Klinefelter syndrome is the presence of 2 or more X chromosomes plus 1 Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis. Treatment may include testosterone supplementation.Klinefelter syndrome is the presence of 2 or more X chromosomes plus 1 Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis. Treatment may include testosterone supplementation.
(See also Overview of Chromosomal Abnormalities and see Overview of Sex Chromosome Abnormalities.)
Klinefelter syndrome is a chromosomal disorder in males characterized by the presence of at least 1 extra X chromosome (47,XXY). It leads to small testes, hypergonadotropic hypogonadism, infertility, tall stature, and variable degrees of cognitive, metabolic, and psychosocial impairment.
Klinefelter syndrome is the most common sex chromosome disorder. Reported prevalence varies, and it is likely underdiagnosed (a national database study reported 6/10,000 male live births) (1). The extra X chromosomes are maternally derived in approximately 50% of cases, and the remaining cases are primarily due to paternal nondisjunction (2). Germ cells do not survive in the testes, leading to decreased sperm and androgens.
General references
1. Berglund A, Viuff MH, Skakkebæk A, et al. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: A nationwide cohort study. Orphanet J Rare Dis. 2019;14(1):16. doi:10.1186/s13023-018-0976-2
2. Jacobs PA, Hassold TJ, Whittington E, et al. Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet. 1988;52(2):93-109. doi:10.1111/j.1469-1809.1988.tb01084.x
Symptoms and Signs of Klinefelter Syndrome
Affected boys tend to be tall with disproportionately long arms and legs. They often have small, firm testes and a small penis. Approximately 30% develop gynecomastia (1).
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Puberty usually occurs at the normal age, but often facial hair growth is light. There is a predisposition for verbal learning disorders. Clinical variation is great, and many 47,XXY males may have a normal appearance and intellect. Testicular development varies from hyalinized nonfunctional tubules to some production of spermatozoa; urinary excretion of follicle-stimulating hormone is frequently increased.
Men with Klinefelter syndrome tend to develop diabetes mellitus, chronic lung disease, varicose veins, hypothyroidism, and breast cancer more often than other men.
Mosaicism occurs in approximately 15% of cases (2). Males with a normal male karyotype (XY) in some cells may be fertile and have less obvious malformations. Some affected men have 3, 4, and even 5 X chromosomes along with the Y.
As the number of X chromosomes increases, the severity of intellectual disability and of malformations also increases. Each extra X is associated with a 15- to 16-point reduction in IQ, with language most affected, particularly expressive language skills.
Symptoms and signs references
1. Nieschlag E. Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Dtsch Arztebl Int. 2013;110(20):347-353. doi:10.3238/arztebl.2013.0347
2. Jacobs PA, Hassold TJ, Whittington E, et al. Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet. 1988;52(2):93-109. doi:10.1111/j.1469-1809.1988.tb01084.x
Diagnosis of Klinefelter Syndrome
Prenatal diagnosis on cytogenetic testing
Detected postnatally on clinical appearance
Cytogenetic testing by karyotyping, fluorescent in situ hybridization (FISH) analysis, and/or chromosomal microarray analysis
Klinefelter syndrome may incidentally be diagnosed when cytogenetic testing, such as karyotyping, is performed. Cytogenetic testing is usually performed for other indications such as advanced maternal age or abnormal results from other prenatal screening tests rather than because of specific suspicion for fetal Klinefelter syndrome itself.
In adolescence, the diagnosis of Klinefelter syndrome is suspected based on physical examination revealing a small penis and testes and gynecomastia (1). Adolescents who present primarily with hypogonadism and who have had blood testing for the sex hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone may require further testing such as karyotyping to exclude Klinefelter syndrome (see figure Laboratory Evaluation of Male Hypogonadism). Many men are diagnosed during an infertility evaluation (probably the majority of nonmosaic 47,XXY males are subfertile).
Diagnosis is confirmed by cytogenetic analysis (karyotyping, FISH analysis, and/or chromosomal microarray analysis). (See also diagnosis of chromosomal abnormalities and Next-generation sequencing technologies.)
Diagnosis reference
1. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998;158(12):1309-1314. doi:10.1001/archinte.158.12.1309
Treatment of Klinefelter Syndrome
Testosterone supplementationTestosterone supplementation
Fertility preservation counseling after onset of puberty
Males with Klinefelter syndrome should be evaluated by an endocrinologist to determine whether testosterone supplementation is indicated. Males with Klinefelter syndrome should be evaluated by an endocrinologist to determine whether testosterone supplementation is indicated.Testosterone therapy is typically started at puberty, or when clinical hypogonadism is evident, to ensure the development of male sexual characteristics, muscle bulk, bone structure, and better psychosocial functioning. More recent studies have suggested that early hormone therapy may help with developmental and behavioral problems in boys with 47,XXY.
Fertility preservation counseling after puberty onset should be initiated early because the likelihood of successful sperm retrieval (via semen analysis or testicular sperm extraction) declines with age and after hormone initiation (1).
Boys with Klinefelter syndrome usually benefit from speech and language therapy and neuropsychologic testing for language comprehension, reading, and cognitive deficits.
Treatment reference
1. Butler G, Srirangalingam U, Faithfull J, Sangster P, Senniappan S, Mitchell R. Klinefelter syndrome: going beyond the diagnosis. Arch Dis Child. 2023;108(3):166-171. doi:10.1136/archdischild-2020-320831
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