{Reference Type}: Journal Article
{Title}: From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-dosage Effect of Supernumerary X Chromosomes.
{Author}: Spaziani M;Carlomagno F;Tarantino C;Angelini F;Paparella R;Tarani L;Putotto C;Badagliacca R;Pozza C;Isidori AM;Gianfrilli D;
{Journal}: J Clin Endocrinol Metab
{Volume}: 109
{Issue}: 8
{Year}: 2024 Jul 12
{Factor}: 6.134
{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.
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.
CONCLUSIONS: 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.