Are You Confident of the Diagnosis?

What you should be alert for in the history

Klinefelter syndrome designates a condition in which a male has an extra X chromosome and has a cluster of typical physical features. These features would include first and foremost small firm testes (low testicular volume), tall slender body habitus, and in some cases breast enlargement (gynecomastia) and learning disabilities. This condition may be suspected in any male who presents with small firm testes at any age. The condition is the most common form of male hypogonadism, occurring in approximately 1 in 500 to 1 in 1000 males, and results from an extra X chromosome giving rise to the 47,XXY karyotype.

Most males with XXY karyotype go unrecognized until adult life. The diagnosis is often suspected as a male approaches adolescence and fails to develop characteristic male secondary sexual features. The designation of Klinefelter syndrome is based on a constellation of features found in the individual, but most individuals with XXY have no other phenotypic features beyond the small firm testes. Most will be normally virilized males. These otherwise normal-appearing males may not be detected until issues with fertility develop.

The appropriate designation for individuals with the extra X chromosome in the absence of other syndrome features is simply XXY male.

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Characteristic findings on physical examination

Physical examination may show decreased facial hair, gynecomastia, decreased pubic hair, and tall stature. Although a small penis may occur in some individuals, the penis is usually normal. Adult males have normal erections and intercourse. Affected males are often taller than expected on the basis of parental heights. A lack of testosterone leads to feminization of body habitus with fat distribution prominent in the thighs and abdomen.

Expected results of diagnostic studies

Laboratory studies include total testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Testosterone levels are uniformly low, and in most cases below the lowest point of the laboratory reference range. FSH and LH are markedly elevated.

Diagnosis confirmation

The diagnosis is established by chromosome analysis revealing the 47,XXY karyotype. The Kleinfelter phenotype may be associated with mosaicism, in which an individual has a normal male cell line 46, XY and a 47, XXY cell line (46,XY/47,XXY).

Who is at Risk for Developing this Disease?

The 47,XXY sex chromosomal variation may be found in males with the typical clinical features of Klinefelter syndrome and in males with normal physical features and a history of infertility. Many males are detected while being screened for infertility and found to have oligospermia or azoospermia. The sex chromosomal variation may be detected prenatally by chromosome analysis of chorionic villus sample cells and amniocentesis. Every male with a history of infertility should be a candidate for chromosomal analysis to rule out 47,XXY karyotype.

The method of ascertaining the XXY male has significant consequences for understanding the broad spectrum of clinical features and health care risks. Prenatal diagnosis by chorionic villus sampling and amniocentesis for advanced maternal age or other risk factors may result in the 47,XXY fetal karyotype as an unexpected finding.

XXY males detected by chance are likely to have normal cognitive development and remain indistinguishable from the 46,XY male population. Observation of these XXY males over 4 decades tends to confirm an increased risk for a wide range of learning disabilities, which are indistinguishable from those that may occur in the general population.

There are no specific fetal factors that would suggest that the fetus has XXY karyotype. The XXY male identified late in childhood or during preadolescence is usually referred for evaluation because of learning issues. Some identified in this fashion will present with tall stature and small testes.

Ascertainment in the midst of puberty almost always is associated with delayed development of pubic and axillary hair, small firm testes, and more typical body habitus. The adult XXY male typically presents with essentially normal male virility and comes to attention because of infertility.

What is the Cause of the Disease?

The sex chromosomal variation is the result of chromosomal nondisjunction during meiosis. The nondisjunction event occurs during maternal meiosis in about 60% of cases and in paternal meiosis in about 40% of cases. Chromosomal nondisjunction may be postzygotic in 10% of affected individuals, giving rise to sex chromosomal mosaicism. The nondisjunction events may result in individuals with multiple X chromosomes with 48, XXXY and 49, XXXXY karyotypes. These individuals show more extensive physical features and developmental disabilities.


The effect of the extra X chromosome on embryonic differentiation and suppression of testosterone production remains unknown. The enhanced dosage effect of the X chromosome has some role on testicular development and function, resulting in primary testicular failure. It is unknown if the gene dosage effect of the extra X chromosome causes an intrinsic germ cell dysfunction, or whether the Sertoli cells are unable to support normal germ cell differentiation. The result is absence or marked reduction of spermatogenesis.

Testosterone levels are generally low and, in some patients, increase during early adolescence and then progressively fall. The level of testosterone production varies from individual to individual as a function of variable degree of Leydig cell dysfunction. Some individuals will have a sufficient testosterone level to initiate puberty and then experience failure of pubertal progression because of low and falling testosterone levels. Concentrations of FSH and LH are usually elevated. Marked elevation of FSH is a consistent and clinically important indicator.

Testes are dysgenetic and histologically show hyalinized fibrosis of the seminiferous tubules, hyperplasia of the Ledig cells, and absence of spermatogenesis. Seminiferous tubules with foci of spermatogenesis may account for 47,XXY males with sperm in ejaculates, but azoospermia is virtually uniform.

Systemic Implications and Complications

Males with XXY karyotype are at increased risk for learning disabilities, speech and language delay, global motor delays, and learning disabilities. XXY males have a slightly increased risk of autoimmune diseases such as insulin-dependent diabetes mellitus, autoimmune thyroiditis, lupus erythematosus, ankylosing spondylitis, and rheumatological disorders. The role of the sex chromosomal variation in compromising the immune system to develop autoantibodies remains unknown.

Breast enlargement occurs in individuals lacking adequate intrinsic testosterone or testosterone replacement therapy, and places the male at an increased risk for breast cancer. The risk of breast carcinoma may be 20-50 times greater in XXY males than among chromosomally normal males. Breast self-examination should began in adolescence, and the practice should continue throughout life. XXY males are advised to consult with their physicians to determine the need for more thorough breast examinations. Testes should also be regularly examined for any nodularity or tenderness.

Hypogonadism is associated with male osteoporosis. The reduced bone density detected in XXY males is underestimated and underdiagnosed. Diagnosis is made on the basis of both T-score and Z-scores. Testosterone regulates male bone metabolism both directly on osteoblasts through the androgen receptor and indirectly by aromatization of androgens to estrogens.

XXY males tend to show evidence of osteoporosis and osteopenia during the later stages of puberty. Bone density is essentially normal through childhood and early pubertal development. Early testosterone replacement therapy appears to reduce this process, but it appears that decreased bone mass may not be entirely reversed by testosterone replacement therapy.

XXY males tend to have an increased risk for leg varicosities. This is suspected to be associated with enhanced platelet aggregation.

Early detection of affected individuals allows for appropriate testosterone supplementation, as needed, and aggressive intervention for learning disabilities. The learning issues may include speech delay, dyslexia, and reading dysfunctions. Psychological and behavioral issues (including attention deficit hyperactivity disorder) occur with increased frequency.

Treatment Options

The medical care of an individual with XXY begins with recognition of the clinical features with confirmation by chromosome analysis. Complete physical examination including height, weight, pulse, blood pressure, and assessment of physical features should be completed at the initial diagnosis.

In infancy, the presenting features may be developmental delay, small phallus, undescended testes, and in a small number of individuals, hypospadias. In adolescence, the XXY male presents with eunuchoid body habitus, gynecomastia, and small testes.

The initial assessment includes assessing gonadal function with FSH and LH levels, which are elevated. Testosterone levels may vary throughout childhood but ultimately attain low levels. The initial hormone testing should include FSH, LH, , testosterone, estradiol, prolactin, and insulin-like growth factor 1.

In adolescence, the initial assessment should include echocardiography because of the increased risk of mitral valve prolapse.

Baseline studies, including a bone survey to determine bone density and assess for other skeletal anomalies, may be indicated.

During this assessment process, the XXY individual and family members need to be told about the significance of the XXY condition and the implications for ongoing healthcare surveillance

Those males with learning disabilities are referred to a developmentalist for comprehensive psychoeducational evaluation to identify their intelligence quotient and to assess their strengths and weaknesses. This information is critical in developing an individual educational program. Referral to early intervention in early childhood is indicated for speech and motor delays. Those individuals with motor skill disabilities may benefit from physical therapy.

Most XXY individuals have normal intelligence, but about 25%-30% will experience specific deficits in language and executive functions. These involve issues with abstract reasoning, concept formation, problem solving, and planning, similar to those challenges found in individuals with dyslexia.

The supervision of testosterone replacement therapy is optimally provided by an endocrinologist.

Optimal Therapeutic Approach for this Disease

Early diagnosis is the key to optimal therapy. Any male at any age with apparent small phallus, hypospadias, and small firm testes deserves chromosomal analysis.

Assessing testicular volume may be a challenge, but there are standards that may be applied throughout infancy and adolescence. An invaluable clinical tool is the Prader orchidometer, with multiple sizes ranging from a few milliliters to 25mL. The normal testicular volume range is 12-30mL, with an average volume of 15-20mL. Ultrasonography may also be used to determine testicular volume.

The phenotype is sufficiently variable throughout childhood, as it may be in the adult, to result in late diagnosis. Learning disability is often the indication for chromosomal analysis and identification of the XXY sex chromosomal variant.

Comprehensive genetic counseling and review of the clinical implications of the diagnosis should be given in an unhurried and timely manner. Coordination of care among the various consultants and the primary care physician is essential to insure optimal understanding, to guarantee appropriate medical surveillance and intervention, and to support the psychological well-being of patient and appropriate family members.

In newborns and young children with Klinefelter syndrome, spermatocytes are present in the testes and begin to undergo degeneration during puberty as the hypogonadism progresses. Recognition that the XXY male has sperm allows for intervention for eventual reproduction. Testicular sperm may be obtained by multiple testicular biopsies for assisted reproduction techniques. In vitro fertilization has produced successful pregnancy outcomes.

Little is known about the reproductive outcomes of individuals with XXY karyotype. It is generally assumed that the risk of a chromosomal abnormality in the offspring of the XXY male is low. With any couple electing in vitro fertilization with the XXY male’s sperm, prenatal fetal testing via chorionic villus sampling at 10-12 weeks gestation, or amniocentesis at 15-16 weeks gestation, for fetal chromosome analysis should be discussed.

Patient Management

The management of the XXY male is directed to the specific symptoms. Initially, in infancy and early childhood, emphasis is placed on providing support for learning disabilities and educating the family. In adolescence, supporting the psychological challenges of the teenager is essential for compliance with therapy and emotional support. The central therapeutic issue issue will be hypogonadism and the need for early treatment with testosterone therapy. Affected males will have low/normal testosterone levels and high levels of LH . These individuals have overt or compensated hypogonadism and should be treated with testosterone.

Controversy remains about when testosterone therapy should be initiated. The general consensus is that therapy should be initiated at the earliest signs of puberty. There also exists a point of view that the XXY male should be allowed to enter puberty spontaneously and then receive replacement therapy as pubertal progression lags. There is also the recommendation to start testosterone therapy very early in life, well before puberty. With these divergent views, early consultation with an endocrinologist is considered imperative.

Testosterone replacement therapy has no effect on fertility.

XXY males have increased risks for speech and language difficulties, attention deficit hyperactivity disorder, learning disabilities, and psychosocial and behavioral problems. These issues are addressed as they would be for any other child with similar challenges. Those children with delayed speech are entered into early intervention for various therapies. Developmental issues such as poor personal-social interaction and language disabilities, raising concern for an autism spectrum disorder, are approached as they would be for any other child.

There is debate about increased risk for autism spectrum disorder in XXY. If the XXY diagnosis is made before the child enters school, comprehensive psychoeducational testing is indicated to determine the child’s intelligence quotient in order to plan an appropriate individual educational program.

Congenital heart defects are common in the general population, but there appears to be an increased risk of mitral valve prolapse and insufficiency in XXY males. Electrocardiogram and echocardiogram are indicated, in general, on the basis of clinical findings, but baseline studies at the time of diagnosis may be appropriate.

Every effort should be made to avoid stigmatization of this diagnosis. Only the parents and the patient’s physicians need to be aware of the chromosomal variation. There is no need for early intervention or for teachers to be aware of the diagnosis; there is no therapeutic advantage for the individual. As the child grows and enters adolescence, he is more likely to begin asking questions about his therapy and the need for ongoing medical evaluation. Information is best given as questions are raised.

Unusual Clinical Scenarios to Consider in Patient Management

Males with tall stature and thin habitus who have behavioral patterns consistent with a pervasive developmental/autistic spectrum disorder may have fragile X syndrome. Although the physical features of XXY and fragile X syndrome may overlap, the cognitive disabilities and behavioral patterns of fragile X syndrome are distinct, and significantly more severe than the relatively mild learning disabilities associated with XXY. Fragile X males have normal to increased testicular volume. Methylation screen to determine number of CGG repeats is diagnostic of fragile X syndrome.

Mosaicism is a combination of normal 46,XY cells and 47,XXY cells, and results from postzygotic sex chromosomal nondisjunction or from the loss of one X chromosome from an XXY conception early in embryogenesis. The 46,XY/47,XXY combination is the most common form of XXY mosaicism. The phenotype of the 46,XY/47,XXY male is highly variable and is considered to be directly related to the relative proportion of the XXY cell line in various tissues of the body, particularly in the gonads. Fertility is dependent upon the effect of the normal cell line on gonadal differentiation. Males with mosaicism may have ejaculates with reduced sperm numbers (oligospermia).

Males with more than one extra X chromosome are rare. These are 48,XXXY, 48,XXYY, 49,XXXXY, and rarely, others. These variants have increased risks for cognitive disabilities, disruptive behaviors, dysmorphic features, neurological abnormalities including seizures, and skeletal abnormalities such as scoliosis and the radial-ulnar synostosis. With increasing number of X chromosomes, height is decreased.

What is the Evidence?

Lanfranco, F, Kamischke, A, Zitzmann, M, Nieschlag, E. ” Klinefelter's syndrome”. Lancet. vol. 364. 2004. pp. 273-83. (This is an outstanding summary of the authors' clinical observations over time of 189 XXY males, providing valuable statistical information on the range of phenotype variability, reviewing age related transition factors including treatment and fertility issues, and emphasising the importance of genetic counseling and psychological support of patient and family.)

Visootsak, J, Graham, JM, Samango-Spouse, C, Serdloff, R, Simpson, JL, Cassidy, B, Allnson, JE. “Kinefelter synrome”. Management of genetic syndromes. 2010. pp. 479-94. (This is the most recent comprehensive summary of the clinical characteristics of Klinefelter syndrome, with emphasis on specific clinical and developmental challenges facing the clinician. Emphasis is placed on early detection and management of issues related to healthcare surveillance.)

Paduch, DA, Fine, RG, Bolyakov, A, Kiper, J. “New concepts in Klinefelter syndrome”. Curr Opin in Urol. vol. 18. 2008. pp. 621-7. (These authors provide an excellent summary of the clinical features of Klinefelter syndrome, with photographs, and review the pathophysiology and epidemiology of gonadal failure. The article provides one of the more comprehensive summaries of the hormonal abnormalities that occur in the XXY male.)

Robinson, A, Bender, B, Linden, MG, Evans, JA, Hamerton, JL. “Summary of the clinical findings in children and young adults with sex chromosome anomalies”. Children and young adults with sex chromosome aneuploidy. 1991. pp. 225-8. (This is a brief summary of the clinical observations made by these authors over three decades on individuals with randomly detected sex chromosomal anomalies, emphasizing the importance of the method of ascertainment as to the developmental challenges for which these individuals may be at risk.)

Wikstrom, AM, Dunkel, L. ” Testicular function in Klinefelter syndrome”. Horm Res. vol. 69. 2008. pp. 317-26. (This is a comprehensive discussion of testicular function in Klinefelter syndrome, noting the evidence for the presence of germ cells in the gonads of these individuals and the process of degeneration in puberty.)

Aksgaede, L, Wikstrom, A, Rajper-De Meyts, Dunkel, L, Skakkebaek, NE, Juul, A. ” Naural history of seminiferous tubule degeneration in Klinefelter syndrome”. Hum Reprod Update. vol. 12. 2005. pp. 39-48. (This is a summary of the classical and endocrinological and histological features of XXY males from fetus to adulthood, with review of the literature about the degeneration of the seminiferous tubules in this condition.)

Giltay, JC, Maburg, MC. “Klinefelter syndrome: clinical and molecular aspects”. Exper Rev Mol Diagn. vol. 10(6). 2010. pp. 765-76. (These authors summarize the molecular aspect of Klinefelter syndrome, provide extensive discussion of the features of the XXY male at different ages, and review the impact of an extra X chromosome on gene expression and dysregulation of hormonal equilibrium.)

Ferlin, A, Schipilliti, M, Di Mambro, A, Vinnzi, C, Foresta, C. “Osteoporosis in Klinefelter's syndrome”. Mol Hum Reprod. vol. 16. 2010. pp. 402-410. (The basis for osteoporosis in the XXY male is thoroughly reviewed and various hypotheses are provided to account for the variation in clinical expression, including an algorithm for the diagnosis and therapeutic intervention for reduced bone mass in the XXY male.)

Fullerton, G, Hamilton, M, Maheshwari, A. “Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?”. Hum Reprod. vol. 25(3). 2010. pp. 588-97. (These authors provide a comprehensive review of the natural history of testicular development in Klinefelter syndrome and specifically address the issue of fertility and the genetic risk to the offspring of the XXY male. The article includes an extensive literature review of the reproductive outcomes of XXY males.)

“Understanding Klinefelter syndrome: a guide for XXY males and their families”. 1997. (This is a 31-page booklet, for families and patients, that describes Klinefelter syndrome. It provides an outstanding summary of the diagnosis, treatment, and management of the XXY male. This is a resource that may be given to all families and patients. The booklet may be obtained via the internet as an HTML document.)