Novel genetic aspects of Klinefelter's syndrome

Klinefelter's syndrome (KS) is the most common chromosome aneuploidy in males, characterized by at least one supernumerary X chromosome. Although extensively studied, the pathophysiology, i.e. the link between the extra X and the phenotype, largely remains unexplained. The scope of this review is to summarize the progress made in recent years on the role of the supernumerary X chromosome with respect to its putative influence on the phenotype. In principal, the parental origin of the X chromosome, gene-dosage effects in conjunction with (possibly skewed) X chromosome inactivation, and--especially concerning spermatogenesis--meiotic failure may play pivotal roles. One of the X chromosomes is inactivated to achieve dosage-compensation in females and probably likewise in KS. Genes from the pseudoautosomal regions and an additional 15% of other genes, however, escape X inactivation and are candidates for putatively constituting the KS phenotype. Examples are the SHOX genes, identified as likely causing the tall stature regularly seen in KS. Lessons learned from comparisons with normal males and especially females as well as other sex chromosomal aneuploidies are presented. In addition, genetic topics concerning fertility and counseling are discussed.