Adverse Impact of Supernumerary X Chromosome on Anthropometric, Endocrinological, and Metabolic Parameters and Cardiac Function in Males

Klinefelter syndrome is the most frequent sex chromosome polysomy, with a prevalence of 1 to 2 per 1000 (1). Most subjects are diagnosed in adulthood for infertility. During childhood the diagnosis usually goes unnoticed since prepubertal boys do not exhibit specific physical features. The clinical manifestations associated with Klinefelter syndrome (47,XXY) are widely described and mainly include hypergonadotrophic hypogonadism beginning in mid-puberty (2), clinically presenting with low testicular volume, gynecomastia, infertility, osteopenia, and metabolic syndrome. Other subtle manifestations present before puberty are not associated with hypogonadism and include learning disabilities, delayed speech development, and minor congenital malformations such as clinodactyly, cleft palate, and inguinal hernia. A smaller proportion of males have other sex chromosome polysomies: 48,XXYY and 48,XXXY are present in 1:17 000 to 1:50 000 male births and the incidence of 49,XXXXY is 1:85 000 to 1:100 000 male births (3); however, their clinical characterization is more limited, probably due to their low frequency. The extra X chromosomes are adequately inactivated in individuals with sex chromosome polysomies. However, about 12% to 15% of X-linked genes escape inactivation, mainly mapping to the homologous pseudoautosomal regions (PAR) present on both the X and Y chromosomes (4). Genes in PAR show different expression across tissues according to sex. An excessive dose of genes that escape inactivation has been proposed as an explanation for the symptoms and signs associated with X polysomies. Some manifestations, such as tall stature, have been related to excess gene dose in SHOX gene (1), while the genes associated with other manifestations still need to be elucidated. The recent work by Spaziani et al (5) evaluates whether the clinical manifestations of sex chromosome polysomies are associated with the number of additional X chromosomes in a large cohort of male adolescents and young adults. If the clinical manifestations were associated with an excessive dose in genes that escape inactivation, they would worsen the more additional X chromosomes were present. As already described, and contrary to what was expected with a quadruple dose of the SHOX gene, subjects with 49,XXXXY karyotypes were shorter than subjects with 2 or 3 additional X chromosomes, reflecting the complexity of growth regulation. The cause of short stature in subjects with 49,XXXXY is not yet known, but the consequences of excess doses of other genes are probably involved (6). Additionally, children with a 49,XXXXY karyotype have higher risk of intrauterine growth restriction and growth hormone deficiency (7). Testicular dysfunction involving the tubular and the interstitial compartment is widely described in XXY subjects. Sertoli cell function, reflected by serum anti-Müllerian hormone (AMH) and inhibin B, is not affected until mid-puberty (2). Germ cell depletion occurs earlier, but it becomes evident only in mid-puberty with the testicular growth arrest. The paper by Spaziani et al adds that subjects with high grade aneuploidies (HGA) have a smaller testicular volume, with a clear trend associated with the number of extra X chromosomes. In males with Klinefelter syndrome, Leydig cell dysfunction begins in mid-puberty and is generally manifested by testosterone concentrations in low normal ranges, compensated by an increase in luteinizing hormone (LH). The possibility of early-onset hypoandrogenism and the benefits of its replacement are still a matter of controversy (8). Spaziani and coworkers found that total and free testosterone were lower in HGA subjects compared with 47,XXY males (5). When the hormones of the hypothalamic-pituitary-gonadal axis were compared according to Tanner stage, the authors found no significant differences suggesting that subjects with HGA had a less advanced puberty than XXY subjects. However, the association between testicular volume with the number of extra X chromosomes persisted. An additional interesting finding reported by Spaziani and colleagues is the compromise of other hormonal axes (5). Subjects with HGA had lower levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) and higher concentration of adrenocorticotropic hormone (ACTH), showing a trend related to the number of extra X chromosomes, suggesting that both testicular and adrenal steroidogenesis are compromised. Also, the increasing number of X chromosomes was associated with lower levels of free T4 and higher free T3/free T4 ratio. The lack of increase in thyroid-stimulating hormone (TSH) concentration suggests the coexistence of hypothalamic-pituitary dysfunction. A high-risk metabolic profile was described in Klinefelter patients (1). Spaziani and coauthors found that subjects with HGA had higher weight and body mass index, lower levels of high-density lipoprotein and higher low-density lipoprotein, higher levels of fasting blood glucose and insulin and after 2 hours in the glucose test than subjects with 47,XXY, but they did not find a trend associated with the number of extra X chromosomes. Probably, the low number of patients in the groups with HGA including 3 or 4 X chromosomes provides insufficient power to find a trend associated with the number of X chromosomes. The echocardiographic evaluation showed a negative trend between supernumerary Xs and lower ejection fraction and a lower right and left ventricular end-diastolic diameter. On the contrary, the epicardial fat thickness, a marker of cardiovascular risk, showed no trend or difference between the groups. HGA are usually referred to as “variants of Klinefelter syndrome.” A better characterization of these “variants” could question such an approach since typical features of Klinefelter syndrome may not be present, for instance the absence of high stature in patient with a 49,XXXXY karyotype or the absence of infertility in 47,XYY subjects. Spaziani's manuscript includes patients who have an additional Y chromosome coexisting with one or more additional X chromosomes, but the characteristics of these patients are not analyzed separately. Although the authors adjusted their analysis for the number of Y chromosomes, patients with Y polysomies represent small subgroups that may have specific features. In fact, testicular function in XYY subjects is less affected. In conclusion, and according to the recent publication by Spaziani et al, males with HGA have more severe dysfunction in the gonadal, adrenal, and thyroid axes, a greater compromise in cardiac function and a worse metabolic profile. Some of these parameters showed an association with the number of additional X chromosomes. The underlying pathophysiology still needs to be clarified. The author has nothing to disclose. high grade aneuploidies pseudoautosomal region