- Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD more...
In 1942, Klinefelter et al published a report on 9 men who had enlarged breasts, sparse facial and body hair, small testes, and an inability to produce sperm.
In 1959, these men with Klinefelter syndrome were discovered to have an extra X chromosome (genotype XXY) instead of the usual male sex complement (genotype XY).
Klinefelter syndrome is the most common chromosomal disorder associated with male hypogonadism and infertility. It is defined classically by a 47,XXY karyotype with variants that demonstrate additional X and Y chromosomes.
The syndrome is characterized by hypogonadism (small testes, azoospermia, oligospermia), gynecomastia in late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules, and elevated urinary gonadotropin levels.
Images of physical characteristics seen in Klinefelter syndrome are shown below:
The X chromosome carries genes that play roles in many body systems, including testis function, brain development, and growth. The addition of more than one extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is directly related to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected.
Skeletal and cardiovascular abnormalities can become increasingly severe. Gonadal development is particularly susceptible to each additional X chromosome, resulting in seminiferous tubule dysgenesis and infertility, as well as hypoplastic and malformed genitalia in polysomy X males. Moreover, mental capacity diminishes with additional X chromosomes. The intelligence quotient (IQ) score is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material.
The major consequences of the extra sex chromosome, usually acquired through an error of nondisjunction during parental gametogenesis, include hypogonadism, gynecomastia, and psychosocial problems.
Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland. Androgen deficiency causes eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, which is presumably the hormone regulator of the follicle-stimulating hormone (FSH) level. The hypothalamic-pituitary-gonadal axis is altered in pubertal patients with Klinefelter syndrome.
A typical patient with Klinefelter syndrome presents with low serum testosterone levels, high luteinizing hormone (LH) and FSH levels, and, often, elevated estradiol levels; however, the decline in testosterone production is progressive over the life span, and not all men suffer from hypogonadism.
Men with Klinefelter syndrome are at a higher risk of autoimmune diseases, diabetes mellitus, leg ulcers, osteopenia and osteoporosis, tumors (breast and germ cells), systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome and historically have increased mortality.[4, 5]
Whether the morbidity associated with Klinefelter syndrome is a result of hypogonadism and hyperestrogenism or due to abnormal function of X chromosome linked genes is unclear.
A study by Close et al reported that in boys with Klinefelter syndrome, the degree of phenotypic abnormality is tied to the risk for impaired quality of life (QOL). Linear regression analysis indicated that phenotype accounted for 22% of the variance in QOL among the 43 boys in the study.
Klinefelter syndrome is the most common genetic form of male hypogonadism.
Approximately 1 in 500-1,000 males is born with an extra sex chromosome; more than 3,000 affected males are born yearly.
The prevalence rate is 5-20 times higher in individuals with mental retardation than in the general newborn population.
Approximately 250,000 men in the United States have Klinefelter syndrome. 
About 40% of concepti with Klinefelter syndrome survive the fetal period.
In general, the severity of somatic malformations in Klinefelter syndrome is proportional to the number of additional X chromosomes; mental retardation and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY.
The mortality rate is not significantly higher than in healthy individuals.
Klinefelter syndrome does not have any racial predilection.
Because the syndrome is caused by an additional X chromosome on an XY background, this condition affects only males.
Klinefelter syndrome goes undiagnosed in most affected males; among males with known Klinefelter syndrome, many do not receive the diagnosis until they are adults. The most common indications for karyotyping are hypogonadism and infertility.
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