When casually considered, gender may appear dichotomous and discrete. However, because of a wide range of disorders of sex differentiation (reviewed in 12
), biological sex is a continuum. A class of disorders of sex differentiation is those with sex chromosomal abnormalities. The common diseases classified as such include Turner's syndrome (45,XO) and Klinefelter's syndrome (47,XXY). We hypothesize that study of disorders of sex differentiation may shed light upon the gender predilection of SLE.
Study of other X chromosome abnormalities has been illuminating in autoimmune disease. For example, acquired X monosomy in peripheral blood cells has been found in autoimmune thyroid disease, systemic sclerosis and primary biliary cirrhosis, but not in SLE (13
). Skewing of X inactivation has been reported in several female-predominate autoimmune diseases (reviewed in 14
), but one study found no skewing in SLE (15
). However, this study also found no skewing in systemic sclerosis, while others have found marked X inactivation skewing in this disease (16
). Skewed X chromosome inactivation has not been found in identical twins discordant for SLE (17
). Skewing of X inactivation could not be determined in our SLE and Turner's syndrome patient because techniques for this determination rely on the androgen receptor gene, which is deleted from the truncated X chromosome in our patient.
Turner's syndrome has been associated with several autoimmune diseases. These include autoimmune thyroid disease and Crohn's disease. Of interest, both these diseases are found among Turner's syndrome patients with particular X chromosome abnormalities, namely, one normal X chromosome and one X isochromosome with two copies of the long arm of X (18
). However, only the study of autoimmune thyroid disease represents a true cohort study of Turner's syndrome patients (19
), while the work describing Crohn's disease in Turner's syndrome is merely a collection of case reports (18
). The other autoimmune disease that reported data most strongly suggest is found in excess among girls with Turner's syndrome is celiac disease, which can be present in up to 10% (20
). While a lack of association of Tuner's syndrome and SLE is not certain, the possibility that Turner's syndrome, skewed X inactivation and acquired X monosomy are associated with some but not all autoimmune diseases is intriguing, and potentially highly informative if mechanisms for these differences can be determined. In addition, the relationship of Turner's karyotype to autoimmune disease may be important.
We have found that Klinefelter's syndrome occurs in excess among men with SLE such that 47,XXY Klinefelter's men are at the same risk of SLE as ethnically similar women (4
). In this same study, we found that no woman with SLE had Turner's syndrome (4
). Further, while there are numerous case reports of Klinefelter's men with SLE (4
, reviewed in 22
), we find only two previous reports of SLE in women with Turner's syndrome: one confirmed and characterized case (7
) and one alleged case (8
). We identified the present family by specifically canvassing our collaborators for patients with both Turner's syndrome and SLE. Thus, these data suggest that Turner's syndrome is certainly not over-represented among SLE patients and may in fact be under-represented, consistent with a gene dose effect for the X chromosome (4
The previous characterized patient with Turner's syndrome/SLE overlap has 45,X/46,XXq+ mosaicism, or a mosaic short-arm deletion of one X chromosome (7
) (). The present report of Turner's syndrome/SLE overlap documents a partial long arm deletion of the second X chromosome [46,X,del(X)(q13)] without mosaicism. Genes found on X that escape X inactivation [~15% of X genes (reviewed in 23
)] are potential gene dose candidates because normal (46,XX) women have two transcribed and translated copies while men have only one active copy. Three potential candidates are CD40LG (Xq26) which is demethylated (i.e., not inactivated) and overexpressed in T cells from women with SLE (24
), IRAK1 (Xq28) (25
), and MECP2 (Xq28) (26
). However, the present reported case of Turner's syndrome/SLE overlap has only one copy of each of these genes due to the Xq13 terminal deletion on 46,X (). While many genes are involved in the susceptibility to SLE, further study of individuals with Turner's syndrome/SLE overlap may help illuminate the location of lupus-related gene(s) on the X chromosome, while further delineating the roles of gene dose effect. Our data suggest that a gene effect could reside on the p arm of X or on the q arm centromeric to q13.1; however, other genes on X for which an allelic difference is important, instead of dose, could still reside on the X chromosome.
Description of X-chromosome anomalies associated with Turner's syndrome/SLE overlap in 3 cases.