Background/Purpose: Diffuse and limited systemic sclerosis (SSc) are autoimmune connective tissue diseases with a strong female predominance, suggesting a potential role for X chromosome dosage in disease susceptibility. While previous studies linked X chromosome aneuploidies to immune dysregulation, their specific impact on diffuse and limited SSc remains unclear. This study evaluates the relationship between Klinefelter syndrome (47, XXY), triple X syndrome (47, XXX), and Turner syndrome (45, XO) and the development of diffuse and limited systemic and limited sclerosis compared to the general population using a large-scale electronic health record database.

Methods: This multicenter, retrospective cohort study utilized TriNetX, a global federated research network comprising 141 healthcare centers. Three cohorts were analyzed: individuals with Klinefelter syndrome compared to the general male population, individuals with Turner syndrome compared to the general female population, and individuals with triple X syndrome compared to the general female population. Patients were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes, between January 1, 2015, and January 1, 2025. The prevalence and risk of diffuse and limited SSc were assessed in each cohort. Relative risk, odds ratios, and 95 percent confidence intervals were calculated. The statistical significance was assessed using Fisher’s exact test.

Results: A total of 88,951,991 patients were identified. Among individuals with Klinefelter syndrome, the prevalence of diffuse SSc prevalence was 0.19% (RR = 9.0, 95% CI: 5.1–15.9, p < 0.001), and the prevalence of limited SSc was 0.22% (RR = 16.9, 95% CI: 9.3–28.6, p < 0.001). In triple X syndrome, the prevalence of diffuse SSc was 0.25% (RR = 5.2, 95% CI: 2.7–8.9, p < 0.001), and limited SSc prevalence was 0.48% (RR = 14.5, 95% CI: 7.1–27.1, p < 0.001). In Turner syndrome, the prevalence of diffuse SSc was 0.047% (RR = 0.98, 95% CI: 0.14-0.56, p = 0.82), and limited SSc prevalence was 0.009% (RR = 0.28, 95% CI: 0.14–0.56, p < 0.001).

Conclusion: Excess X chromosome in Klinefelter syndrome and triple X syndrome is associated with significant increased risk of having diffuse and limited systemic sclerosis in a nonproportional, synergistic manner. Deficient X chromosome in Turner syndrome is associated with a lower risk of having limited systemic sclerosis but no effect on diffuse SSc when compared with the general population. These findings support the role of X chromosome dosage in susceptibility of developing systemic sclerosis and highlight the complex interplay between X chromosome dosage and immune regulation. This study underscores the need for heightened clinical awareness and targeted screening in individuals with Klinefelter and Triple X syndromes.

Table 1. Demographic Characteristics of the Study Population

Table 2. Prevalence and Relative Risk of Diffuse and Limited Systemic Sclerosis in X Chromosome Aneuploidies

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-x-chromosome-dosage-on-the-development-of-diffuse-and-limited-systemic-sclerosis-in-klinefelter-triple-x-and-turner-syndromes-a-multicenter-cohort-study/