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Klinefelter Syndrome

Klinefelters Syndrome

Klinefelter syndrome is a genetic disorder associated with male hypogonadism, gynecomastia and reduced fertility. Other symptoms include erectile dysfunction, osteoporosis, language and learning impairment and behavioral problems.


Hypogonadism gynecomastia and infertility are the most common symptoms that suggest a diagnosis of Klinefelter syndrome [1] [10] [13]. Newborn screening programs have led to earlier diagnosis. However, these are not widely employed. Infants and young children are of normal height, weight, and head circumference [1] [13]. By age 5 years growth in height velocity increases and adults with Klinefelter syndrome are usually taller average with disproportionately long arms and legs [2] [7] [13]. About 40% of patients with Klinefelter syndrome have taurodontism, enlargement of the molar [1]. The symptoms of Klinefelter syndrome are primarily the result of androgen deficiency. These include [4] [6] [10] [13] [14]:

Individuals with Klinefelter syndrome typically presents with [2] [4] [10]:

  • Low serum testosterone levels
  • Elevated luteinizing hormone (LH) and FSH levels
  • Elevated estradiol levels

Individuals with Klinefelter syndrome usually have small, firm testes with seminiferous tubular atrophy and focal hyperplasia of Leydig cells [2] [13]. Germ cells are deficient or absent and spermatogenesis is rare [2] [5]. Men with Klinefelter syndrome are at a higher risk for cardiovascular, autoimmune, and endocrine diseases [1] [13]. Associated disorders frequently seen with Klinefelter syndrome include [4] [6]:

The cognitive ability of patients with Klinefelter syndrome is typically in the low normal intellectual range [10]. There is evidence of general impairment in language especially in verbal communication, auditory processing, and comprehension [8]. Other psychosocial disabilities including emotional immaturity, anxiety, obsessive compulsive behavior, impulsivity, behavioral problems, and tic disorders are more common in this condition than in the general population [7]. All symptoms and characteristics of Klinefelter syndrome appear to be accentuated in the disorder’s variants, increasing with the number of additional X chromosomes [7]. These variants are also associated with additional physical findings, congenital malformations, medical problems and psychological disability [6] [7]. Mental capacity diminishes with additional X chromosomes. All areas of development are affected by the extra X chromosome material [7].

Differential diagnoses [4]:

Tall Stature
  • These patients usually present with tall stature. We report a case of KS with short stature due to growth hormone deficiency. The boy's height was below the 3rd centile with significant delay in bone age.[ncbi.nlm.nih.gov]
  • Physical examination revealed tall stature, thin built, small testes size, and absence of beard and pubic hairs.[ncbi.nlm.nih.gov]
  • It is characterized by a 47, XXY or a mosaic karyotype, hypergonadotrophic hypogonadism, infertility, reduced body hair, gynecomastia, and tall stature.[ncbi.nlm.nih.gov]
  • Three main clinical signs should suggest the diagnosis in a child: small testes, tall stature, and mental retardation or learning problems. We present a patient with Klinefelter syndrome and short stature due to growth hormone deficiency.[ncbi.nlm.nih.gov]
  • They tend to have tall stature and long legs and may have difficulties with speech and language development.[icd9data.com]
Male Hypogonadism
  • Affected males carry an additional X chromosome, which results in male hypogonadism, androgen deficiency, and impaired spermatogenesis.[ncbi.nlm.nih.gov]
  • Klinefelter syndrome is the most common cause of male hypogonadism with a variety of clinical signs and symptoms. The principal effect is the hypogonadism predisposing to infertility and requiring testosterone replacement therapy.[ncbi.nlm.nih.gov]
  • Discussion: Klinefelter syndrome is the most common cause of male hypogonadism with a variety of clinical signs and symptoms. The principal effect is the hypogonadism predisposing to infertility and requiring testosterone replacement therapy.[dx.doi.org]
Long Leg
  • They tend to have tall stature and long legs and may have difficulties with speech and language development.[icd9data.com]
  • Symptoms may include any of the following: Abnormal body proportions (long legs, short trunk, shoulder equal to hip size) Abnormally large breasts ( gynecomastia ) Infertility Sexual problems Less than normal amount of pubic, armpit, and facial hair Small[nlm.nih.gov]
  • Patients tend to have long legs and a slim, tall stature. GYNECOMASTIA is present in many of the patients. The classic form has the karyotype 47,XXY.[fpnotebook.com]
  • Signs and Symptoms of Klinefelter's Syndrome Male phenotype Before puberty, small testes and disproportionately long legs are present. The verbal IQ might be reduced.[urology-textbook.com]
Long Arm
  • These findings indicate that extra copies of the long arm of X have phenotypic expression, even though activated only in early development.[ncbi.nlm.nih.gov]
  • No spermatozoon was found on microdissection testicular sperm extraction, and the testis biopsy histology showed only Sertoli cells and hyalinised seminiferous tubules. 47,XY, i(X)(q10) has an additional isochromosome made of the long arm of the X chromosome[ncbi.nlm.nih.gov]
  • Boys may have learning disabilities, long arms and legs, small testes, and infertility. The diagnosis is suspected at puberty when most of the symptoms develop. Treatment with testosterone may be of benefit to some people.[msdmanuals.com]
  • Most boys with Klinefelter syndrome are tall and have relatively long arms and legs. Although early in puberty, the testicles may produce normal amounts of the male hormone testosterone, this often lags as puberty progresses.[healthychildren.org]
  • Symptoms of Klinefelter’s syndrome vary between individuals, but typically include small testicles, lack of facial, pubic and underarm hair, gynaecomastia (breast tissue enlargement), poor muscle development, disproportionately long arms and legs (compared[theconversation.com]
Compulsive Behavior
  • Other psychosocial disabilities including emotional immaturity, anxiety, obsessive compulsive behavior, impulsivity, behavioral problems, and tic disorders are more common in this condition than in the general population.[symptoma.com]


Klinefelter syndrome is definitively diagnosed by standard karyotype (chromosome analysis) or chromosomal microarray which show the presence of extra X and/or Y chromosomes [7]. Newborn screening programs for this disorder, where they exist, can identify infants with the abnormality in the neonatal period. However, most men are diagnosed in adulthood when the syndrome is suspected due to its characteristic signs and symptoms. Suggested laboratory studies include [6] [11] [13]:

  • Prenatal cytogenetic analysis of a fetus for karyotype
  • Chromosomal evaluation, when Klinfelter syndrome is suspected due to clinical signs 
  • Androgen receptor gene analysis
  • Gonadal function: Follicle-stimulating hormone (FSH), luteinizing hormone (LH) levels, inhibin B decreased to undetectable levels, testosterone levels return, androgen deficiency
  • Further hormone testing: Estradiol, prolactin, and insulin-like growth factor (IGF)-1 levels
  • Cortisol levels
  • Urinary gonadotropin levels are increased because of abnormal Leydig cell function
  • Serum osteocalcin levels decreased and hydroxyl-proline–to-creatinine ratio increased, due to bone demineralization
  • Hypercoagulability screening because of increased risk of deep vein thrombosis and pulmonary embolism [3]

Other recommended studies [4] [13]:

Karyotype Abnormal
  • This disorder is the most frequent karyotypic abnormality reported in infertile men ( 4 ). Mosaic patients occasionally have sperm in their ejaculate ( 5 ), but men with nonmosaic Klinefelter syndrome were considered sterile ( 2 ).[dx.doi.org]
  • abnormality detected in infertile subjects is represented by Klinefelter’s syndrome, and the most frequent non-chromosomal alteration is represented by Y chromosome long arm microdeletions.[dx.doi.org]
Androgens Decreased
  • Nishizawa H et al. (2002) Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 51 : 2734–2741 41.[dx.doi.org]
  • Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes. 2002; 51 :2734–41. [ PubMed ] [ Google Scholar ] 83. Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, et al.[ncbi.nlm.nih.gov]
Testosterone Decreased
  • Total testosterone decreased with age ( Figure 3 ), and a negative correlation ( r 0.50, P 0.001) was found between these variables. In the adult group as a whole, total testosterone was below normal in 45.1% of the cases.[ncbi.nlm.nih.gov]
Left Ventricular Hypertrophy
  • His echocardiogram demonstrated symmetrical left ventricular hypertrophy with minimal diastolic dysfunction. Subsequent investigations confirmed the diagnosis of Fabry cardiomyopathy.[ncbi.nlm.nih.gov]


Intervention for Klinefelter syndrome should be aimed at optimum hormone supplementation, preservation of fertility in adolescents, and development of universal early screening programs [3]. Treatment should address three major symptoms of the disease, hypogonadism, gynecomastia, and psychosocial problems [3] [4]. Androgen therapy is the primary treatment for Klinefelter syndrome [5] [8]. Testosterone replacement should begin at puberty, (around 12 years) and the dose should increase until it is sufficient to maintain age-appropriate serum levels of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) [8] [9]. Testosterone therapy corrects androgen deficiency, induces a virilization, increases strength and facial hair growth, builds muscle and bone, increases sexual desire, and improves psychosocial status [5] [9] [13]. However, the optimal testosterone regimen and timing, for patients with Klinefelter syndrome, has not been established and vary between sources [4] [7] [8].

Developmental delays, cognitive impairments and behavioral disorders are common and require long term multi-disciplinary treatment plans [2] [3] [7]. Treatment should include providing anticipatory guidance regarding issues related to endocrinology, behavior, development, and preventive medical care [7]. Microdissection testicular sperm extraction in men with azoospermia due to Klinefelter syndrome treated with preoperative hormonal therapy may enable these individuals to parent children via invitro fertilization [17] [20]. Recent reports have shown an increased incidence of XY spermatozoa in males with 46, XY/47, XXY karyotypes [2] [21]. Therefore, there is some concern that chromosomes generated through this infertility treatment will produce abnormal embryos [19] [21]. Studies have shown by prenatal cytogenetic analysis of fetuses conceived by this method had a rate of 12.7% chromosome aberrations [17] [21]. Patients with Klinefelter syndrome should therefore be counseled about this possibility [5] [17].

Speech and behavioral therapy can improve speech, verbal skills, learning difficulties, and other psychosocial and behavioral problems [4] [14]. All males with Klinefelter syndrome should have a comprehensive psychosocial and educational evaluation to plan appropriate intervention [4] [6] [14]. Physical therapy is recommended for boys with hypotonia or delayed gross motor skills, balance and coordination problems [4]. Occupational therapy is advised in those with Klinefelter syndrome with motor dyspraxia and fine motor delays [4]. Mastectomy may be indicated for severe gynecomastia. This condition increases the risk of breast cancer [4]. It also places considerable psychological stress on the patient and increases the possibility of psychosocial disability [6] [14]. There are no special dietary needs. No activity restrictions are required. Consultations should include [4]:

  • Clinical geneticist
  • Endocrinologist
  • Surgeon
  • Psychologist
  • Speech therapist


Early diagnosis, treatment, and testosterone replacement therapy can improve the quality of life and the overall health of men with Klinefelter syndrome [11]. Early studies of men with XXY Klinefelter syndrome found a significantly increased risk of psychiatric disturbance, criminality, and mental retardation. These results are considered highly questionable because of selection bias from institutionalized populations [6]. Newer studies show much lower incidence of these disorders concluding that men with Klinefelter syndrome usually have normal intelligence and educational and career success [6] [13]. Life span of men with Klinefelter syndrome is normal [4] [10].

Until 1996 men with Klinefelter syndrome were considered sterile [20]. The fact that sperm can be found in the testes of men with Klinefelter syndrome has changed this assumption [5] [9] [20]. The risk of developing breast carcinoma is at least 20 times higher in men with Klinefelter syndrome than in healthy individuals [4]. It appears unlikely that the birth of one child with Klinefelter syndrome increases the risk of the parents having a second affected child [16].


Klinefelter syndrome is the most common chromosomal aberration in men [3] [11]. Approximately 1 in 500-1,000 males are born with an extra sex chromosome. More than 3,000 infant males affected with the disorder are born yearly [3] [4]. In 1959, Klinefelter syndrome was found to be caused by one or more extra X chromosomes in male infants [1]. The karyotype 47, XXY is the most prevalent form [1] [8], but many other karyotypes occur infrequently including 48, XXXY, 49, XXXXY, and 47, XYY. The exact etiology of the disease is unknown [1] [4], but parental age may be a factor [12].

The X chromosome plays a role in multiple body systems [10] [13], including hormone production, testicular function, brain development, and growth. The addition of one or more extra X or Y chromosomes can result in a variety of physical and cognitive abnormalities as well [1] [13]. Klinefelter syndrome effects normal development, growth, social interactions, bone structure, and sexual and reproductive function [3]. The typical man with Klinefelter syndrome can be described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testicles, androgen deficiency, azoospermia and decreased verbal intelligence [8]. About 70% of patients have minor developmental and learning disabilities [10] [14]. Recent studies have shown a broader spectrum and milder impairments than originally thought [7]. Psychiatric disorders involving anxiety, depression, neurosis, and psychosis are more common in this group than in the general population [6] [10]. Patients may exhibit behavioral problems and psychological distress [10] [14]. This may be due to poor self-esteem and psychosocial development or a decreased ability to deal with stress.

Klinefelter syndrome results in progressive testicular failure causing aspermatogenesis and androgen deficiency [8] [15]. However, Klinefelter patients have normal male sex differentiation, and genital anomalies are rare [15]. Men with Klinefelter syndrome usually present with various hormonal and spermatogenic testicular failure that include infertility, low testosterone, erectile dysfunction, and low bone mineral density [11] [13].

Klinefelter syndrome is a significantly underdiagnosed condition [7] [14]. This is based on the comparison of the number of cases identified by medical professionals and the known incidence from newborn screening (1:650 male births) [7]. Few of those not diagnosed in the neonatal period are diagnosed before puberty [8]. Many men are never diagnosed [3] [7]. The most common reasons for karyotyping and therefore diagnosis are hypogonadism and infertility [8].

Until recently men with Klinefelter syndrome were assumed to be sterile. However, current studies show that almost 50% of men with Klinefelter syndrome have viable sperm and therefore are not sterile [4]. Only 40% of fetuses with Klinefelter syndrome survive the fetal period [3]. However of those born with the condition life expectancy is generally normal. Exogenous androgen (testosterone) is the treatment of choice for Klinefelter syndrome [4] [10]. The therapeutic aims are reduced serum gonadotropin concentrations, increased virilization, proper masculine development of sexual characteristics, increased muscle bulk and bone structure, and to prevent the long-term complications of androgen deficiency [8]. Patients with Klinefelter syndrome should be treated with lifelong testosterone supplementation beginning at puberty [10]. Earlier identification and treatment of Klinefelter syndrome are needed to prevent the physical and psychological complications associated with the disorder and improve the quality of those afflicted with it [4].


This condition affects only males. The incidence of Klinefelter syndrome is  about 1:650 to 1000 live births of male infants [1] [4] [10] [16]. There are currently about 250,000 men with the disorder in the United States [3] [11]. Men with Klinefelter syndrome doe make up 3 to 4% of patients in male reproductive practices [3]. Klinefelter syndrome occurs equally in all races and ethnic groups [3]. The prevalence rate of Klinefelter syndrome is 5-20 times higher in individuals with mental retardation than in the general newborn population [3]. Whether this is the result of the disorder on mental development or the result of increased suspicion of Klinefelter syndrome in this population and therefore more testing for the condition is not clear.

Sex distribution
Age distribution


Klinefelter syndrome is a sex chromosome aneuploidy, a disorder characterized by an abnormal number of X or Y chromosomes [8]. Most cases of Klinefelter syndrome are thought to result during gametogenesis with the production of either an abnormal spermocyte or an abnormal oocyte. The abnormal cells are produced through non-disjunction in either meiosis I or meiosis II and occasionally in the post-zygotic period [7] [16]. Post-fertilization non-disjunction 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 [12] [16]. Most cases of other human trisomies are due to errors at maternal meiosis I. Klinefelter syndrome is the exception. Nearly 50% of non-disjunction errors in this disorder occur during spermatogenesis [16] [17].

Through specialized cell division haploid gametes are produced by one round of DNA replication and two stages of cell division, meiosis I and meiosis II [12] [16]. Between these two stages chromosomes undergo recombination with chiasmata formed to link together the homologues [16] [17]. Non-disjunction errors occur when the haploids fail to disconnect and gametes with multiple X chromosomes remain [16].

The X chromosome influences growth, pubertal development and testicular degeneration in adolescent boys [9]. The presence of one or more additional X chromosome(s) above the typical 46, XY leads to testicular dysgenesis and hypergonadotropic hypogonadism [7] [9]. Other variants of Klinefelter syndrome, 48,XXYY, 48,XXXY and 49,XXXXY, share the characteristics of 47,XXY including tall stature and hypergonadotropic hypogonadism [7] [19]. They may be associated with additional physical findings, congenital malformations, medical problems and psychological disability [17] [18].

Symptoms of Klinefelter syndrome are related to the effects of androgen. Testosterone acts via the X-linked androgen receptor gene [4] [7] [18]. Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland [7]. The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome [4] [18]. 

Testicular dysfunction and testosterone deficiency becomes most apparent during adolescence [7]. Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone are normal in infancy and childhood. In the prepubescent period FSH and LH rise gradually with a steep increase in total testosterone in early puberty that then plateaus in the low-normal range or decreases in adolescence [4] [7]. In adults testicular histology shows hyalinization and fibrosis of the seminiferous tubules, loss of germ cells and Leydig cell hyperplasia resulting in testosterone deficiency and infertility [7].

The only identified factor affecting the incidence of Klinefelter syndrome is parental age [16]. The average frequency of XY sperm increases significantly with age. Fathers in their 20s have an average of 7.5 XY sperm per 10,000 compared with frequencies of XY sperm 10% higher in fathers in their 30s, 31% higher in men their 40s, and 160% higher among those in their 50s [12] [19]. These findings indicate that older fathers are at higher risk of fathering boys with Klinefelter syndrome [12] [16] [19].

Whether the morbidity associated with Klinefelter syndrome is the direct result of hypogonadism and hyperestrogenism is unclear [11]. These co-morbidities include increased risk for diabetes, cardiovascular events, and osteoporosis, as well as developmental delays, mild retardation, learning disabilities, and social and psychiatric problems [11] [13]. There is a relationship between a lower bone mineral density and testosterone levels in patients with Klinefelter syndrome [13]. Social, language, and cognitive development can also be affected. These deficits may be due the effects of testosterone deficiency and increased estrogen levels, but other factors probably contribute: low self-esteem, environmental influences, and poor response to stress [7] [11] [13].


Klinefelter syndrome cannot be prevented, but the symptoms and complications of the disorder can be prevented or minimized with early detection and treatment. In some states, newborn screening programs for Klinefelter syndrome are already in place [11]. These programs can assure early interventions and hormone replacement to prevent the complications of the disorder [14].

Androgen therapy can correct androgen deficiency which is the cause of all the other symptoms, physical and psychosocial [3] [11]. Regular life-long testosterone injections can improve strength and facial hair growth, build muscle, increase sexual desire, enlarge the testes, improve mood, self-image, and behavior, and protect against osteoporosis, diabetes, and heart disease [14].


Klinefelter Syndrome is a spontaneous genetic chromosomal abnormality occurring only in males [1] [2]. It involves the presence of one or more additional X or Y sex chromosomes. This is thought to occur due to abnormal cell division [1]. Klinefelter syndrome (KS) is the most common chromosomal aberration in men [3] [4]. The most common variant is 47, XXY which accounts for 90% of Klinefelter syndrome cases [4] [6]. Other frequent variants include 48, XXXY, 49, XXXXY, and 48, XXYY [5] [6].

The effects of additional X chromosomes are due to hormonal changes, decreased androgen production and increased estrogen levels [4]. Symptoms include enlarged breasts, sparse facial and body hair, small testes, an inability to produce sperm, and feminization of body fat distribution [4] [6]. Complications of Klinefelter syndrome include osteoporosis, increased cardiovascular risk, mild to moderate developmental and learning disabilities, and increased psychosocial disabilities [6] [7].

Diagnosis of the condition is usually made by the characteristic features of the disorder with confirmation by karyotyping [3] [5] [8]. Because signs and symptoms are non-specific, most men with Klinefelter syndrome are not diagnosed until adulthood or never. Newborn screening is an effective means of early diagnosis and therefore treatment.

Androgen replacement therapy is the recommended treatment for the condition. It is very effective in achieving virilization and preventing the abnormalities and complications of the condition [8] [9]. Fetal death is increased significantly due to the chromosomal abnormalities. However, life expectancy for those born with Klinefelter syndrome is normal [8] [10].

Patient Information

What is Klinefelter syndrome?

Klinefelter syndrome is a spontaneous genetic chromosomal abnormality occurring only in males. It involves the presence of one or more additional X or Y sex chromosomes. This is thought to occur due to abnormal cell division. Klinefelter syndrome (KS) is the most common chromosomal aberration in men.

What are the symptoms?

The symptoms of Klinefelter syndrome are the result of androgen (testosterone) deficiency. These include:

What causes Klinefelter syndrome?

The direct cause of Klinefelter syndrome is the occurrence of additional X chromosome(s) in the affected male. The extra X chromosomes result in failure to produce androgen (testosterone) hormones and increased estrogen. The additional X chromosome results from a failure of the copies of this chromosome to separate during the creation of sperm or egg before conception. The exact cause of this failure is not known, but increased age of either parent is a factor.

Who gets Klinefelter syndrome?

Klinefelter syndrome occurs only in men. There are no other known associated factors, except parental age, that increase the possibility of the condition. Klinefelter Syndrome is not affected by race, ethnicity, or geography.

How is it diagnosed?

Klinefelter syndrome is diagnosed by karyotyping which is the analysis of an individual’s chromosomes. The condition may be suspected from its clinical picture. Most men are first identified when they seek medical care for gynecomastia or infertility.

How is Klinefelter syndrome treated?

The treatment of Klinefelter syndrome is testosterone replacement therapy which is required for the rest of their lives. Treatment should also include treatment for the associated symptoms and complications of the disorder, osteoporosis, diabetes, heart disease, delayed development, learning disabilities, and psychosocial issues.

What are the complications?

Associated disorders frequently seen with Klinefelter syndrome include:

How can Klinefelter syndrome be prevented?

Klinefelter syndrome cannot be prevented but the symptoms and complications of the disorder can be prevented or minimized with early detection and treatment.



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Last updated: 2019-07-11 21:06