(See also Overview of Chromosomal Abnormalities.)
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 60% of cases. Germ cells do not survive in the testes, leading to decreased sperm and androgens.
Affected boys tend to be tall with disproportionately long arms and legs. They often have small, firm testes, and approximately 30% develop gynecomastia.
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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 have 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. 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.
Reference
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 14(1):16, 2019. doi: 10.1186/s13023-018-0976-2
Diagnosis of Klinefelter Syndrome
Prenatal diagnosis often when cytogenetic testing is done for other reasons such as advanced maternal age
Detected postnatally on clinical appearance
Cytogenetic testing by karyotyping, fluorescent in situ hybridization (FISH) analysis, and/or chromosomal microarray analysis
The diagnosis of Klinefelter syndrome is suspected based on physical examination of an adolescent with small testes and gynecomastia. 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.)
Treatment of Klinefelter Syndrome
Fertility preservation counseling just after onset of puberty
Testosterone therapy is typically started at puberty 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.
Boys with Klinefelter syndrome usually benefit from speech and language therapy and neuropsychologic testing for language comprehension, reading, and cognitive deficits.
After the onset of puberty, boys should receive counseling regarding fertility preservation.
