Klinefelter’s syndrome is a male sex chromosome disorder affecting 1 in 500 males across all ethnic groups. Men with Klinefelter’s syndrome possess an additional X chromosome, resulting in a 47,XXY genotype. The additional X chromosome comes from sporadic errors during sperm or egg formation. In an individual with Klinefelter’s syndrome, the extra X chromosome forms a dense mass, or Barr body, within the nucleus of cells, but exactly how the presence of this extra chromosome leads to the characteristics of Klinefelter’s syndrome remains a mystery.
Individuals with Klinefelter’s syndrome have testicular failure, which results in impairments in both sperm and testosterone production. Klinefelter’s syndrome can be diagnosed at almost any age: in utero (after amniocentesis), in a prepubertal boy, in a male adolescent, or even in an adult male presenting to a medicine or infertility clinic. Because testicular failure occurs before puberty, many of the normal developmental changes of puberty either do not occur or progress slowly. This leads to some typical adult characteristics of individuals with Klinefelter’s syndrome, including tall height with long arms and legs, increased breast tissue (gynecomastia), decreased muscle mass, decreased facial and body hair, and small testes—which often measure less than 5 milliliters in volume (normally greater than 15 milliliters). The penis may be decreased in size but is often of normal length. Gynecomastia is variable but is often prominent and may require surgical correction. Infertility secondary to impaired sperm production is almost universal. In childhood, common presenting features can include delayed speech development, learning difficulties at school, and unusually rapid growth in middle childhood.
At one time, individuals with Klinefelter’s syndrome were thought to be at increased risk for criminal behavior; however, these conclusions were based on flawed studies of preselected (usually committed or incarcerated) populations and are probably inaccurate. When tested, groups of individuals with Klinefelter’s syndrome can exhibit deficits in language processing skills, including reading and spelling, verbal processing speed, judgment, and motor dexterity. In general, this leads to lower than average school performance. It is important to remember that individual variation in mental function is marked; some individuals with Klinefelter’s syndrome perform well above average on intelligence tests. Moreover, it seems likely that early developmental interventions and language tutoring in boys can assist in preventing disabling difficulties with language skills later in adult life.
Laboratory analysis of an individual with Klinefelter’s syndrome reveals low or low-normal serum testosterone and elevated serum gonadotropin levels. The diagnosis is confirmed using chromosomal analysis (karyotyping), which usually reveals a 47,XXY genotype, although infrequently additional X chromosomes may be present or an individual may be mosaic (47,XXY/46,XY).
Testosterone therapy of individuals with Klinefelter’s syndrome results in a more “male” phenotype, with improved mood and increases in facial and pubic hair, muscle size, strength, libido, and bone mineral density. Optimally, testosterone therapy is begun at puberty, allowing boys with Klinefelter’s syndrome to experience pubertal changes in tandem with their peers. In addition, this allows for optimal enhancement of bone mineral density. Even if testosterone therapy is not initiated until adulthood, it is still associated with beneficial improvements in mood, behavior, and sense of wellbeing. Testosterone therapy has no beneficial impact on either infertility or gynecomastia, which are optimally treated with surgical resection if bothersome to the individual.
For most men with Klinefelter’s syndrome, artificial insemination with donor sperm or adoption are the only options for fatherhood. Recently, however, new approaches to the treatment of infertility, including intracytoplasmic injection of sperm aspirated from the testes, have been reported for Klinefelter’s syndrome patients and may be successful in the subset of patients in whom sperm are present on testicular biopsy.
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- Klinefelter, F., Jr., Reifenstein, E. C., Jr., & Albright, F. (1942). Syndrome characterized by gynecomastia, aspermatogenesis without aleydigism and increased excretion of follicle-stimulating hormone. Journal of Clinical Endocrinology, 2, 615–627.
- Klinefelter’s patient support: Klinefelter Syndrome and Associates, P.O. Box 119, Roseville, CA 95678-0119; e-mail: firstname.lastname@example.org
- Palermo, G. P., Schlegel, P. N., Sills, E. S., Veeck, L. L., Zaninovic, N., Menendez, S., et al. (1998). Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with non-mosaic Klinefelter syndrome. New England Journal of Medicine, 338, 588–590.