Received Sep 15; Accepted Oct This article has been cited by other articles in PMC. Abstract The term Klinefelter syndrome KS describes a group of chromosomal disorder in which there is at least one extra X chromosome to a normal male karyotype, 46,XY. XXY aneuploidy is the most common disorder of sex chromosomes in humans, with prevalence of one in males. Other sex chromosomal aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 per 17, to 1 per 50, male births.
In addition, 46,XX males also exist and it is caused by translocation of Y material including sex determining region SRY to the X chromosome during paternal meiosis. Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes.
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, 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 age 12 years, in increasing dosage sufficient to maintain age appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone FSH , and luteinizing hormone LH. The effects on physical and cognitive development increase with the number of extra Xs, 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.
The classic form is the most common chromosomal disorder, in which there is one extra X chromosome resulting in the karyotype of 47,XXY. Background In , Dr Harry Klinefelter published a report on nine men with a constellation of features: It was believed to be an endocrine disorder of unknown etiology, until , when Jacobs et al.
During the early 's, a number of centers began screening newborns for sex chromosomal abnormalities, because there was a need to obtain accurate information about childhood development in this condition [ 3 ].
Previous studies of XXY individuals were extremely biased toward more severely affected individuals, since these patients were drawn largely from mental or penal settings where large numbers of men could be screened. These earlier studies implied a risk for mental deficiency and behavioral problems.
As prospective, unbiased studied have reported their results in recent years, it has become clear that most XXY boys demonstrate reductions in speech and language abilities which are correlated with decreased reading and spelling achievement [ 4 ].
Most, but not all XXY males, are infertile with small testicles, increased numbers of Leydig cells, tubular sclerosis, and interstitial fibrosis of varying degrees [ 5 ].
Their ejaculate is usually azoospermic, and levels of testosterone are typically low to low-normal. Diagnostic criteria Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes. Chromosome analysis on lymphocytes from peripheral blood, or on amniocytes or chorionic villi from prenatal specimens is used to make this diagnosis.
In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism [ 6 ]. In the toddler years, boys may present with developmental delay, especially with expressive language skills [ 7 ]. 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 [ 8 ].
Adults are often evaluated for infertility or breast malignancy [ 9 ]. Epidemiology XXY aneuploidy is the most common disorder of sex chromosomes in humans, with a prevalence of one in males [ 3 ].
Cases of 46,XX males have also been reported. Physical characteristics Boys with 47,XXY have variable phenotypic characteristics and do not have obvious facial dysmorphology; thus, they are indistinguishable from other boys with normal karyotypes [ 6 ].
Small testicular size is the only consistent physical feature in 47,XXY. The presence of gynecomastia and other findings of eunuchoid body habitus and sparse body hair are variable. The increase in height is most significant between ages 5 and 8 and results in the mean final height of Affected individuals have longer arms and legs [ 11 , 12 ].
Secondary sexual characteristics Many 47,XXY boys appear to enter puberty normally with a tendency for testosterone concentrations to decline at late adolescence and early adulthood.
With a decrease in androgen production, secondary sexual characteristics do not completely develop, and features of eunuchoidism and gynecomastia can develop. This also results in sparse facial, body, and sexual hair [ 8 ]. Gonads Features that are constant in 47,XXY males are small, soft testes with elevated gonadotropins. Testicular volume is typically less than 10 ml in postpubertal 47,XXY individuals [ 5 ]. Fertility Although most patients with Klinefelter syndrome are infertile, there have been a few patients with reports of pregnancy without assisted medical technology, typically in mosaic cases.
With the introduction of intracytoplasmic sperm injection, which involves the use of sperm extraction from deep within the testicles of patients with nonmosaic Klinefelter syndrome, some XXY men will have an increased chance of fathering a child [ 9 , 13 - 15 ]. Thus, testicular sperm extraction and intracytoplasmic sperm injection may be considered in males with azoospermia and Klinefelter syndrome [ 15 ].
Psychological characteristics Intelligence A wide range of intelligence quotient IQ has been noted and extends from well below average to well above average. Most of the differences between Verbal IQ and Performance IQ appear to relate to deficits in verbal abilities and to decreased auditory memory and processing [ 16 ]. Language development Several longitudinal studies of males with 47,XXY have revealed a tendency for language deficits that often causes academic difficulties during the school years.
Most 47,XXY boys have a lag in language skills with mildly delayed expression of single words. These individuals also demonstrate that the production of expressive language is affected more than that of comprehension or receptive skills [ 4 ]. The pattern of deficits includes problems in understanding of complex grammatical constructions, problems in oral language production, and deficits in morphology, word retrieval abilities, and oral narrative construction.
The variability of their speech and language deficits is reflected in the lower mean verbal scales scores being significantly lower than performance scale scores [ 4 ]. Behavior and personality The personalities of 47,XXY males are variable. One study characterized 47,XXY males as timid, immature, and reserved, with difficulty relating to their peer group, whereas other studies described 47,XXY subjects as friendly, kind, helpful, and relates well with other people. Most are described to be quiet, sensitive, and unassertive.
The majority of 47,XXY males rate themselves as more sensitive, apprehensive, and insecure than their peers. An increased incidence of anxiety, depression, and substance abuse is reported in adolescents with 47,XXY [ 17 ]. The language difficulty experienced by these males possibly contributes to the challenges in behavioral and social domains [ 18 ]. The cause may result from the estradiol to testosterone ratio being severalfold higher than that of karyotypically normal men or possibly due to an increased peripheral conversion of testosterone to estradiol in men with Klinefelter syndrome [ 19 ].
Etiology The extra X chromosome in 47,XXY results sporadically from either meiotic nondisjunction where a chromosome fails to separate during the first or second division of gametogenesis or from mitotic nondisjunction in the developing zygote.
The likelihood of X chromosome nondisjunction increases with advancing maternal age. The effects on physical and mental development increase with the number of extra Xs, and each extra X is associated with an IQ decrease of approximately 15—16 points, with language most affected, particularly expressive skills [ 10 ]. Diagnostic testing A karyotype analysis of peripheral blood is the gold standard. Elevated follicle stimulating hormone FSH , luteinizing hormone LH and estradiol, and low to low-normal testosterone level without testosterone therapy.
Urinary gonadotropins are increased due to abnormal Leydig cell function. Differential diagnosis The physical manifestations of Klinefelter syndrome are often variable.
When the following features are present in an undiagnosed male, a karyotype analysis may be indicated: