Klinefelter Syndrome

OVERVIEW: What every practitioner needs to knowAre you sure your patient has Klinefelter syndrome? What are the typical findings for this disease?

Klinefelter syndrome is characterized by the presence of an extra (one or more) X chromosome in male individuals, giving a 47,XXY rather than 46,XY karyotype.

Klinefelter syndrome occurs in 1/500-1000 live births and is the most common chromosomal cause of male infertility. Variants of Klinefelter syndrome can include three or more copies of the X chromosome and are typically more severe. Phenotypic manifestations include hypogonadism, gynecomastia after puberty, and infertility due to testicular failure.

Males with Klinefelter syndrome typically have low testosterone levels, causing sparse body hair, decreased muscle mass, small testes and penis, feminized body habitus, and decreased libido. Affected males can be taller and thinner than their siblings but have no dysmorphic features. They have high estradiol levels and gynecomastia after puberty.

Significant developmental delay/mental retardation is not a common feature of 47,XXY, but decline in cognitive skills can occur with increasing extra X chromosomes (e.g., 48,XXXY). On the whole, IQ score typically decreases by 10-20 points for each extra X chromosome present in an individual.

The incidence of mitral valve prolapse is increased. Individuals with Klinefelter syndrome are at an increased risk for breast cancer, autoimmune diseases, diabetes, osteoporosis, and deep vein thrombosis.

What other disease/condition shares some of these symptoms?

Kallman syndrome, characterized by gonadotropin-releasing hormone deficiency and anosmia, has several characteristics similar to those of Klinefelter syndrome, but it is much rarer. Similar features include hypogonadism, sparse body hair, decreased libido, and infertility. Other manifestations of Kallman syndrome can include digital abnormalities, renal agenesis, sensorineural hearing loss, cleft lip/palate, and/or agenesis of the corpus callosum. None of these are seen in association with Klinefelter syndrome.

The mode of inheritance in Kallman syndrome can be autosomal dominant, autosomal recessive, or X-linked. Six genes associated to date (KAL1, FGFR2, PROKR2, PROK2, CHD7, and FGF8) account for only 25%-35% of cases. Female individuals with an autosomal dominant or recessive form can also be affected, whereas Klinefelter syndrome occurs only in male patients.

Complete SRY-positive 46,XX gonadal dysgenesis can lead to a male phenotype in the presence of a female karyotype resulting from the translocation of part of the Y chromosome containing the SRY gene to an X chromosome. Similar features can include hypogonadism, gynecomastia, and infertiliy. Determination can be made by karyotype.

Mosaic Klinefelter syndrome occurs in the presence of a normal cell line and a cell line with an extra X chromosome (47,XY/47,XXY). Mosaic Klinefelter syndrome can have a milder presentation (such as the presence of fertility), depending on the number of cells in the body with the extra X and where those cells are located.

Males with variants of Klinefelter syndrome with increased copies of the X chromosome (48,XXXY, 48,XXYY, 49,XXXXY, and so on) typically have a more severe presentation than do those with 47,XXY, because of the presence of more X chromosome material. Individuals with 47,XXXY can have mild to moderate mental retardation along with the sexual characteristics and may have radioulnar synostosis. Those with 47,XXYY may have mild mental retardation in addition to the sexual characteristics of Klinefelter syndrome.

What caused this disease to develop at this time?

Klinefelter syndrome is caused by the presence of an extra X chromosome in every cell of the body (47,XXY) in a male individual. The extra X rises from nondisjunction in either meosis I or meosis II in the maternal or paternal gametes. Approximately half of Klinefelter syndrome cases occur because of maternal nondisjunction and half occur because of paternal nondisjunction. Around 75% of maternally derived cases are due to meosis I errors, which are associated with advanced maternal age.


A karyotype, or chromosome analysis, should be ordered if Klinefelter syndrome is suspected. The presence of one (or more) extra X chromosomes in each cell in addition to a Y chromosome confirms the diagnosis. Additionally, male patients with Klinefelter syndrome usually have low testosterone and high luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Estradiol levels may also be elevated. Testosterone levels decreases over the life span, and not all men with Klinefelter syndrome have hypogonadism.

Would imaging studies be helpful? If so, which ones?

An echocardiogram should be obtained to examine for the possibility of mitral valve prolapse. Radiography may be indicated for possible radioulnar synostosis (particularly in variant Klinefelter syndrome), and a dual-emission x-ray absorptiometry scan should be evaluated for osteoporosis.


When the diagnosis of Klinefelter syndrome is initially made, genetic counseling regarding the natural history of Klinefelter syndrome, including infertility, should ensue and be tailored to the age of the patient. Often in the pediatric period, the diagnosis is unsuspected because of the lack of outward phenotypic characteristics.

Testosterone replacement therapy is important for treating the low testosterone levels and secondary manifestations of Klinefelter syndrome. Male patients with Klinefelter syndrome should begin testosterone replacement through regular injections at 12 years of age (or at diagnosis if later) to normalize serum levels of testerone, LH, FSH, and estradiol. Increased testosterone levels can increase muscular strength, promote body hair development, increase libido, improve mood and attentiveness, and decrease the risk of osteoporosis.

Regular monitoring of testosterone, LH, FSH, estradiol, prolactin, insulin growth factor-1, and cortisol levels should occur.

Men with Klinefelter syndrome have successfully reproduced in recent years resulting from advances in assisted reproductive technology. In vitro fertilization techniques involve the removal of viable sperm from the testes of men with Klinefelter syndrome, called microsurgical testicular sperm extraction and injecting them into eggs by intracytoplasmic sperm injection.

More than 50% of male patients with Klinefelter syndrome have been found to have viable sperm present in the testes. Additionally, adolescent boys with Klinefelter syndrome have rarely been able to freeze viable sperm from ejaculate. Referral to a reproductive endocrinologist is suggested if reproductive options are being considered.

Referral to early intervention may be warranted if decreased muscle mass causes hypotonia and/or delayed gross motor skills, in the presence of speech delay, or if other developmental delays are evident during the evaluation.

What are the adverse effects associated with each treatment option?

Testosterone injections may have side effects, including priapism, edema, hypertension, polycythemia, and/or increased gynecomastia.

What are the possible outcomes of this disease?

Klinefelter syndrome is associated with hypogonadism leading to low testosterone and its secondary manifestations including gynecomastia, sparse hair growth, more feminine body habitus, and decreased libido. Males with 47,XXY do not usually have developmental delay/mental retardation but may have mild learning difficulties and poor coordination resulting from decreased muscle mass or hypotonia.

Almost all male patients with Klinefelter syndrome have infertility associated with testicular failure. Male patients with Klinefelter syndrome do not have an increased likelihood of being homosexual. Increased health risks can include breast cancer, autoimmune diseases, diabetes, osteoporosis, and deep vein thrombosis.

Testosterone replacement therapy is an accepted and common treatment for Klinefelter syndrome and can lead to increased quality of life by improving mood and affect, increasing libido, increasing muscle strength, masculinizing body habitus, and decreasing the risk of osteoporosis.

What causes this disease and how frequent is it?

Klinefelter syndrome is caused by the presence of an extra X chromosome in a male chromosomal complement (47,XXY). About half of cases are caused bymaternal nondisjunction, with the other half resulting from paternal nondisjunction. The risk of Klinefelter syndrome increases with advanced maternal age (considered 35 years or older by most institutions).

The incidence is around 1/500-1/1000 male individuals.

The AR gene is located on the X chromosome and plays a role in the sensitivity of the androgen receptor to androgen. A trinucleotide CAG repeat is located in exon 1, and a short number of repeats is associated with a greater response to androgens. In male individuals with Klinefelter syndrome, the X chromosome with the shortest CAG repeat has been found to be preferentially inactivated. However, body weight is positively correlated, whereas bone density and the presence of gynecomastia and small testes are negatively correlated with CAG repeat length. Those with shorter CAG length are more likely to have a strong reponse to androgens and have a higher educational level.

How do these pathogens/genes/exposures cause the disease?

In female and male individuals with Klinefelter syndrome, almost all of one of the two X chromosomes is inactivated in every cell in the body. Typically, which X chromosome is inactivated is random but can be preferential, which is called skewed inactivation. In variant Klinefelter syndrome with more than two X chromosomes, all but one X chromosome is inactivated. However, a small portion of the X chromosome remains active. Those genes that are expressed in duplicate are thought to cause the features of Klinefelter syndrome because of a dosage effect. Additional X chromosomes thus cause a more severe phenotype because of the presence of an additive dosage effect.


Male patients with Klinefelter syndrome are at an increased risk for breast cancer, thus regular self-examination and physical examination by a primary care provider should be initiated. Additionally, these individuals have an increased risk for diabetes, autoimmune disease, osteoporosis, and deep vein thrombosis.

How can this disease be prevented?

There is no way to prevent the occurrence of Klinefelter syndrome. First- and second-trimester maternal serum screening during pregnancy does not screen for Klinefelter syndrome, and there is no particular anomaly visible on prenatal ultrasonography. However, the pregnancies of women who have prenatal diagnostic testing by chorionic villus sampling or amniocentesis will also be tested for Klinefelter syndrome in the resulting karyotype.

What is the evidence?

Radicioni, AF, Ferlin, A, Balercia, G. "Consensus statement on diagnosis and clinical management of Klinefelter syndrome". J Endocrinol Invest. vol. 33. 2010. pp. 839-50.

(Workshop from the Italian Society on Andrology and Sexual Medicine with discussion of appropriate management and treatment of Klinefelter syndrome, including testosterone replacement therapy.)

Rogol, A, Tartaglia, N. "Considerations for androgen therapy in children and adolescents with Klinefelter syndrome (47,XXY)". Pediatr Endocrinol Rev. vol. 8(suppl 1). 2010. pp. 145-150.

(Discusses benefits and limitations of androgen replacement therapy and appropriate management strategies.)

"Genetics home reference: Klinefelter syndrome".

(Patient-friendly information about Klinefelter syndrome and available support groups.)

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