Klinefelter Syndrome

Practice Essentials

In 1942, Klinefelter et al published a report describing nine men with a constellation of features: testicular dysgenesis, microorchidism, eunuchoidism, gynecomastia, elevated urinary gonadotropins, and azoospermia.^[1]  The etiology was thought to be due to an endocrine disorder of unknown cause, until 1959, when Jacobs et al recognized that Klinefelter syndrome was a chromosomal disorder in which there is an extra X chromosome, resulting in the karyotype 47,XXY.^[2]

Today, the term Klinefelter syndrome (KS) refers to a group of chromosomal disorders in which the normal male karyotype, 46,XY, has at least one extra X chromosome. XXY aneuploidy, the most common human sex chromosome disorder, has a prevalence of 1 in 500 males.^[3] It is also the most common chromosomal disorder associated with male hypogonadism and infertility. 

Other sex chromosomal aneuploidies are included in the KS group of chromosomal disorders. Arising less frequently, 48,XXYY and 48,XXXY occur in 1 per 17,000 to 50,000 male births, while 49,XXXXY has an incidence of 1 per 85,000 to 100,000 male births.^[3]

Signs and symptoms of Klinefelter syndrome

Klinefelter syndrome is characterized by hypogonadism (micro-orchidism [small testes], oligospermia/azoospermia), gynecomastia in late puberty, hyalinization and fibrosis of the seminiferous tubules, elevated urinary gonadotropin levels, and behavioral concerns.

Images of phenotypic features seen in Klinefelter syndrome are shown below:

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Adolescent male with gynecomastia and Klinefelter syndrome.

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Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.

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Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.

Workup in Klinefelter syndrome

Klinefelter syndrome may be diagnosed prenatally from fetal cytogenetic analyses performed on chorionic villi or amniocytes. If Klinefelter syndrome is not diagnosed prenatally, a patient with 47,XXY karyotype may demonstrate various subtle, age-related clinical signs that would prompt diagnostic testing. Karyotype analysis on peripheral blood lymphocytes, the XCAT-KS buccal swab test, fluorescence in-situ hybridization (FISH), and microarrays are options for postnatal diagnostic testing.

Management

Early identification and anticipatory guidance are extremely helpful in Klinefelter syndrome. Management and treatment should focus on 3 major facets of the syndrome: hypogonadism, gynecomastia, and psychosocial problems. Androgen (testosterone) replacement therapy is an important aspect of treatment.

A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems.

Physical therapy is recommended for boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. Occupational therapy is advised in boys with motor dyspraxia.

Until 1996, men with Klinefelter syndrome were considered infertile. Since then, however, developments in microsurgical techniques and advances in artificial reproductive technologies (ART) have enabled over 50% of men with Klinefelter syndrome to sire their own children.^{[4, 5, 6, 7, 8]}

• References

Pathophysiology

The X chromosome carries genes that have a role in many organ systems, playing a part, for example, in testes function, brain development, and growth.^[9] Consequences of an extra X chromosome, usually acquired through a nondisjunctional error during parental gametogenesis, include hypogonadism, gynecomastia, and psychosocial behavioral concerns.

The addition of more than one extra X or Y chromosome to a normal male karyotype results in variable cognitive and physical abnormalities. As the number of supernumerary X chromosomes increases, somatic and cognitive development are more likely to be affected. Skeletal and cardiovascular abnormalities can become increasingly severe. Gonadal development is particularly susceptible to each additional X chromosome, resulting in seminiferous tubule dysgenesis and infertility, as well as hypoplastic and malformed genitalia, as seen in polysomy X males. A form of primary testicular failure occurs in males with Klinefelter Syndrome, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland.

Moreover, mental capacity diminishes with additional X chromosomes. The intelligence quotient (IQ) score is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material.

A study by van Rijn et al indicated that information processing becomes more difficult in individuals with a 47,XXY karyotype as the social load related to the task increases. For example, with regard to visuospatial processing, which was associated with no social load, 17% of subjects in the study had trouble with the task, while in terms of facial recognition (medium social load) and facial expression of emotion (high social load), 26% and 33% of individuals, respectively, encountered difficulties.^[10]

 Androgen deficiency causes the following:

• Eunuchoid body proportions/female distribution of adipose tissue
• Sparse or absent facial, axillary, pubic, or body hair
• Gynecomastia 
• Decreased muscle mass and strength
• Decreased physical endurance
• Small testes and penis
• Diminished libido
• Loss of functional seminiferous tubules and Sertoli cells, causing decrease in inhibin B levels (the hormone regulator of the follicle-stimulating hormone [FSH] level)
• Altered hypothalamic-pituitary-gonadal axis in pubertal boys 

Men with Klinefelter syndrome have a higher risk of autoimmune diseases, diabetes mellitus and its associated complications, osteopenia and osteoporosis, tumors (breast and germ cells), systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome.^{[11, 12]}  This higher risk is comparable to the disease risk for 46,XX females.

Sera laboratory results of a typical male with Klinefelter syndrome demonstrate low to low-normal testosterone levels, high luteinizing hormone (LH) and FSH levels, and, often, elevated estradiol levels. Decline of testosterone production progresses over the patient's life span, but not all male patients have hypogonadism.^[13]  It is unclear if the morbidity associated with Klinefelter syndrome is a result of hypogonadism and hyperestrogenism or is due to abnormal function of X chromosome–linked genes.^[6]

A study by Close et al reported that in boys with Klinefelter syndrome, the degree of phenotypic abnormality is tied to the risk for impaired quality of life. Linear regression analysis indicated that phenotype accounted for 22% of the variance in quality of life among the 43 boys in the study.^[14]

A Danish survey report, by Skakkebæk et al, indicated that persons with Klinefelter syndrome tend to have reduced mental and physical quality of life, caused directly by Klinefelter syndrome and indirectly by factors that, compared with controls, include lower levels of income, physical activity, and sexual function.^[15]

• References

Epidemiology

Frequency

United States

Klinefelter syndrome (XXY aneuploidy) is the most common human sex chromosome disorder.

• Approximately 1 in 500-600 males is born with an extra X chromosome.
• The prevalence rate is 5-20 times higher in males who are mentally challenged than in the general male population.
• Approximately 250,000 men in the United States have Klinefelter syndrome.^[16]

Mortality/Morbidity

About 40% of concepti with Klinefelter syndrome survive in utero to the postnatal period.

• In general, the severity of somatic malformations in Klinefelter syndrome is proportional to the number of supernumerary X chromosomes; mental retardation and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY.
• The mortality rate is not significantly higher than in healthy individuals.

Race

Klinefelter syndrome does not have any racial predilection.

Sex

Klinefelter syndrome (47,XXY) results from an additional X chromosome on an XY background; therefore, this condition affects only males.

Age

Klinefelter syndrome is often undiagnosed in young males. Diagnosis frequently occurs in adulthood; however about 75% of sex chromosome aneuploidies are never diagnosed. For suspected 47,XXY males, common indicators for karyotype analysis on peripheral blood are hypogonadism and infertility.

• References

History

Hypogonadism, gynecomastia, and infertility are common symptoms that lead to the diagnostic evaluation of males for Klinefelter syndrome.

Other symptoms include the following:

• Tall height with long arms and legs
• Delayed or incomplete pubertal development
• Sparse facial, body, and sexual hair
• Erectile dysfunction
• Osteoporosis
• Breast malignancy
• Speech and language deficits (especially expressive language)
• Learning disabilities (lower verbal IQ than performance IQ scores)
• Poor self-esteem (increased incidence of anxiety, depression)
• Behavioral problems (substance abuse)

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Physical

Frequently associated medical disorders

These include the following.^[17]

Motor, cognitive, and behavioral dysfunction

Poor muscle tone and strength, as well as impaired gross and fine motor skills, coordination, dexterity, and running ability, are observed. Synkinetic movements and tremor can be seen in early childhood and may persist into adulthood.^{[18, 19]}

Cognitive phenotype is manifested as deficits in the specific domains of language and executive functions. Expressive language is affected more than comprehension or receptive language skills. Problems in understanding complex grammatical constructions, oral language production, word retrieval, and oral narrative construction are observed in these patients.^[20]  A study by Skakkebæk et al suggested that in persons with KS, the level of social engagement has an impact on executive cognitive functioning and/or vice versa. The study indicated that while lower general intelligence seems to be the principal factor in memory deficits among these individuals, a combination of decreased intelligence and lower social skills produce deficits in executive function.^[21]

Schizophrenia, psychosis, and bipolar disorder have been reported in males with Klinefelter syndrome.^[22]

Tumors/Cancer

Mediastinal tumors may occur in young patients, presenting as precocious puberty; histologically, these neoplasms are classified as mixed germ cell tumors. Mediastinal tumors in older males present with thorax-associated symptoms, primarily chest pain, dyspnea, and cough; mixed germ cell tumors are more common, but teratomas and other mixed tumors occur.^[23]

Breast cancer and testicular cancer are reported, although a clear relationship between Klinefelter syndrome and testicular cancer has not been documented.

Vascular disease

Vascular diseases associated with Klinefelter syndrome include hypostatic ulceration, deep vein thrombosis, pulmonary embolism, and ischemic heart disease.

Endocrine/metabolic and autoimmune diseases

Hypogonadism (pathognomonic) and associated osteoporosis occur. Bone density decreases in 25% of males with Klinefelter syndrome, with this most likely being related to decreased bone formation, increased bone resorption, and/or hypogonadism.

An increased incidence of diabetes mellitus, obesity, hypothyroidism, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus have been reported in males with Klinefelter syndrome.

Other observations

Growth

Infants and children achieve normal height, weight, and head circumference. Height velocity shows a notable increase between ages 5 and 8 years. Adults with Klinefelter syndrome are usually taller than nonaffected adult males, reaching a mean final height of about 185 cm (73 in). XXY males (see the image below) also have disproportionately long arms and legs. About 25% of patients have fifth-finger clinodactyly. Some males with Klinefelter syndrome variant 49,XXXXY have short stature.

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G-banded 47,XXY karyotype.

CNS

Contrary to other genetic syndromes that arise from chromosomal trisomy (eg, Down syndrome, trisomy 18), the overall cognitive abilities of males with Klinefelter syndrome typically are within the range of average intellectual ability.^[24]  Most males with the 47,XXY karyotype have normal intelligence. Intellectual disability occurs in males with Klinefelter syndrome variants, who have a higher number of X chromosomes.

About 70% of patients have minor developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder. Evidence for more general impairments in language has been consistent, with the most widely observed deficits having been reported in encoding of verbal information, auditory processing, comprehension, and processing speed. Expressive speech and verbal fluency are also affected.^[25]

Behavioral problems and psychological distress are reported and may be due to poor self-esteem, compromised psychosocial development, or an inability to deal with stress. Psychiatric disorders with features of anxiety, depression, neurosis, and psychosis are more common than in the general population.

Dental

About 40% of patients have taurodontism, a dental finding characterized by enlargement of the molar teeth by an extension of the pulp. In comparison, the incidence of taurodontism is about 1% in XY males.

Sexual characteristics

Genital abnormalities are not commonly observed in 47,XXY males. This is an important observation because Klinefelter syndrome is considered a cause of genital abnormality or ambiguity.^[26]  The genital phenotype can include complete sex reversal, true hermaphroditism (eg, ovotestes), testicular feminization, and ambiguous genitalia/undervirilization (eg, hypospadias, micropenis, epispadias, female external genitalia).

Pubertal changes with lack of secondary sexual characteristics are due to decreased androgen production. This results in sparse facial, body, or sexual hair; a high-pitched voice; and body fat distribution as is observed in females. By late puberty, 30-50% of boys with Klinefelter syndrome present with gynecomastia, which is due to elevated estradiol levels and an increased estradiol:testosterone ratio. The risk of developing breast carcinoma in Klinefelter syndrome is at least 20 times higher than in healthy individuals. There is also an increased risk of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.

Postpubertal males may have testicular dysgenesis (small firm testis; testis size < 10 mL). Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Most males with a 47,XXY karyotype are infertile, but patients with Klinefelter syndrome mosaicism (46,XY/47,XXY) can be fertile. Guidelines for the assessment and treatment of people with fertility problems have been established.^[27]

A literature review by Deebel et al indicated that, while azoospermia is a characteristic of Klinefelter syndrome, patients are frequently positive for spermatogonia. Indeed, spermatogonial cells were found in 100% of fetal/infantile patients and in 83%, 42.7%, and 48.5% of prepubertal, peripubertal, and adult patients. In addition, positive spermatogonia results were found in 46.4% of peripubertal/adolescent patients and 24.3% of adult patients, who were negative for spermatozoa.^[28]

Cardiac and circulatory problems ^[29]

Mitral valve prolapse occurs in 55% of patients. Varicose veins occur in 20-40% of patients. The prevalence of venous ulcers is 10-20 times higher than in healthy individuals, and the risk of deep vein thrombosis and pulmonary embolism is increased.

A Swedish study found the standardized incidence ratio for venous thromboembolism (VTE) in Klinefelter syndrome to be 6.43, with a ratio of 12.10 in persons younger than age 30 years and 2.07 in persons aged 70 years or older. Based on the study's findings, an association exists between Klinefelter syndrome and a high risk for VTE. The authors suggest that Klinefelter syndrome could be recognized as a genetic hypercoagulable state.^[30]

A study by Chang et al also found the thrombosis risk to be higher in Klinefelter syndrome, with hazard ratios for VTE and total thrombotic death, as measured against a comparison cohort, being 3.95 and 1.76, respectively. The investigators also reported an insignificant decrease in venous thromboembolism and thrombotic deaths in patients who received testosterone treatment.^[31]

Klinefelter syndrome variants/sex chromosome aneuploidies

Variants of Klinefelter syndrome are as follows^{[32]  [33]} :

• 48,XXYY variant: Patients typically have intellectual challenges (IQ range 60-80, delayed speech, learning disabilities); tall stature (adult height >6 feet); eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes and penis.
• 48,XXXY variant: Patients typically have intellectual challenges (IQ range 40-60, marked speech delay, slow motor development, poor coordination), average or tall stature, abnormal face (epicanthal folds, ocular hypertelorism, flat nasal bridge), gynecomastia (33-50%), hypergonadotrophic hypogonadism, hypoplastic penis, small testes, fifth-finger clinodactyly, and radioulnar synostosis. 
• 49,XXXYY: Patients typically have severe intellectual disabilities; passive, but occasionally aggressive, behavior and temper tantrums; tall stature; dysmorphic facial features; gynecomastia; and hypogonadism.
• 49,XXXXY variant: Males are severely intellectually challenged (IQ range 20-60). Patients have short stature and are microcephalic with dysmorphic facial features (ocular hypertelorism, epicanthal folds, flat nasal bridge, prognathism), and a short or broad neck. Other clinical features include severely impaired language, behavioral problems, low birth weight, cleft palate, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (radioulnar synostosis, genu valgus, pes cavus, fifth-finger clinodactyly), muscular hypotonia, hyperextensible joints, hypergonadotropic hypogonadism, hypoplastic genitalia, and cryptorchidism. 

• References

Causes

In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male.^[34]

The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis).^[35] Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. Seventy-five percent of maternal nondisjunction cases are caused by meiosis I errors, which are associated with increased maternal age. Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome.^[36]

Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. Men with mosaicism are less affected and are often not diagnosed.^[6]

The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome.

• The AR gene contains a highly polymorphic trinucleotide (CAG) repeat sequence in exon 1, and the length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens.
• In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.
• Individuals with short AR CAG repeats have been found to respond better to androgen therapy, to form more stable partnerships, and to achieve a higher level of education compared with individuals with long CAG repeats.^{[37, 38]} Conversely, long AR CAG repeat lengths are associated with increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia.
• Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals.
• In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.

The most common karyotype is 47,XXY, which accounts for 80-90% of all cases. Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY, are rare.

• The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote. These forms can arise from a 46,XY zygote or a 47,XXY zygote.
• Variant forms of Klinefelter syndrome include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY.

• References

Laboratory Studies

Prenatal and postnatal diagnostic testing

Klinefelter syndrome may be diagnosed prenatally from fetal cytogenetic analyses performed on chorionic villi or amniocytes. Noninvasive prenatal tests (NIPT) that analyze cell-free fetal DNA circulating in maternal blood are also available.^{[40, 41]}

If Klinefelter syndrome is not diagnosed prenatally, a patient with 47,XXY karyotype may demonstrate various subtle, age-related clinical signs that would prompt diagnostic testing. These include the following^[33] :

• Infants - Hypospadias, small phallus, cryptorchidism (undescended testes)
• Toddlers - Developmental delay (especially expressive language skills), hypotonia 
• Elementary school–aged boys - Language delay (especially expressive language skills), learning disabilities, delayed social development, pervasive developmental disorder (PDD-NOS), mild autism spectrum disorder, attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD)
• Older boys and adolescent males - Tall stature; delayed or incomplete pubertal development with eunuchoid body habitus; gynecomastia; small, firm testes; sparse body hair
•  Adults - Testicular failure, significantly diminished or absent sperm count and/or breast malignancy, dental problems, delay in vocational success, anxiety and/or depression, mood disorders

Karyotype analysis on peripheral blood lymphocytes, the XCAT-KS buccal swab test, fluorescence in-situ hybridization (FISH), and microarrays are options for postnatal diagnostic testing.

The 47,XXY karyotype is found in 80-90% of males who are diagnosed with Klinefelter syndrome. About 10% of patients have mosaicism (more than one cell line): 46,XY/47,XXY; 46,XY/48,XXXY; and 47,XXY/48,XXXY. Remaining cases include karyotype variants such as 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY. About 1% of cases are due to a structurally abnormal X in addition to a normal X and Y, such as 47,X,i(Xq)Y and 47,X,del(X)Y.

Androgen receptor gene quantitative real-time polymerase chain reaction (AR-qPCR) technique

This is a simple and reliable screening method for the diagnosis of patients with Klinefelter syndrome or other chromosomal disorders involving an aberrant number of X chromosomes.^[42]

The screening method determines the copy number assessment of the androgen receptor (AR) gene, located at Xq11.2-Xq12. 

Gonadal function

From childhood with progression to early puberty, the pituitary-gonadal function observed is within normal limits for 47,XXY males.^[43]

At midpuberty and later, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations rise to hypergonadotropic levels, inhibin B levels fall until they are undetectable, and testosterone levels are at low or low-normal levels after an initial increase. Hence, most adult males with Klinefelter syndrome have hypergonadotropism with varying degrees of androgen deficiency.^[43]

Hormone testing

A complete hormonal evaluation includes plasma levels of FSH, LH, testosterone, estradiol, prolactin, and insulinlike growth factor (IGF)–1. Young males (aged 12-14 years) tend to have high plasma FSH, LH, and estradiol levels and low plasma testosterone levels.

Forty-seven percent of men with Klinefelter syndrome have adrenal steroidogenic deficiency, so cortisol levels should be routinely measured.^[44]  

Serum osteocalcin levels are decreased and the hydroxyl-proline:creatinine ratio is increased, reflecting decreased formation and increased resorption of bone.

Urinary gonadotropins are increased due to abnormal Leydig cell function.

Administration of human chorionic gonadotropin (hCG) will increase testosterone levels in men with Klinefelter syndrome, but the response is diminished when compared with the unaffected male population.

Routine bone density screening

Bone density screening is recommended because androgen deficiency significantly increases the risk of osteopenia and osteoporosis.

Hypercoagulability screening

Men with Klinefelter syndrome have an increased risk of deep vein thrombosis and pulmonary embolism. Consider screening men with 47,XXY or other sex chromosomal aneuploidies for genetic mutations that lead to hypercoagulability states.^[6]

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Imaging Studies

Echocardiography is performed to assess for mitral valve prolapse.

Radiography is performed to assess for bone density, radioulnar synostosis, and dental concerns (taurodontism).

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Histologic Findings

In prepubertal boys with Klinefelter syndrome, testicular biopsies may reveal preservation of seminiferous tubules with reduced numbers of germ cells; Sertoli and Leydig cells appear normal.^[43]

Testicular biopsies of adult males with Klinefelter syndrome are characterized by extensive fibrosis and hyalinization of the seminiferous tubules and hyperplasia of the interstitium; however, the tubules may show residual foci of spermatogenesis. Histologic findings may include small, firm testes with seminiferous tubular hyalinization; sclerosis; and atrophy with focal hyperplasia of mostly degenerated Leydig cells. Germ cells are markedly deficient or absent.^[43]

In Klinefelter syndrome males with mosaicism, a progressive degeneration and hyalinization of seminiferous tubules occurs following puberty, despite the presence of normal-sized testes and spermatogenesis at puberty.

Histology of gynecomastic breasts reveals hyperplasia of interductal tissue.

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Medical Care

Early identification and anticipatory guidance are extremely helpful in Klinefelter syndrome. Management and treatment should focus on 3 major facets of the syndrome: hypogonadism, gynecomastia, and psychosocial problems.

Androgen replacement therapy

Androgen (testosterone) replacement therapy is an important aspect of treatment. Historically, testosterone replacement was started at puberty, around age 12 years, with the dose increased over time, until it was sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).^[33]  Currently, the Association for X and Y Chromosome Variations (AXYS) advocates for close monitoring of development and progression of puberty, in order to properly determine if and when testosterone treatment should be initiated. For some XXY males, gender counseling may be requested.^[45]

Androgen replacement therapy corrects androgen deficiency; hence, the treatment promotes normalization of body proportions and development of normal male secondary sex characteristics. Regularly scheduled testosterone injections promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis. In addition, there are the long-term beneficial effects of decreasing the risks of autoimmune disease and breast cancer. However, testosterone therapy does not treat infertility or gynecomastia.^[33]

A study by Samango-Sprouse et al suggested that early hormonal therapy (EHT) can improve social behavior in boys with Klinefelter syndrome. The study participants were boys diagnosed prenatally with 47,XXY. Twenty-nine young boys each received three injections of 25 mg testosterone enanthate and were compared with 57 controls (young boys who received no EHT). As tested using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale (2nd ed), and Child Behavior Checklist for Ages 6-18, the investigators found significant social behavior improvements in the EHT group when compared with the control group.^[46]  The authors of the study believe that EHT helps to significantly minimize developmental challenges and behavioral issues in 47,XXY boys.

A double-blind, randomized trial by Ross et al of low-dose androgen treatment in prepubertal boys with KS found improvement at 24 months in visual-motor function, with secondary analyses indicating that androgen therapy had also positively impacted anxiety, depression, and social problems. However, cognitive function and hyperactive and aggressive behaviors were not significantly affected.^[47]

Speech and behavioral therapy

A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems. In children, early speech and language therapy is particularly helpful for developing skills in the understanding and production of more complex language.

Boys with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation (IEP) to assess their learning strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate educational resources and classroom placement.

Physical and occupational therapy

Physical therapy is recommended for boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. Occupational therapy is advised in boys with motor dyspraxia.

Treatment for infertility

Until 1996, men with Klinefelter syndrome were considered infertile. Since then, however, developments in microsurgical techniques and advances in artificial reproductive technologies (ART) have enabled over 50% of men with Klinefelter syndrome to sire their own children. Success has been achieved through a combination of microsurgical testicular sperm extraction (TESE) and the use of freshly retrieved sperm for in-vitro fertilization (IVF).^{[4, 5, 6, 7, 8]}  TESE is the process of removing a small portion of testicular tissue under local anesthesia and extracting the few viable sperm present in that tissue for intracytoplasmic sperm injection (ICSI). Intracytoplasmic sperm injection (ICSI) has offered XXY men an increased chance to father a child. A study of 42 men with Klinefelter syndrome revealed a sperm retrieval rate of 72% per testicular sperm extraction attempt, with adequate sperm for ICSI found in 69% of subjects (29 of 42 men). Thus, TESE and ICSI may be considered for males with azoospermia and Klinefelter syndrome.^[4]  

Men with Klinefelter mosaic cell lines may have viable sperm in their ejaculate and hence be able to father a child without assisted reproductive technology.

Genetic counseling

The etiology of 47,XXY and sex chromosome aneuploidies is due to a chromosomal nondisjunction process. Recurrence risk is not known to be increased above the risk in the general population; hence there is no increased likelihood of a nondisjunctional event reoccurring in a particular family. Physicians and genetic counselors should provide parents with information from unbiased follow-up studies of boys diagnosed with Klinefelter syndrome. Revealing the condition to an affected male is probably best at the time of mid- to late adolescence, when he is old enough to understand his condition.

Reproductive genetic counseling

Sperm from patients with presumptive nonmosaic 47,XXY karyotype have been used successfully in medically assisted reproduction. However, the origin of meiotic products of men with the nonmosaic 47,XXY karyotype remains unclear. Mosaicism cannot be excluded in the nonmosaic 47,XXY karyotype.^[48]  The presence of a normal XY germ cell line in the testis could explain the production of normal haploid sperm in these apparently nonmosaic patients. Nevertheless, peripheral lymphocyte karyotyping neither predicts the chromosomal constitution of the testis cells nor the presence or absence of spermatogenesis.^[49]

ICSI is associated with an increased risk of producing a chromosome anomaly in offspring.^[50] IVF is also associated with an increased risk for de-novo chromosomal aberrations, especially those involving the sex chromosomes.^{[51, 52]}

Reproductive genetic counseling of patients with the 47,XXY karyotype remains difficult. Some authors have recommended preimplantation or prenatal diagnosis after ICSI using sperm cells from patients with the 47,XXY karyotype.^{[53, 54, 55, 56]} Arguments from authors who propose a preimplantation genetic diagnosis (PGD) include the increased risk of producing sex chromosomal–abnormal offspring (the unbalanced offsprings are 47,XXX or 47,XXY karyotypes).^{[57, 58, 59, 60, 56]}

The genetic risk in the offspring of patients with 47,XXY karyotype remains unknown but is presumably low. This risk concerns sex chromosomal and autosomal aneuploidy. Genetic counseling should be reassuring, and management of the pregnancy should proceed with caution.^[61]

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Surgical Care

Mastectomy may be indicated for gynecomastia, which can place considerable psychological strain on the patient.

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Consultations

Consultations may include the following:

• Clinical geneticist/genetic counselor
• Endocrinologist (treatment approach to androgen replacement therapy)
• Surgeon (evaluation for breast tissue removal) 
• Dentist (focus on dental health preservation/restoration)
• Psychologist
• Speech therapist

In a mixed-method study by Close et al, parents reported that a lack of guidance and case coordination increased the challenges of providing childcare for their sons with Klinefelter syndrome. The study also found parental age–related differences with regard to the stress, quality of life, and family management difficulties associated with raising a son with 47,XXY.^[62]  

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Diet

No special diet is needed.

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Activity

No activity restrictions are required.

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Medication Summary

Androgen replacement therapy is used to correct androgen deficiency, to provide appropriate virilization, and to improve psychosocial status. Regular testosterone injections can promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis.

• References

Testosterone enanthate (Delatestryl) or cypionate (Depo-Testosterone)

• Dosing, Interactions, etc.

Clinical Context:  Major therapeutic aims are to reduce serum gonadotropin concentrations to the upper limits of normal and to gradually induce virilization.

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Class Summary

Exogenous androgen (testosterone) is the treatment of choice for many aspects of Klinefelter syndrome.

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Further Outpatient Care

Management of Klinefelter syndrome includes the following:

• Endocrinologist - To assist in management and treatment with testosterone replacement therapy
• Speech therapy
• Occupational and physical therapy
• Behavioral consultation
• Regular exercise and upper body strengthening 

The Association for X and Y Chromosome Variations (AXYS) is an outreach and outpatient group that serves individuals and their families affected by X and Y chromosome aneuploidies, such as Klinefelter syndrome and its variants. Their web address is www.axysgenetic.org

• References

Further Inpatient Care

Admission for supportive care is not necessary in patients with Klinefelter syndrome.

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Inpatient & Outpatient Medications

Administer regular testosterone injections.

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Complications

Patients with Klinefelter syndrome have an increased risk of extratesticular germ cell tumors and possibly increased risk of breast cancer.^[63] The risk of breast carcinoma in 47,XXY men may approach 20 times that of 46,XY men. The cause may be related to the estradiol:testosterone ratio being several fold higher in 47,XXY men than in karyotypically normal men or is possibly due to an increased peripheral conversion of testosterone to estradiol in men with Klinefelter syndrome.^[64]   Other neoplasias, occurring in 1.6% of patients, include acute leukemia, Hodgkin and non-Hodgkin lymphomas, chronic myelogenous leukemia, and other myeloproliferative diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell tumors, teratoma, teratocarcinoma, choriocarcinoma) may also occur.

Psychological and psychiatric complications may occur in 47,XXY men with lower-than-average intelligence, hypogonadism, or impotence. The results of one study found that patients with Klinefelter syndrome are at elevated risk for psychopathologies such as autism and schizotypal traits, with schizotypal traits increasing with age. Deficiencies in verbal abilities are associated with increased autism traits, whereas deficiencies in visuospatial abilities are more strongly associated with increased schizotypal traits.^[65]

Decreased bone density occurs in 25% of men with Klinefelter syndrome, possibly reflecting the impact of reduced bone formation, increased bone resorption, and/or hypogonadism. Vertebral collapse may result from osteoporosis.^[66]

All patients with Klinefelter syndrome should be informed about the increased risk of deep vein thrombosis and should have their hematocrit levels monitored to avoid increased viscosity.^[67]

Associated endocrine complications include diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious puberty in association with human chorionic gonadotropin (hCG)–producing germ cell tumors. A study reported that prepubertal boys (aged 4-12 years) with Klinefelter syndrome are at elevated risk for truncal obesity, insulin resistance, and childhood metabolic syndrome. Reduced physical activity is associated with these risk factors.^[68]

Autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis, are more common, with frequencies similar to those found in 46,XX females.

Benign prostatic hyperplasia may result from testosterone supplementation. Adults undergoing such therapy should be screened for prostatic enlargement starting at age 30 years.

In males with polysomic X Klinefelter syndrome, the mortality rate due to cerebrovascular diseases such as aortic valvular disease and berry aneurysm rupture is more than 6 times that in healthy males aged 25-84 years. Enhanced platelet aggregation, thrombotic disease, and hypercoagulability have been demonstrated and may be related to increased estrogen levels. Development of varicose veins and leg ulcers may result from venous stasis.^[67]

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Prognosis

Early studies of men with XXY Klinefelter syndrome produced disturbing findings of an increased risk of psychiatric disturbance, criminality, and mental retardation. These results are considered highly questionable because of selection bias from institutionalized populations.

Babies with the XXY form differ little from healthy children. The results of one cohort study on nonmosaic XXY infants younger than 2 years found that most reported XXY neonates had normal external genitalia and height and weight within the normal range and were not dysmorphic. Indications for postnatal karyotyping included delayed ambulation and speech skills. These findings, along with previously reported clinical and biological features, suggest that early detection of Klinefelter syndrome is vital in monitoring potential developmental problems.^[69]

Although boys with the 47,XXY karyotype may struggle through adolescence with limited academic success, many frustrations, and, in a few instances, serious emotional or behavioral difficulties, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning.

The findings of a study including 87 Australian men with Klinefelter syndrome suggest that adults diagnosed with this disease later in life experience similar personal and psychosocial difficulties compared with those diagnosed at younger ages. These individuals would benefit from early detection and intervention.^[70]

Life span is presumably normal.

Hypogonadism, low libido, and psychosocial problems can be helped by testosterone treatment.

Gynecomastia can be corrected by mastectomy.

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Patient Education

Useful resources for patients and families include the following:

• Association for X and Y Chromosome Variations
• PO Box 861
• Mendenhall, PA 19357
• Phone: 888-999-9428
• American Speech-Language-Hearing Association
• 2200 Research Boulevard
• Rockville, MD 20850
• Phone: 800-498-2071

• References