Klinefelter’s syndrome and SLE, two very different conditions, occur in the population with similar prevalence rates. Herein, we show that these diseases occur together more often than expected by chance alone (). There are reasons to suspect that Klinefelter’s syndrome and SLE might be associated. First, numerous case reports document the co-existence of the two diseases (1
). Second, sex hormone similarities between women and men with Klinefelter’s are associated with SLE (1
). This argument is bolstered by data from some animal models of SLE demonstrating increased susceptibility with estrogen and protection with androgens (reviewed in 1
). Third, Klinefelter’s syndrome is also associated with several conditions related to gender. For example, Klinefelter’s syndrome men die of breast cancer at a similar rate as women (27
). About two in 50 men with breast cancer have Klinefelter’s syndrome (28
), a rate similar to that found for male SLE herein. There may be an increase in rheumatoid factor in the serum of patients with Klinefelter’s syndrome (29
). Testosterone treatment reverses immune activation abnormalities in Klinefelter’s syndrome (30
), and has also led to therapeutic improvement of SLE in individual case reports (5
), as observed in one of our patients (Scofield, Bruner, Harley, unpublished data). These observations may be related to the beneficial effect of the mild androgen dehydroepiandrosterone (DHEA or prasterone) upon mild SLE in women (32
X chromosome polymorphisms do not detect 47,XXY caused by duplication of the X chromosome and produced by a maternal meiosis II nondisjunction, which we discovered in one man from his clinical presentation. Any subclinical 47,XXY caused by this mechanism would not have been detected by X chromosome polymorphism screening, as applied to some of our sample. The actual population prevalence of 47,XXY in our male SLE sample may be higher, therefore, than the 5 in 213 we detected. However, the best estimate suggests that only 18% of patients with Klinefelter’s syndrome have this mechanism of supernumerary X chromosomes (19
). Therefore, there is a small but finite possibility of an additional undiscovered Klinefelter’s man among the SLE men studied by genotyping of the X chromosome only. Of course, typing of X chromosome markers is not the usual clinical modality of diagnosis for Klinefelter’s syndrome, but karyotype and FISH, the usual clinical tests, require cells, which were not available in some of subjects. In other work, we have typed several hundred X chromosome single nucleotide polymorphisms. We find heterozygocity in from 40% to 60% of these markers in the men identified as 47,XXY in the present study by microsattelite markers. This rate of heterozygocity is similar to that found in normal women. Thus, we are confident that the techniques used herein have accurately identified men with Klinefelter’s syndrome as well as 46,XY men.
Klinefelter’s syndrome is a genetic abnormality in which androgen and estrogen levels are abnormal from at least the initiation of puberty (33
). Klinefelter’s syndrome may specifically predispose men to SLE compared to other more common forms of hypogonadism, such as primary testicular failure. However, 5 of 35 men with SLE were found to have hypergonadotropic hypogonadism in one study but the etiology of the hypogonadism was not otherwise delineated (34
). Another study found a high rate of hypogonadism in men with rheumatic diseases (only 2 of which had SLE). Of interest, of 13 men with rheumatic disease and untreated hypogonadism, 5 had Klinefelter’s syndrome, 2 had Kallman’s syndrome and 2 had idiopathic cryptorchism. Thus, 9 of 13 had a congenital from of hypogonadism (6
). There are case reports of Klinefelter’s syndrome with other female-predominant autoimmune diseases (35
). However, our data are the first to conclusively demonstrate an association of Klinefelter’s syndrome with a female-predominate autoimmune disease.
We estimate that one SLE patient will be found in every 960 Klinefelter’s males. This is much closer to the one SLE patient in 1324 women based on the ethnic distribution in our population than it is to the estimated prevalence of 1 in ~14,000 for the SLE males. Thus, the 47,XXY males have the 46,XX female risk of lupus and not the approximately 10-fold lower 46,XY male risk. This result is consistent with a gene dose effect for lupus risk originating from the X chromosome where XX (whether 46,XX or 47, XXY) confers a 10-fold higher risk than 46,XY.
Perhaps, subsequent studies of large numbers of women with SLE will estimate the relative risk for SLE in 45,XO, Turner’s syndrome. If the gene dose hypothesis is correct, then the rate of SLE 45,XO should be similar to the 46,XY male rate. Our sample of 768 SLE women is too small to determine whether this is the case. Turner’s syndrome is about four-fold less prevalent than Klinefelter’s at 4 per 10,000 (11
). Even so, SLE in Turner’s syndrome is virtually unreported (37
). In contrast, autoimmune thyroid disease has an increased prevalence in Turner’s syndrome, especially in those with an Xq isochromosome (39
). These differences suggest that SLE and autoimmune thyroid disease, both female dominated autoimmune diseases, have distinct X chromosome dependent susceptibilities. In particular, our data imply that X chromosome monosomy, either congenital or acquired, may not be a risk factor for SLE, as has been suggested for primary biliary cirrhosis (40
) or autoimmune thyroid disease (41
The 46,XX and 47,XXY karyotypic risks for SLE appear to be similar. Consequently, some feature or features of Klinefelter’s syndrome must be sufficient to give the full female risk of SLE; and, applying parsimony, the many differences between normal 46,XX females and 47,XXY males are not sufficient to alter risk for SLE. The decreased estrogen in 47,XXY compared to 46,XX, for example, does not alter the SLE risk. Thus, our data support the notion that differences in estrogens alone do not explain the much lower incidence and prevalence of SLE in 46,XY men compared to 46,XX women. Some might construe the lack of an association of oral contraceptive use with exacerbation in established SLE (42
) as being consistent with this interpretation.
Meanwhile, the increased androgens of 47,XXY compared to 46,XX do not protect from SLE. The other implication from the 47,XXY prevalence in male SLE is that the Y chromosome does not appear to influence the overall risk of SLE in men. The increased prevalence of 47,XXY in SLE supports the difference between the SLE prevalence of 46,XY men and 46,XX women being dominated by the X chromosome dose.
Our data show that the clinician treating male SLE, however, is working in a population enriched for 47,XXY and increased awareness of Klinefelter’s may improve diagnostic recognition. Three of three SLE men with Klinefelter’s syndrome answered the fertility question in a way that increased suspicion of infertility. There were only six other responses from other men. This question, which was asked and answered before this study was initiated, may be the most generally discriminating initial question for a man with SLE when screening to identify the 47,XXY SLE patients. Certainly, in any male SLE patient whose fertility is questionable, an evaluation for the physical and, perhaps, laboratory features of Klinefelter’s syndrome is suggested.
The increased prevalence of 47,XXY Klinefelter’s in males with SLE has genetic implications for understanding SLE by suggesting a gene dose effect at the X chromosome. In addition, diagnosing those who are 47,XXY from among the male SLE patients provides them access to potentially important medical management.