The Extra X Chromosome and Autoimmune Susceptibility in Klinefelter Syndrome

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ID: 319631
2026
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Abstract
OBJECTIVE: To systematically evaluate and quantitatively synthesize the association between Klinefelter syndrome (47,XXY karyotype) and autoimmune susceptibility. METHODS: PubMed/MEDLINE, Scopus, and Web of Science were systematically searched from database inception to April 30, 2026, for studies evaluating autoimmune diseases or autoimmune serological markers in individuals with KS. The protocol was registered in PROSPERO (CRD420261399097). Random-effects models were prespecified, summary data were extracted from published reports, and pooled effect estimates were expressed as odds ratios (ORs) with 95% CIs. Subgroup analyses were performed according to outcome definition (isolated autoantibody positivity vs clinically manifest autoimmune disease). Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Eight studies were included in the qualitative synthesis and six studies (eight datasets) in the quantitative analysis, comprising 2,289 individuals with KS and 51,250,114 controls. KS was associated with markedly increased autoimmune susceptibility compared with control populations (OR 23·25, 95% CI 9·96-54·31), with moderate-to-substantial between-study heterogeneity (I2 = 66·4%). Associations were stronger for clinically manifest autoimmune diseases (OR 48·46, 95% CI 17·68-132·87) than for isolated autoantibody positivity (OR 9·99, 95% CI 1·18-84·77). The autoimmune spectrum predominantly involved female-predominant and interferon-associated disorders, including systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and type 1 diabetes mellitus. CONCLUSION: KS is associated with increased autoimmune susceptibility, particularly for clinically overt autoimmune diseases. These findings support a potential contribution of sex chromosome complement to immune dysregulation and reinforce the importance of clinical awareness of autoimmune comorbidities in individuals with KS.
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Authors Elisa Gatta, Andrea Delbarba, Virginia Maltese, Caterina Buoso, Carlo Cappelli
Journal the journal of clinical endocrinology & metabolism
Year 2026
DOI
10.1210/clinem/dgag268
URL
https://doi.org/10.1210/clinem/dgag268
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