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

• Published in: The journal of clinical endocrinology and metabolism Vol. 109; no. 8; pp. e1564 - e1573
• Main Authors: Spaziani, Matteo, Carlomagno, Francesco, Tarantino, Chiara, Angelini, Francesco, Paparella, Roberto, Tarani, Luigi, Putotto, Carolina, Badagliacca, Roberto, Pozza, Carlotta, Isidori, Andrea M, Gianfrilli, Daniele
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2024
• Subjects: Adolescent; Adrenocorticotropic hormone; Adult; Aneuploidy; Body mass index; Child; Chromosomes; Chromosomes, Human, X - genetics; Comparative analysis; Cross-Sectional Studies; Dextrose; Gene Dosage; Glucose; Glucose tolerance; Glucose tolerance tests; Heart; Humans; Klinefelter Syndrome - genetics; Klinefelter Syndrome - pathology; Klinefelter's syndrome; Male; Metabolism; Puberty; Sex Chromosome Aberrations; Sex chromosomes; Steroidogenesis; Structure-function relationships; Supernumerary; Thyroid; Thyroid gland; X chromosomes; Young Adult; Israel; Klinefelter syndrome; 48,XXYY; 48,XXXY; HGA; 49,XXXXY; X chromosome; 49,XXXYY; aneuploidy; 47,XXY; sex chromosomes
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgad730

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.