Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies

Abstract

There are reports suggesting that people with Klinefelter's syndrome (KS) may be at increased risk of some autoimmune diseases, but the evidence is not substantial. We wanted to add to the evidence by systematically assessing the risk of autoimmune diseases in a national cohort of people with KS. We selected records of all people with KS in a record-linked dataset of all hospital day cases and inpatient admissions in England, 1999-2011; and we followed them up by electronic record linkage to identify the occurrence of autoimmune diseases. We compared their occurrence in the KS cohort with a control cohort, studied in the same way, and expressed the results as rate ratios (RR). Of 30 autoimmune diseases studied in people with KS, there were significantly increased risks of seven-Addison's disease (RR 11.7, 95% confidence interval 2.4-34.4), diabetes mellitus type 1 (6.1, 4.4-8.3), multiple sclerosis (4.3, 1.2-11.0), acquired hypothyroidism (2.7, 1.8-4.0), rheumatoid arthritis (3.3, 2.0-5.2), Sjogren's syndrome (19.3, 4.0-57.0) and systemic lupus erythematosus (18.1, 2.2-65.6). We concluded that people with KS have increased risk of some autoimmune diseases, particularly those that are female-predominant. The increased risk of autoimmune diseases associated with the XXY karyotype may hold clues to the pathogenesis of some aspects of autoimmunity.

Difference in clinical presentation between women and men in incident primary Sjögren’s syndrome

“…Differential immune regulation [12–14], X-chromosome gene dosage effects [15, 16], sex hormones [17–19], and sex-specific exposure to environmental factors [20, 21] have all been implicated to contribute to these sex differences. In addition to the difference in disease susceptibility, the clinical manifestations of autoimmune diseases can also differ between the sexes.…”

Autoimmune rheumatic diseases and Klinefelter syndrome Autoimunitné reumatické choroby a Klinefelterov syndróm

“…A relative increase of peripheral CD8+ T cells carrying either HLA-DR or CD57 was found in the patient (Ishihara et al, 1997). Although there are no epidemiological studies demonstrating higher prevalence of Sjogren´s syndrome until recently, the relative risk for Sjogren´s syndrome in the English national record linkage study in people with KS was significant (RR 19.3, 95% CI 4.0 -5.7) (Seminoq et al, 2015). The potential role of additional X chromosome in the development of Sjogren´s syndrome is supported by a recent case report from Japan describing a 16-year-old patient with trisomy X (47 XXX) who developed MCTD and Sjogren´s syndrome.…”

“…However, it appears that patients with KS should be monitored from the aspect of the development of various autoimmune diseases. Seminoq et al, 2015 …”

“…Recently, in the English national record linkage study, approximately 30 autoimmune diseases were studied in a large group of people with KS. The risk for rheumatoid arthritis was significantly higher in KS (RR 3.3, 95% CI 2.0-5.2) and the disease was identified among seven most common autoimmune disorders associated with KS (Seminoq et al, 2015). Pathogenesis of association of autoimmune disorders including RA and KS is still completely unrecognized.…”

Advances in the Interdisciplinary Care of Children with Klinefelter Syndrome

“…A recent medical record linkage study of hospitalized men in England found significantly higher rates of several autoimmune diseases in men with KS including rheumatoid arthritis (RR 3.3), lupus, multiple sclerosis (RR18.1), Addison’s disease (RR 11.7), Sjogren’s syndrome (RR 19.3), autoimmune hypothyroidism (RR 2.7), and type 1 diabetes mellitus (RR 6.1). 147 Although these are all significantly higher in adult men with KS compared to men in the general population, most of these autoimmune conditions are known to have a female predominance, and the risk of these autoimmune diseases is similar to women in the general population. 148 No studies have evaluated autoimmune diseases in children with KS.…”