From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-dosage Effect of Supernumerary X Chromosomes

Abstract

Objective: High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs.

Design and methods: In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed.

Results: The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction.

Conclusion: The increase in the number of extra-Xs is associated with a "dose-dependent" progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance.

Keywords: 47,XXY; 48,XXXY; 48,XXYY; 49,XXXXY; 49,XXXYY; HGA; Klinefelter syndrome; X chromosome; aneuploidy; sex chromosomes.

Figure 1.

Anthropometric and US-BTV in patients with KS and HGAs. Note: Data of patients with KS are shown by violin plots, whereas the means adjusted for the number of Y chromosomes and their respective BCa 95% CI are reported for patients with HGAs. The bar indicates statistical significance for linear trend analyses, whereas the brackets indicate comparisons across groups. The single, double, and triple stars represent statistical significance levels below .05, .01, and .001, respectively, before adjustment by FDR.Abbreviations: BCa, bias-corrected and accelerated; CI, confidence interval; FDR, false discovery rate; HGA, high-grade aneuploidies of X and Y sex chromosomes; KS, Klinefelter syndrome; US-BTV, ultrasonographic bitesticular volume.

Figure 2.

Hormonal parameters in patients with KS and HGAs. Note: Data of patients with KS are shown by violin plot, whereas the means adjusted for the number of Y chromosomes and their respective BCa 95% CI are reported for patients with HGAs. The bar indicates statistical significance for linear trend analyses, whereas the brackets indicate comparisons across groups. The single, double, and triple stars represent statistical significance levels below .05, .01, and .001, respectively, before adjustment by FDR.Abbreviations: BCa, bias-corrected and accelerated; CI, confidence interval; FDR, false discovery rate; HGA, high-grade aneuploidies of X and Y sex chromosomes; KS, Klinefelter syndrome.

Figure 3.

Metabolic parameters and echocardiographic data in patients with KS and HGAs. Note: Data of patients with KS are shown by violin plot, whereas the means adjusted for the number of Y chromosomes and their respective BCa 95% CI are reported for patients with HGAs. The bar indicates statistical significance for linear trend analyses, whereas the brackets indicate comparisons across groups. The single, double, and triple stars represent statistical significance levels below .05, .01, and .001, respectively, before adjustment by FDR.Abbreviations: BCa, bias-corrected and accelerated; CI, confidence interval; FDR, false discovery rate; HGA, high-grade aneuploidies of X and Y sex chromosomes; KS, Klinefelter syndrome.