patient on what the expected results are [ 17 ].
Signs and symptoms appearing during infancy such as longer legs [ 17 , 18 ] and speech disabilities [ 19 , 20 ] have been attributed to the genetic abnormality rather than to hypogonadism [ 5 , 7 , 10 ] Table 1.
The main sign, which is always present in KS, is represented by small testes. Thus, testes volume does not increase at puberty while the penis and secondary sexual characteristics progress in a normal fashion through all the pubertal stages. The degree of virilization varies widely in adult men with KS, but it shows a tendency to decrease and to worsen progressively with advancing age Table 1 , similarly to what happens to other clinical conditions associated with KS such as diabetes and metabolic syndrome [ 16 , 22 , 23 ].
Indeed, non-disjunction represent the failure of chromosome to separate at anaphase during meiosis I, meiosis II or mitosis giving rise to cells with an aberrant number of chromosomes. In KS patients with an additional maternal X chromosome, non-disjunction in either the first or second meiotic division is most likely to have occurred, while in paternal cases the supernumerary X chromosome can only derive from a non-disjunction in the first meiotic division, since meiosis II error will result in either XX or YY gametes and therefore XXX or XYY zygotes [ 25 ].
The origin of the supernumerary X chromosome has also been associated with phenotypic differences, although evidence is not conclusive. In particular, it has been reported that KS patients with a paternal origin of the supernumerary X chromosome have a later onset and slower pubertal progression [ 26 ]. Other studies, however, suggested that the parental origin of the supernumerary X chromosome has no particular influence on the phenotype of the patients [ 27 — 29 ].
An advanced maternal, and possibly paternal, age has been reported as a risk factor for KS. The maternal age effect was also shown in KS patients with post-zygotic mitotic non-disjunction. Indeed, the first three mitotic divisions are controlled by maternal protein and RNA; thus, with the increase of the mother age, the chance of mitotic errors increases accordingly and the possibility of KS of post-zygotic origin as well.
On the contrary, only some, albeit debatable, evidences for a relation with sex chromosomal trisomies and advanced paternal age were so far demonstrated [ 30 ]. In the somatic cells of females, the transcription of one of the two X chromosome is known to be randomly inactivated in order to ensure a dosage-compensation of the X-encoded genes to that of male cells. Although several genes are escaping inactivation, the Barr body sex chromatin in female cells is microscopically identifiable and represents the visible inactivated X chromosome [ 31 ].
The untranslated RNA product of the X-inactive-specific transcript Xist gene, located on the long arm of the inactive X chromosome, mediates the coating and silencing of the extra X chromosome in human somatic cells [ 32 , 33 ]. Thus, the expression of Xist indicates the presence of the second and any other supernumerary X chromosome in the somatic cell [ 34 ]. Recent studies demonstrated that Xist methylation in KS patients and in the 41,XX Y KS mouse animal model is comparable with the one observed in female subjects [ 35 — 37 ].
These data together with the expression of Xist in the blood cells of KS patients, while not in healthy 46,XY men [ 38 ] and the findings of the Barr body in KS Leydig and Sertoli cells [ 39 , 40 ] probably means that the somatic cells in KS males inactivate properly the extra X chromosome as the female cells.
Thus, any increase in gene dosage in these cell types will only concern genes that escape the X chromosome inactivation. The genes that escape inactivation are mapping prevalently on the short arm of the X chromosome Xp. Nevertheless, these genes that escape X inactivation are putatively contributing to the KS phenotype, since they would be present in double gene dosage in male patient KS, whose metabolism may not be suitable for female dosage of certain X-linked genes.
Werler et al. They are equally or less expressed in the liver and kidney of, respectively, 40,XX or 40,XY mice, while they are more expressed in the brain of the 41,XX Y mice compared to the normal karyotyped mice, either male or female.
Moreover, the skewed X chromosome inactivation, defined as the preferential inactivation of one of the two X chromosome in female, is present in the KS patients as well and this phenomenon may influence the clinical phenotype. The situation in the germ cells seems to be different and more complex since the X inactivation in these cells follows a distinct pathway [ 48 , 49 ].
Earlier studies demonstrated that germ cells were the only cell type in the testis expressing the Xist and this allows the first conclusion that the unique X chromosome in male germ cells was inactivated in the adult testis [ 50 ]. Nevertheless, later studies have shown that X inactivation does not fully occur in adult spermatogonia since a large number of X chromosome genes are expressed in the testicular germ cells [ 51 ].
It was demonstrated that X reactivation occurs during the germ cell development in the 41,XXY mouse model, and it is assumed that a proper X chromosome gene dosage is crucial for the survival of germ cell in the mature testis [ 53 ].
Thus, either in the germ cells of the KS patients, the altered X-linked gene dosage of these testis specific genes, due to their X inactivation escape, may compromise testicular function or influence the meiotic process itself and therefore play a role in the etiology of infertility in KS males [ 54 — 57 ]. A recent study demonstrated that the over expression in the mouse germ-cell-derived GC-1 and GC-2 cells of the gene Testis-expressed 11 TEX11 , an X chromosome-encoded germ-cell-specific protein that is expressed most abundantly in spermatogonia and early spermatocytes in the testes, results in a suppression of the cell proliferation [ 58 ].
These results suggest that increased expression of TEX11 in the germ cells of KS patients, following the X inactivation escape, may partially contribute to the germ cell death and make TEX11 a potential candidate gene responsible for the KS spermatogenetic failure.
The androgen receptor AR gene, which mapped to Xq The length of this stretch is inversely correlated with the receptor activity [ 59 ]. In KS patients, one of the two AR alleles is inactivated [ 12 , 60 , 61 ], theoretically with the same probability. Nevertheless, Suzuki et al. Moreover, the KS series patients characterized by Zitzmann et al. This correlation was found regarding their social status, body height, bone density, testicular volume, presence of gynecomastia and response to androgen substitution [ 12 ].
Another study demonstrated that KS patients with longer CAG stretch present later onset and slower progression of puberty and slower testicular degeneration process [ 26 ]. More recently another study confirmed the association with the CAG repeats and the phenotypic variability of the KS patients positive correlation of the length of CAG stretch with final height and span and negative with cholesterol and hematocrit level without any significant evidence either of preferential inactivation of the shorter allele or the correlation between the skewed X inactivation and the clinical manifestation of the analyzed KS series [ 13 ].
However, other studies [ 62 , 63 ] did not found evidence for a preferential inactivation of AR with shorter or longer CAG repeats, nor found associations with some clinical features osteoporosis, artery diameter and weighted CAG repeat length. The PAR behave like an autosome and recombine during meiosis. Thus genes in this region are inherited in an autosomal rather than a strictly sex-linked manner [ 64 ]. PAR1 is located at the terminal region of the short arms and PAR2 at the tips of the long arms of these chromosomes [ 64 ].
To date, 24 genes have been assigned to the PAR1 region [ 52 , 64 ], being half of them with a known function. PAR1 is required during male meiosis for X—Y chromosomes pairing, a process which is known to have a critical function in spermatogenesis, at least in humans and mouse [ 65 — 67 ].
In contrast, so far only 4 genes have been discovered in the PAR2 region [ 52 , 64 ]. All characterized genes within PAR1 escape X inactivation, which means that it is normally present a double gene dosage of these gene product in males and female. Moreover, this also means that in KS male three active copies of the X—Y homologous genes of PAR will be present with possible influence in modulating the clinical phenotype.
This suggests that the sole hypogonadism cannot explain completely this phenotype and, indeed, the excessive expression of growth-related genes such as SHOX is implicated [ 68 ]. Moreover, brain natriuretic peptide and fibroblast growth factor receptor 3 are transcriptionally targets of SHOX [ 69 , 70 ] and further studies on this molecular interaction may enhance our understanding of the phenotypic consequences of the syndrome.
Other than gene dosage effects and parental origin of the supernumerary X chromosome, recent evidence suggested that additional features of the X chromosome might have a role in phenotypic differences among KS subjects. In particular, it has been found that KS subjects have more frequently than controls X-linked copy number variations CNVs This means, for example, that duplication in these genes in KS subjects increases the copy number and the expression to four rather than to three as in KS men without a duplication, suggesting that X-linked CNVs especially duplications might contribute to the clinical phenotype [ 71 ].
Hypogonadism remains silent until pubertal onset. Data on serum testosterone and estradiol in healthy prepubertal children are scanty, and there are no studies investigating sex steroids secretion in KS during infancy [ 24 ]. Usually, boys with KS enter puberty regularly and testosterone rises in a physiological way allowing epiphyseal closure and satisfactory development of secondary sexual characteristics i.
Low to normal serum testosterone at puberty contributes in part to the development of tall stature and worsens the ratio between upper to lower skeletal segments by exacerbating the growth of legs that are still longer since infancy [ 17 ]. Some authors also hypothesized that androgen deficiency in the first trimester of life during mini-puberty might contribute to these skeletal features, but clear evidence is still lacking [ 17 ] Table 1. However, the age of onset of hypogonadism is extensively variable [ 5 ].
Hypogonadism is always coupled with elevated gonadotropins hypergonadotropic hypogonadism and the latter are usually higher than normal even in patients with serum testosterone still in the normal range [ 1 , 5 , 10 , 77 , 78 ]. Due to heterogeneous values of serum testosterone in KS, the adequate threshold below which serum T should be considered insufficient in these patients is lacking.
Controlled studies showing a different age-related hypogonadism in patients with KS are not available, so the use of inter-society guideline criteria for male hypogonadism seems to be, at present, the most appropriate one also in this context [ 79 , 80 ]. Other reproductive hormones might be altered in KS. Serum estradiol might be almost normal or sometimes elevated, but the estradiol to testosterone ratio seems to be constantly higher than in normal men [ 5 , 81 ] Table 1. This may account for the development of gynecomastia, the latter being associated with low testosterone even in non Klinefelter patients [ 82 ].
In adult men with KS, serum inhibin B is undetectable due to the tubular damage [ 83 , 84 ] and serum anti-mullerian hormone is lower than normal [ 76 , 85 — 87 ].
More recent studies have provided also evidence of lower INSL3 levels in comparison with normal subjects [ 88 ]. Likewise signs and symptoms of hypogonadism e.
When serum testosterone is below normal, obesity and gynoid fat distribution are common in men with KS [ 16 ], in addition reduced muscle strength may develop [ 5 , 7 , 10 , 11 ]. Testosterone replacement therapy is effective in improving symptoms related to androgen deficiency, but not all other features related to the genetic abnormality Table 1.
For this reason, it is important to unravel symptoms due to testosterone deficiency from the others. Several other clinical features of KS have been related to hypogonadism, but with a variable degree of uncertainty. The finding of bone mineral density lower than normal is prevalent in patients with KS, but it seems not directly related to low serum testosterone [ 90 ].
Accordingly, several cognitive and psychological aspects are associated with KS [ 5 ]. Intellectual abilities are not impaired, but deficits in specific domains of cognition e. Speech disabilities remain confined in the range of normal general cognitive abilities [ 92 ].
The overall cognitive ability standard score, in fact, on average falls within the normal range and not in the intellectual disability range [ 92 , 93 ]. As language and learning disabilities become manifest during infancy, their relationship with hypogonadism may be ruled out. In addition, this kind of speech problems is common also in other sex chromosome trisomy not associated with hypogonadism [ 93 ], thus suggesting that they depend from genetic factors [ 92 ].
However, it is not possible to exclude that early exposure to low androgens levels during prenatal life might represent a causal factor for the development of speech disabilities. Several psychiatric disorders e. Finally, the old concept of a strong association among KS and criminal behavior, severe psychiatric disorders, and mental retardation is now considered outdated, since no evidence-based data have subsequently confirmed this erroneous long-held view [ 5 , 7 , 10 , 11 ].
A case of a year-old adult man affected by both KS and congenital adrenal hyperplasia CAH due to 21 hydroxylase deficiency, the first causing androgen deficiency, the latter leading to androgen excess was helpful in disclosing testosterone-dependent signs and symptoms in KS [ 95 ].
Under-virilization and abnormalities of sexual behavior in particular of libido, erectile function and sexual intercourses occurred in this patient soon after starting cortisone acetate, due to the reduction in adrenal steroids and the impairment of the balance in the androgen status previously created by the two syndromes [ 95 ].
Thus, the normalization of adrenal androgens revealed clinical features due to testosterone deficiency and KS [ 95 ]. Patients with a diagnosis of KS needs to be followed throughout life and have to be treated with testosterone in case of hypogonadism.
Particular attention should be paid to adequate titration of testosterone dosage in these patients since they mostly have a mild testosterone deficiency, especially those with mild phenotype. The gene can cause a deficiency, mostly seen in males, that might show risk for aggressive or antisocial behavior.
Begin typing your search term above and press enter to search. Press ESC to cancel. Skip to content Home Philosophy Why do females have Barr bodies? Ben Davis September 16, Why do females have Barr bodies?
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Advanced search. Skip to main content Thank you for visiting nature. Abstract THE demonstration of sex chromatin has become an important aspect of human genetics, both for practical reasons, and for the purpose of establishing the theoretical relationship between sex chromatin and the X-chromosome.
Access through your institution. Buy or subscribe. Rent or Buy article Get time limited or full article access on ReadCube. References 1 Davidson, W. Article Google Scholar 3 Sohval, A. Google Scholar 5 Jacobs, P. Google Scholar 13 Turpin, R. Google Scholar 14 Shapiro, A. Google Scholar 16 Mittwoch, U. Google Scholar 19 Krivit, W. Article Google Scholar 31 Wiedemann, H. Google Scholar 32 Tonomura, A. Rights and permissions Reprints and Permissions.
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