Pathophysiology Of Klinefelters Syndrome

Most cases of KS occur through sporadic chromosomal nondisjunction during parental gametogenesis in either the sperm or the egg. A seminal study using DNA probes to X chromosome restriction-site polymorphisms demonstrated that in one series of 32 individuals with KS the additional X chromosome was of paternal origin in 17 (53%) of cases and of maternal origin in 14 (44%) of cases and resulted from a postzygotic mitotic error in 1 (3%) case (see Table 1) (10). Because these are sporadic errors in gametogenesis, there is no evidence that KS is familial or is likely to recur within a given family after one child is born with KS. Recent chromosomal analysis of sperm has demonstrated that older men produce higher frequencies of XY sperm that could increase their chances of fathering a child with KS (11).

In an individual with KS, the extra X chromosome forms a dense chromatin mass, or "Barr body," within the nuclei of somatic cells; but exactly how the presence of this extra chromosome leads to testicular failure remains a mystery. Testicular biopsy specimens from infants with KS may reveal only a reduced number of germ cells (12). After puberty, fibrosis of the seminiferous tubules begins, eventually leading to small, firm testes and azoospermia (4). Testicular biopsy specimens from adults with KS reveal marked seminiferous tubule hyalinization, with focal areas of immature seminiferous tubule formation and fibrosis with a resulting increase in the amount of intersti-tium (see Fig. 1). An absence of functional Sertoli cells in the seminiferous tubules is accompanied by low levels of serum inhibin-B (5), the hormone whose existence Klinefelter and colleagues had hypothesized in their original article.

The hormonal axis in boys with KS can appear normal until puberty, with no apparent differences in the levels of testosterone LH, or FSH when compared to controls (13-15). In addition, gonadotropin production in response to gonadotropin-releasing hormone (GnRH) stimulation is normal. However, at the time of puberty, elevated basal FSH and LH levels and an exaggerated FSH and LH response to GnRH stimula-

Testicular Biopsy Klinefelter

Fig. 1. Testicular biopsy specimen from a 21-yr-old with Klinefelter's syndrome. The peripheral blood karyotype and the karyotype of 100 cells grown from a testicular biopsy sample was 47, XXY. Note focal areas of immature seminiferous tubules interspersed with completely hyalinized tubules and an increase in intersitial tissues. (Photo courtesy of Dr. C. Alvin Paulsen.)

Fig. 1. Testicular biopsy specimen from a 21-yr-old with Klinefelter's syndrome. The peripheral blood karyotype and the karyotype of 100 cells grown from a testicular biopsy sample was 47, XXY. Note focal areas of immature seminiferous tubules interspersed with completely hyalinized tubules and an increase in intersitial tissues. (Photo courtesy of Dr. C. Alvin Paulsen.)

tion and low or low-normal testosterone levels are seen, presaging the hormonal abnormalities seen in adults with KS. Testosterone production in men with KS declines with aging in a fashion similar to normal men (16).

The cause of the language difficulties often encountered by individuals with KS is not well understood; however, recently, high-resolution magnetic resonance imaging (MRI) scans of the brains of individuals with KS has demonstrated a relative reduction in left temporal lobe gray matter compared with control subjects (17). Interestingly, individuals with KS who had been treated with testosterone had larger left temporal lobe volumes than individuals with KS who had not received testosterone therapy. Moreover, verbal fluency scores were significantly improved in the testosterone-treated KS patients compared with the individuals with KS who were never treated with testosterone. This finding implies that levels of testosterone, especially during development, may play a major role in the verbal and language problems related to KS.

The pathophysiology of KS-related gynecomastia is also not entirely clear. Individuals with KS do exhibit mildly elevated plasma levels of estradiol, probably from increases in peripheral aromatization and decreased clearance. However, histologic analysis of breast tissue from individuals with KS demonstrates intraductal hyperplasia rather than the ductal hyperplasia seen in high estrogen states in the male, such as cirrhosis (18).

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