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Clinical features, diagnosis, and management of Klinefelter syndrome

Clinical features, diagnosis, and management of Klinefelter syndrome
Literature review current through: Jan 2024.
This topic last updated: Oct 28, 2022.

INTRODUCTION — Klinefelter syndrome is the most common cause of primary hypogonadism. The majority of men with Klinefelter syndrome are not diagnosed. Many of these missed diagnoses are likely due to the failure of clinicians to recognize the symptoms and signs of hypogonadism and the distinctive phenotype (eg, small, very firm testes) of classic Klinefelter syndrome. Recognition and treatment of Klinefelter syndrome is important for prevention or treatment of its consequences, such as micropenis, learning disabilities, delayed puberty, infertility, and osteoporosis.

The epidemiology, pathogenesis, clinical features, diagnosis, and management of Klinefelter syndrome are reviewed here. The use of advanced reproductive technologies for men with Klinefelter syndrome and reviews of other male hypogonadal disorders are found separately. (See "Treatments for male infertility", section on 'Retrieval of sperm' and "Clinical features and diagnosis of male hypogonadism".)

EPIDEMIOLOGY — The prevalence of Klinefelter syndrome is approximately 1 to 2.5 per 1000 boys and men (0.1 to 0.25 percent) [1-4]. Only 25 to 50 percent of patients with Klinefelter syndrome are diagnosed during their lifetimes [1,3,4].

PATHOGENESIS — Klinefelter syndrome results from supernumerary X chromosomes in an XY male (X1+nY). Approximately 80 to 90 percent of men with Klinefelter syndrome are 47,XXY (47 chromosomes with an extra X) [1,5]. The extra X chromosome is due to maternal or paternal meiotic nondisjunction of the X chromosome during gametogenesis (ova or sperm production) [1,5]. Maternal and paternal nondisjunction occurs equally in Klinefelter syndrome [1,5].

Approximately 10 percent of men with Klinefelter syndrome have mosaicism (47,XXY/46XY) with 47,XXY present in some cells or tissues and the normal karyotype in other cells or tissues [1,5]. Mosaic Klinefelter syndrome is due to post-fertilization mitotic nondisjunction during early fetal development. Men with mosaic Klinefelter syndrome have a milder phenotype.

Very rarely, men may have more than two X chromosomes (eg, 48,XXXY) [5]. Men with three or more X chromosomes have a more severe phenotype of Klinefelter syndrome than those with 47,XXY karyotypes [5].

The phenotype of Klinefelter is also affected by androgen responsiveness [1,6,7]. Androgen sensitivity is related partly to polymorphic variations in the number and length of cytosine, adenine, and guanine (CAG) trinucleotide repeats in the noncoding region of the androgen receptor gene. Men with Klinefelter syndrome typically have longer CAG repeats in the androgen receptor, and the longer length of CAG repeat inversely correlates with the severity of the phenotype [1].

The genetic abnormality of Klinefelter syndrome results in progressive fibrosis and destruction of both the seminiferous tubules and the Leydig cells, causing decreased sperm production and decreased testosterone production. Abnormalities of spermatogenesis generally precede and are more severe than abnormalities in testosterone production.

CLINICAL FEATURES — The clinical features of Klinefelter syndrome differ by developmental stage and severity of the phenotype (figure 1). Because of the variability of phenotype severity and the failure of many clinicians to recognize the clinical features of Klinefelter syndrome, the majority of diagnoses are made in adulthood; the mean age at diagnosis of Klinefelter syndrome is approximately 30 years [1]. The diagnosis of Klinefelter syndrome should be suspected in any neonatal boy with micropenis, hypospadias, or cryptorchidism, in teenage boys with delayed puberty, or men who present with small testes and androgen deficiency or infertility.

Neonates and prepubertal boys — Only the most severe phenotypes of Klinefelter syndrome are recognized before puberty. Neonates with Klinefelter syndrome may present with micropenis (<1.9 cm for neonate) or clinodactyly, hypospadias, or cryptorchidism. Prepubertal boys with Klinefelter syndrome may present with behavioral abnormalities, language delay, learning disabilities, or hypertelorism. (See 'Psychosocial and cognitive abnormalities' below.)

Puberty — Many males with Klinefelter syndrome are often recognized and diagnosed at the usual age of puberty because they do not begin or complete pubertal development (including failure of testes to grow normally, incomplete virilization [eg, scant pubic and facial hair]) and gynecomastia. Boys of pubertal age with Klinefelter syndrome tend to be taller than expected based on mid-parental height and have legs that grow out of proportion to arm length. Their leg length is, on average, 4 to 8 cm greater than men without Klinefelter syndrome. This difference varies by the severity of the Klinefelter syndrome phenotype as well as genetic background. We do not recommend measuring leg length, as there is no consensus on how the measurement should be performed [7].

Adults

Typical presentation — Less severe phenotypes of Klinefelter syndrome are recognized and diagnosed in adulthood. Adult men with Klinefelter syndrome may present with infertility due to azoospermia or symptoms and signs of androgen deficiency (gynecomastia, sexual dysfunction, or osteoporosis). Men with classic Klinefelter syndrome have very small, firm testes (≤4 cc each). The small testicular volume is due to progressive fibrosis and destruction of both functional (steroidogenic and spermatogenic) compartments of the testes. Men with nonclassic Klinefelter syndrome (including men with mosaic Klinefelter syndrome) may have testes that are larger (and even normal-sized) [8-10]. Abnormalities of spermatogenesis generally precede and are more severe than abnormalities in testosterone production (figure 1).

Biochemical findings — The characteristic laboratory findings in men and boys older than pubertal age are the following: low serum total and free testosterone and high follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations. Because serum sex hormone-binding globulin (SHBG) concentrations are also higher in Klinefelter syndrome, serum free testosterone concentrations are disproportionately lower than serum total testosterone concentrations. We do not measure serum estradiol (E2) in these men, but they tend to be high-normal to slightly high. (See "Clinical features and diagnosis of male hypogonadism", section on 'Diagnosis'.)

Some men with Klinefelter syndrome may present with normal serum total testosterone concentrations and low serum free testosterone concentrations. Rarely, men with Klinefelter syndrome will have normal serum total and free testosterone concentrations at the initial evaluation; over time, serum testosterone concentrations fall as progressive fibrosis destroys the normal testicular tissue. Serum FSH concentrations are uniformly elevated and are always higher than serum LH concentrations. Most men with Klinefelter syndrome have high serum LH concentrations, but men with Klinefelter syndrome may initially present with normal serum testosterone concentrations and high-normal serum LH concentrations that rise as serum testosterone concentrations decline. Karyotype results are described below. (See 'Diagnosis' below.)

Comorbidities

Cardiovascular – Klinefelter syndrome has been associated with an increased relative risk of ischemic heart disease, mitral valve prolapse, lower extremity varicose veins and venous stasis ulcers, and deep venous thrombosis and pulmonary embolism [1,11]. The increased cardiovascular risk of deep venous thrombosis and pulmonary embolism is likely due to Klinefelter syndrome and not an adverse effect of testosterone therapy [12,13].

Pulmonary – Chronic obstructive pulmonary disease and pneumonia are more likely to be diagnosed in men with Klinefelter syndrome [11].

Musculoskeletal – In addition to an increased lifetime risk of osteoporotic fracture, osteoarthritis appears to be more common [1]. Men with Klinefelter syndrome also may have persistently decreased muscle mass and weakness (even after testosterone therapy) that is at least partially due to congenital and peripubertal hypogonadism.

Neurologic – There is an increased prevalence of essential tremor and a Parkinson-like syndrome with tremor in men with classic Klinefelter syndrome. More than 25 percent of patients with Klinefelter syndrome may have a tremor [1].

Cancer – The risk of breast cancer is up 50-fold higher in men with Klinefelter syndrome, but the absolute lifetime risk of breast cancer in these men is <1 percent [1,14]. Men with Klinefelter syndrome account for 4 percent of all cases of male breast cancer. Extragonadal germ cell tumors (especially mediastinal germ cell tumors) and non-Hodgkin lymphoma also appear to occur at higher frequency, but the absolute risk is small [1]. The lifetime risk of prostate cancer appears to be lower than the general adult male population [1]. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Klinefelter syndrome' and "Breast cancer in men", section on 'Alterations of the estrogen to androgen ratio'.)

Autoimmune disorders – Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune endocrinopathies (eg, Hashimoto's thyroiditis and type 1 diabetes mellitus) are relatively more common in men with Klinefelter syndrome [1]. However, the absolute risk appears to be small [11].

Dentofacial abnormalities – Certain dentofacial abnormalities have been associated with Klinefelter syndrome including taurodontism (an enlargement of the pulp of molars on dental radiography that might be associated with increased risk of caries), mandibular prognathism, and the absence of permanent teeth [15]. The causal relationship and the absolute and relative risk of these dentofacial abnormalities is being studied [15].

Mortality — In addition to gynecomastia, infertility, osteoporosis, genital abnormalities, and variable androgen deficiency, males with classic Klinefelter syndrome are at increased risk for other potential adverse health consequences (table 1) [1,11,14,16,17]. Any conclusions about the mortality and morbidity of Klinefelter syndrome must be tempered by the fact that the many men with Klinefelter syndrome are not recognized and diagnosed; the published reports are biased by more severe phenotypes and other factors.

The effects on mortality have been established in several epidemiologic studies of national health registries worldwide. Although these epidemiologic studies have demonstrated an increased relative risk of a broad range of morbidities and Klinefelter syndrome, the absolute increased risk of these morbidities is uncertain, but it is generally small [1,11]. Lifespan is reduced by five to six years; younger age at diagnosis is associated with a greater reduction in longevity [1]. It is likely that younger age of diagnosis is associated with a more severe phenotype that explains the greater effect on mortality. It appears that the decreased lifespan and increased risk of morbidities are due to Klinefelter syndrome per se and are not testosterone therapy [18].

Psychosocial and cognitive abnormalities — Learning and developmental disabilities are common (present in >50 percent diagnosed with classic Klinefelter syndrome) [1]. Behavioral problems occur commonly in males with Klinefelter syndrome after the neonatal period. These effects might be due to psychosocial consequences of learning disabilities and in later in life due to untreated androgen deficiency. Neuropsychiatric illness such as anxiety, attention deficit disorder, major depression, autism spectrum disorder, and schizophrenia appears to be more common in men with classic Klinefelter syndrome [1,19-22].

DIAGNOSIS

Karyotype — Klinefelter syndrome is diagnosed definitively by sex chromosome karyotyping of serum white blood cells that demonstrates a supernumerary X chromosome plus a Y chromosome. Klinefelter syndrome is generally diagnosed based on clinical presentation and confirmatory laboratory testing, including karyotype [1,23]. However, the diagnosis may also be made presumptively based on clinical presentation in adults [1]. The diagnostic approach differs according to the age of the patient and the patient's clinical presentation.

Karyotype analysis of sex chromosomes is expensive and should be done by experienced personnel in a laboratory that performs such testing frequently. If traditional cytogenetic testing is performed, at least 20 cells in metaphase should be examined to reduce the likelihood of false negative results [24]. The addition of fluorescence in situ hybridization (FISH) is superior to cytogenetic testing alone [25]. Barr body cytology is too insensitive and nonspecific, and this test is no longer used routinely in clinical practice. Cytogenetic testing is usually performed on cultured circulating blood lymphocytes, but in cases of suspected mosaicism, additional testing of cultured cells from skin and testicular tissue is required. Quantitative polymerase chain reaction (PCR) assays are less expensive and might be as accurate as cytogenetic test with FISH, but this technique has not been fully validated [26].

Prenatal and newborn diagnosis — Diagnosis in the prenatal or newborn boy requires karyotyping. Routine prenatal and newborn screening for Klinefelter syndrome are not recommended, although some experts have advocated for screening newborns [4]. Neither prenatal nor newborn screening is currently offered routinely.

If performed, prenatal screening is done on a maternal blood sample with karyotyping of fetal DNA that circulates in an unbound, cell-free state [23]. The diagnosis must be confirmed with karyotyping of cells from prenatal amniocentesis or chorionic villous sampling or postnatal testing of cells from the infant boy's blood sample. Although pregnancy termination based on prenatal diagnosis was common in the past, the largest study indicates that a minority of couples elect to terminate a male fetus with an XXY karyotype [27,28]. The clinician plays a large role in this decision-making process because couples are influenced by the perception of the consequences of this syndrome that are generally less severe than other common trisomies, such as Down syndrome.

Prepubertal and peripubertal diagnosis — Karyotyping must be done to make a definitive diagnosis of Klinefelter syndrome in prepubertal and peripubertal boys and boys at the time of puberty.

Adult diagnosis — The authors and some other experts believe that it is reasonable to make a presumptive diagnosis of Klinefelter syndrome without confirmatory sex chromosomal karyotyping in adult men with primary hypogonadism and classic phenotypic features (including small firm testes) of Klinefelter syndrome if they are not interested in conceiving. However, we do perform a karyotype analysis for all men with primary hypogonadism and clinical features of Klinefelter syndrome who are pursuing fertility with assisted reproductive technology, such as intracytoplasmic injection. We also do a karyotype in men who want a definitive confirmation of their diagnosis. (See 'Karyotype' above.)

We perform a sex chromosome karyotype in men with primary hypogonadism who are considering infertility treatment that will include intracytoplasmic injection of sperm into an ovum; there is a small risk of passing on supernumerary X chromosomes to male offspring with this technique, and the information might be useful to the prospective parents. Other potential candidates for sex chromosome karyotype analysis include men with primary hypogonadism and a classic phenotype of Klinefelter syndrome (eg, very small, firm testes ≤4 cc or prominent gynecomastia), although Klinefelter syndrome might also be diagnosed clinically in these men. (See 'Mortality' above and "Intracytoplasmic sperm injection" and 'Options for male infertility' below.)

In contrast, some experts recommend sex chromosome karyotype analysis for all men with primary hypogonadism without an obvious cause. This recommendation is based on the potential added value of knowing whether the patient is at increased risk for the morbidities that have been associated with Klinefelter syndrome. However, the increase in absolute risk of these morbidities is small, and knowledge of this small increased risk does not affect the preventive care or therapy of men with Klinefelter syndrome. (See 'Mortality' above.)

MANAGEMENT — The treatment of Klinefelter syndrome varies based on the age of the patient at diagnosis, the severity of the phenotype, and the specific clinical endpoint (figure 2). The European Academy of Endocrinology (endorsed by the European Endocrine Society) published a 2021 clinical practice guidelines on the diagnosis and management of Klinefelter syndrome [29]. Patients with a severe phenotype of Klinefelter syndrome may benefit from care from a multidisciplinary group that might include primary care physicians, endocrinologists, mental health professionals, and infertility specialists.

Inform about the diagnosis — The first step in treatment is to inform the patient of the diagnosis. The diagnosis must be provided in a gentle, sensitive manner that openly discloses the genetic basis and the potential consequences. The clinician must explain that Klinefelter syndrome is not inherited per se and that there is no fault to be assigned to either parent or to the patient. When initially discussing the potential consequences, it is important to stress the broad range of variability of the phenotype and focus on the features that are universal: a very high likelihood of eventual permanent androgen deficiency and infertility. Because the increased absolute risk of other consequences of Klinefelter syndrome is generally low, we typically review those later.

Informing a child (under 18 years old) of the diagnosis requires prior discussion and collaboration with the parents/caregiver. There is no best way to disclose the diagnosis although the following principles are useful [25].

The clinician should inform the parents of the diagnosis and answer questions related to genetics, prognosis, and treatment. Then, ask them to describe the syndrome in their own words and educate them about any misconceptions that they might express. The clinician should discuss the options for informing the child (either with or without the parents present).

For a younger boy (5 to 10 years), the key information to convey is that he does not have a condition that is deadly or contagious. He should also be informed that there is nothing that he or his parents could have done to prevent the condition.

We sometimes present information about Klinefelter syndrome in stages. An adolescent needs to be informed that this syndrome does not affect either sex or sexual orientation. It may be useful to inform an adolescent that the X chromosome is partially inactivated ("just like the other boys that they know") [30].

Clinicians must respect the wishes of parents who want to delay disclosure, but clinicians should gently inquire periodically about whether the boy might be ready for disclosure. When a boy begins to ask specific questions about his health, that is an indication of readiness. Limited evidence suggests that more children with sex chromosome abnormalities such as Klinefelter syndrome experience positive (eg, relief) or neutral reactions than negative reactions (eg, anger or anxiety) when informed of their diagnosis [31].

Informing an adult of the diagnosis of Klinefelter syndrome might also require staging of information. Many men (particularly those with prominent gynecomastia) might be concerned that they are "partially female," and they should be told that they are male (if they self-identify as male). Virtually all men who are diagnosed with Klinefelter syndrome as adults have initially presented with androgen deficiency and/or infertility. The initial focus of disclosure of the diagnosis in an adult should be on the lifelong benefit of testosterone therapy and the options for androgen replacement therapy. The clinician should also discuss the permanent damage to spermatogenesis. For a man who expresses interest in conceiving children in the future, the clinician should be prepared to discuss the options: adoption, insemination with sperm from a donor, or an attempt at extraction of sperm from the testes. The low success rate of assisted reproductive techniques should be discussed. (See "Testosterone treatment of male hypogonadism" and 'Options for male infertility' below and "Treatments for male infertility", section on 'Assisted reproductive technologies'.)

Some adult men with newly diagnosed Klinefelter syndrome and a history of significant learning disabilities or behavioral problems will be relieved to learn that these might be due to Klinefelter syndrome. The absolute risk of other potential extragonadal effects is low, so we often discuss these risks gradually (eg, when they have questions about what to expect, or if they begin to develop features of comorbidities).

Preventive and routine health care — Although there are many adverse health consequences associated with Klinefelter syndrome, there is no evidence that specific preventive or screening measures should differ from the general population. The absolute risks of adverse effects of Klinefelter syndrome appear to be low, and these risks do not justify a divergence from published guidelines for preventive health care in males.

We suggest a periodic breast examination (eg, every one to two years) because of the increased risk of breast cancer. Ultrasound or radiographic mammography is rarely useful, and imaging should be reserved for a suspicious breast or axillary mass. Clinicians should be familiar with the nongonadal disorders associated with Klinefelter syndrome. For example, the clinician should be more attentive to the possibility of autoimmune disease and psychiatric disease in these boys and men; a man with Klinefelter syndrome and unexplained arthritis is more likely to have rheumatoid arthritis or systemic lupus than the average man. (See 'Comorbidities' above.)

Testosterone therapy — Testosterone therapy is the most important component of long-term management of pubertal boys and adult men with Klinefelter syndrome. The principles, goals, and dosing of testosterone are the same as for other men with hypogonadism; these are discussed in detail separately. (See "Testosterone treatment of male hypogonadism".)

Neonates and prepubertal boys — We suggest a short course of testosterone cypionate or enanthate (eg, 25 mg injected monthly for three doses) to treat micropenis in neonatal boys and infants (up to age 1) with Klinefelter syndrome. This treatment may modestly increase penile length and girth [32,33]. Although some evidence suggests that androgen therapy may benefit specific aspects of behavioral, social, and cognitive function in prepubertal boys (ages 1 to 12) with Klinefelter syndrome [34,35], the authors of this topic recommend against this treatment because of the potential risks of early onset of puberty and decreased adult height (figure 2) [36].

Boys of pubertal age — Testosterone treatment options for boys ≥13 years old and men with Klinefelter syndrome are the same as those for any man with primary hypogonadism (see "Testosterone treatment of male hypogonadism", section on 'General approach to treatment'). For boys 13 to 18 years, the goal of testosterone therapy is to cause gradual virilization (eg, genital development [penile growth], facial and pubic hair, muscle development) without inducing early closure of bony epiphyses and decreased growth and height. We recommend low doses (50 to 100 mg) of monthly intramuscular testosterone enanthate or cypionate until growth ceases or until age 18 to 19 years.

Transdermal testosterone products and testosterone enanthate administered subcutaneously have not been approved for use in boys (due to lack of efficacy and safety data). However, transdermal and subcutaneous formulations can be used off-label at low doses (eg, one-half the usual daily adult dose) for adolescent males. Although transdermal testosterone application obviates the need for injections, adherence to monthly injections might be easier for some patients. We do not currently recommend monthly subcutaneous testosterone injections for boys, because there are no data on effectiveness of this regimen. We also do not recommend the very long-acting testosterone formulations (such as intramuscular testosterone undecanoate given every 12 weeks or testosterone pellets) in teenage boys, because it is not possible to deliver low doses of these preparations reliably.

Adults — For adult men, full doses of testosterone replacement should be used (figure 2). Serum gonadotropin concentrations should not be used to determine the testosterone dose, because this approach results in nonphysiologic doses and supraphysiologic testosterone concentrations in many men [37,38]. Instead, the testosterone dose should be based on the usual adult replacement regimens for male hypogonadism. (See "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)

We suggest initiation of testosterone therapy at typical adult replacement doses for adult men with hypogonadism. Men with very low serum testosterone concentrations should be informed that they might experience behavioral and mood changes (eg, due to increased libido) with immediate initiation of typical adult replacement doses of testosterone. In this setting, it may be prudent to initiate one-quarter to one-half of the usual replacement dose of testosterone with gradual escalation to a full adult replacement dose over a few months. For men who experience mood symptoms with full dose testosterone, we typically reduce the dose of testosterone temporarily. (See "Testosterone treatment of male hypogonadism".)

Although some men with Klinefelter syndrome have normal serum testosterone concentrations, we suggest treating with testosterone if the serum luteinizing hormone (LH) concentration is elevated, particularly in pubertal boys and men with symptoms and/or signs of testosterone deficiency or those with low-normal serum testosterone concentrations. Elevation of serum LH indicates that the serum testosterone is low enough to activate the hypothalamic-pituitary-testicular axis. Our approach is different from the European Academy of Endocrinology guidelines. In general, men with Klinefelter syndrome and low serum testosterone concentrations report improved sense of well-being and sexual function with testosterone replacement therapy [1]. However, many aspects of Klinefelter syndrome persist or do not completely remit. For example, certain aspects of cognition might improve, but overall cognition is not improved in boys and men with Klinefelter syndrome who are treated with an androgen [1]. Bone density increases with testosterone, but it generally does not normalize compared with peers, and the quality of bone might remain below average in patients with Klinefelter syndrome [1].

Options for male infertility

Assisted reproductive technologies — The two most effective treatments for infertility in men with Klinefelter syndrome remain adoption and the use of donor sperm. However, patients with Klinefelter syndrome who are interested in having children should be informed about the development of microscopic testicular extraction of sperm (microTESE). Between 45 to 50 percent of men with Klinefelter syndrome have sperm that can be extracted by microTESE for use in assisted reproductive techniques such as intracytoplasmic injection of sperm into an ovum [39-41]. Approximately one-half of these men will conceive with assisted reproductive techniques. The reported rates of microTESE extraction of sperm reflect the experience of highly specialized centers; the rates of successful sperm extraction with microTESE are lower for less experienced specialists. (See "Treatments for male infertility", section on 'Retrieval of sperm'.)

Although there are no data to support the practice, testosterone therapy is often withheld for six months prior to an attempt to harvest sperm. Normal or high serum and intratesticular gonadotropin concentrations are required for optimal spermatogenesis so exogenous testosterone therapy is discontinued to ensure that elevated serum gonadotropins that might stimulate sperm production are not suppressed. Because spermatogenesis takes three months from initiation to release of mature sperm, testosterone therapy is withheld for at least three months and usually six months.

Extraction and cryopreservation of sperm in boys and men — The natural history of Klinefelter syndrome is progressive testicular fibrosis. An area of uncertainty is whether to harvest and freeze sperm in teenage boys and men soon after the diagnosis. It is difficult to persuade peripubertal boys to submit a seminal fluid sample, and rarely will peripubertal boys (or men) with Klinefelter syndrome have sperm in their ejaculate [39,40]. Based on very limited data, it appears that peripubertal boys with Klinefelter syndrome are not more likely than men with Klinefelter syndrome to have sperm found during attempted surgical extraction [39-41].

We suggest against surgical extraction and cryopreservation of sperm before desired conception. The rationale for this recommendation is that it is storage of cryopreserved sperm is expensive (approximately USD $1000 to $3000 per year), with some risk of degradation of sperm viability. In addition, there is no good evidence of better outcomes (conception or live births) compared with waiting to do sperm extraction when conception is desired.

Males with mosaic Klinefelter syndrome, normal or slightly elevated serum LH concentrations, or testes with total volume 8 cc or larger are more likely to have sperm in the ejaculate [10]. We recommend that seminal fluid analysis be performed promptly in such patients because it is likely cost effective to cryopreserve sperm for them. As noted above, sperm can be extracted from approximately one-half of men with Klinefelter syndrome using microTESE; sperm can then be used for assisted reproductive techniques. (See 'Assisted reproductive technologies' above and "Treatments for male infertility", section on 'Retrieval of sperm'.)

Ineffective therapies — We do not recommend the use of gonadotropins, aromatase inhibitors, or selective estrogen receptor modulators to increase spermatogenesis. Although some experts postulate that gonadotropin therapy or treatments that further increase serum gonadotropins (eg, aromatase inhibitors, selective estrogen receptor modulators) might increase residual spermatogenesis, this hypothesis has little supportive evidence.

Behavioral abnormalities and cognitive and learning disabilities — Many boys with Klinefelter syndrome have behavioral abnormalities and learning disabilities. Most individuals with Klinefelter syndrome have normal or slightly low overall cognitive function, but good overall health. Specific education such as speech and reading therapy might be beneficial. Counseling might be useful to address anxiety about their cognition and health [1].

Gynecomastia — For adolescents and men with cosmetically bothersome gynecomastia, reduction mammoplasty is beneficial. This surgery should be delayed until several months after testosterone therapy has been initiated because untreated hypogonadism will cause recurrent breast tissue growth. (See "Management of gynecomastia", section on 'Surgery'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testosterone therapy in men" and "Society guideline links: Male infertility or hypogonadism" and "Society guideline links: Male sexual dysfunction".)

SUMMARY AND RECOMMENDATIONS

Epidemiology – Klinefelter syndrome (47,XXY) is the most common cause of primary hypogonadism. The majority of men with Klinefelter syndrome are never diagnosed because clinicians fail to recognize the phenotypic features. (See 'Epidemiology' above.)

Clinical features – Klinefelter syndrome should be suspected in infants with hypospadias or micropenis, teenage boys with delayed puberty and small testes (≤4 cc each), and men with low or low-normal serum testosterone concentrations and high serum gonadotropin concentrations (follicle-stimulating hormone [FSH] greater than luteinizing hormone [LH]). (See 'Adults' above.) (table 1 and figure 1).

In addition to infertility and the complications associated with androgen deficiency, Klinefelter syndrome increases the risk of learning and language disorders, metabolic syndrome and diabetes mellitus, cardiovascular events, thromboembolic disease, autoimmune disease, as well as certain cancers (table 1 and figure 1). (See 'Clinical features' above.)

Diagnosis – The definitive diagnostic test for Klinefelter syndrome is sex chromosome karyotyping that reveals at least one supernumerary X chromosome with a Y chromosome. (See 'Diagnosis' above.)

Testosterone therapy

Prepubertal boys – We suggest not starting testosterone therapy in prepubertal boys, as the potential benefits on behavioral, social, and cognitive function are outweighed by the risks of early onset of puberty and decreased adult height (Grade 2C). (See 'Neonates and prepubertal boys' above.)

Pubertal boys and adult menTestosterone therapy is the most important component of long-term management of pubertal boys and adult men with Klinefelter syndrome. The principles, goals, and dosing of testosterone are the same as for other men with hypogonadism. (See "Testosterone treatment of male hypogonadism".)

We suggest starting testosterone therapy in all pubertal boys and adult males with low serum testosterone concentrations (Grade 2C). In addition, we typically start testosterone therapy in those who have a normal serum testosterone but elevated serum LH. This is particularly important in pubertal boys and men with symptoms and/or signs of testosterone deficiency or those with low-normal serum testosterone concentrations.

-Pubertal boys – We use low doses (50 to 100 mg) of monthly intramuscular testosterone enanthate or cypionate for pubertal boys starting at age 13 years until either growth ceases or until age 18 to 19 years. The goal of testosterone therapy in this age group is to cause gradual virilization (eg, genital development [penile growth], facial and pubic hair, muscle development) without inducing early closure of bony epiphyses and decreased growth and height. (See 'Boys of pubertal age' above.)

We recommend not using subcutaneous testosterone injections for boys, because there are no data on effectiveness of this regimen (Grade 2C). We also recommend not using the very long-acting testosterone formulations (such as intramuscular testosterone undecanoate given every 12 weeks or testosterone pellets) in teenage boys, because it is not possible to accurately deliver low enough doses of these preparations (Grade 2C).

-Adult men – For adult men with Klinefelter syndrome (figure 2), we suggest full doses of testosterone replacement (Grade 2C). (See 'Adults' above and "Testosterone treatment of male hypogonadism", section on 'Hypogonadal adult men'.)

Infertility treatment – Options for men who are infertile due to Klinefelter syndrome include adoption, insemination of the female partner with donor sperm, or sperm harvesting with microscopic testicular sperm extraction (microTESE) and use of assisted reproductive techniques for insemination (figure 2). (See 'Options for male infertility' above and "Treatments for male infertility", section on 'Retrieval of sperm'.)

Males with mosaic Klinefelter syndrome, normal or slightly elevated serum LH concentrations, or testes with total volume 8 cc or larger are more likely to have sperm in the ejaculate. Seminal fluid analysis should be performed promptly in such patients because it is likely cost effective to cryopreserve sperm for these individuals. (See 'Extraction and cryopreservation of sperm in boys and men' above.)

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Topic 13921 Version 9.0

References

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