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Klinefelter syndrome (KS) defines a group of chromosomal disorders in which there is at least one extra X chromosome compared with the normal 46,XY male karyotype. 47,XXY aneuploidy is the most common sex chromosome disorder in humans, with a prevalence of one in 500 males. Other sex chromosome aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 in 17,000 to 1 in 50,000 male births. The incidence of 49,XXXXY is between 1 in 85,000 and 1 in 100,000 male births. In addition, 46,XX males have also been described and in this case the syndrome results from the translocation of Y material (including the sex determining region, SRY) to the X chromosome during paternal meiosis. The effects on physical features and on physical and cognitive development increase with the number of extra X`s, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15-16 points, with language most affected, particularly expressive language skills. Formal cytogenetic analysis is necessary to make a definite diagnosis. If the diagnosis is not made prenatally, 47,XXY males may present with a variety of subtle clinical signs that are age-related. In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism, or developmental delay. The school-aged child may present with language delay, learning disabilities, or behavioral problems. The older child or adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy. Androgen replacement therapy should begin at puberty (around 12 years of age) and the dose should be increased so that it is sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH). |