Klinefelter Syndrome


Klinefelter syndrome (KS) is the result of 2 or more X chromosomes in a phenotypic male. The clinical phenotype of KS was first described in males with tall stature, small testes, gynecomastia, and azoospermia with the genetic etiology of supernumerary X chromosomes identified in 1959. Extra X chromosomes lead to testicular hyalinization, fibrosis and testicular hypofunction which may result in genital abnormalities, and usually hypogonadism and infertility. Neurocognitive differences associated with KS began to be recognized through the middle and latter part of the 20th century. Often, androgen replacement and neuropsychological and adaptive therapies are beneficial in the medical management of KS. However, deficits in clinical care do exist as there are gaps in diagnosis, lack of standardization of care, and access to treatments are not always available or affordable.


Klinefelter syndrome occurs as a result of a random error that causes a male to be born with an extra sex chromosome. It isn’t an inherited condition.

Humans have 46 chromosomes, including two sex chromosomes that determine a person’s sex. Females have two X sex chromosomes (XX). Males have an X and a Y sex chromosome (XY).

Klinefelter syndrome can be caused by:

  • One extra copy of the X chromosome in each cell (XXY), the most common cause
  • An extra X chromosome in some of the cells (mosaic Klinefelter syndrome), with fewer symptoms
  • More than one extra copy of the X chromosome, which is rare and results in a severe form

Extra copies of genes on the X chromosome can interfere with male sexual development and fertility.

Differential Diagnosis

The physical findings in patients with Klinefelter syndrome vary. When the following features are present in an undiagnosed male, a chromosome analysis may be indicated:

  • Small testes (only consistent phenotypic feature in 47,XXY males)
  • Gynecomastia
  • Long arms and legs
  • Developmental delay
  • Speech and language deficits
  • Psychosocial difficulties/behavioral concerns
  • Learning disabilities/academic issues
  • Infertility

Other causes of hypogonadism should also be considered. These include Kallmann syndrome and 46,XX karyotype (in males). The 46,XX male is caused by translocation of Y material (including the sex-determining region [SRY]) to the X chromosome during paternal meiosis. The presence of SRY on the X chromosome leads to normal male sexual development with male external genitalia, but hypospadias or cryptorchidism may be seen


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

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


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.


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. 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. 

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

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.

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.

Possible Complications

Klinefelter syndrome may increase the risk of:

  • Anxiety and depression
  • Social, emotional and behavioral problems, such as low self-esteem, emotional immaturity and impulsiveness
  • Infertility and problems with sexual function
  • Weak bones (osteoporosis)
  • Heart and blood vessel disease
  • Breast cancer and certain other cancers
  • Lung disease
  • Metabolic syndrome, which includes type 2 diabetes, high blood pressure (hypertension), and high cholesterol and triglycerides (hyperlipidemia)
  • Autoimmune disorders such as lupus and rheumatoid arthritis
  • Tooth and oral problems that make dental cavities more likely
  • Autism spectrum disorder

Possible Treatment

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). 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.

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.

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. 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.

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). 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.

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. 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.

ICSI is associated with an increased risk of producing a chromosome anomaly in offspring. IVF is also associated with an increased risk for de-novo chromosomal aberrations, especially those involving the sex chromosomes.

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. 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).

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.

Surgical Care

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

Primary Prevention

Klinefelter syndrome can’t be prevented.


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. 

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. 

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.

Risk factors

Klinefelter syndrome stems from a random genetic event. The risk of Klinefelter syndrome isn’t increased by anything a parent does or doesn’t do. For older mothers, the risk is higher but only slightly.

Secondary Prevention

Consultations as a way of secondary prevention 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

Signs or Symptoms

Signs and symptoms of Klinefelter syndrome vary widely among males with the disorder. Many boys with Klinefelter syndrome show few or only mild signs. The condition may go undiagnosed until adulthood or it may never be diagnosed. For others, the condition has a noticeable effect on growth or appearance.

Signs and symptoms of Klinefelter syndrome also vary by age.


Signs and symptoms may include:

  • Weak muscles
  • Slow motor development — taking longer than average to sit up, crawl and walk
  • Delay in speaking
  • Problems at birth, such as testicles that haven’t descended into the scrotum

Boys and teenagers

Signs and symptoms may include:

  • Taller than average stature
  • Longer legs, shorter torso and broader hips compared with other boys
  • Absent, delayed or incomplete puberty
  • After puberty, less muscle and less facial and body hair compared with other teens
  • Small, firm testicles
  • Small penis
  • Enlarged breast tissue (gynecomastia)
  • Weak bones
  • Low energy levels
  • Tendency to be shy and sensitive
  • Difficulty expressing thoughts and feelings or socializing
  • Problems with reading, writing, spelling or math


Signs and symptoms may include:

  • Low sperm count or no sperm
  • Small testicles and penis
  • Low sex drive
  • Taller than average height
  • Weak bones
  • Decreased facial and body hair
  • Less muscular compared with other men
  • Enlarged breast tissue
  • Increased belly fat



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Typical Test

Physical examination

In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).

Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males’ gynecomastia is noticeable enough to require surgery.

There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype testing.

Hypogonadism in XXY symptoms is often misinterpreted to mean “small testicles” or “small penis”. In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men often also have “microorchidism” (i.e. small testicles).

Laboratory workup

A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

The following tests may be performed:

  • Semen count
  • Serum estradiol levels (a type of estrogen)
  • Serum follicle stimulating hormone
  • Serum luteinizing hormone
  • Serum testosterone

Diagnosis can also be made prenatally via chorionic villus sampling or amniocentesis, tests in which fetal tissue is extracted and the fetal DNA is examined for genetic abnormalities. A 2002 literature review of elective abortion rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.










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