Related Terms

• 47 XXY males, 48 XXYY syndrome, 48, XXXY syndrome, 49, XXXXY syndrome, chromosome aneuploidy, estradiol, fertility treatments, follicle stimulating hormone, FSH, infertility, karyotype, Klinefelter, LH, luteinizing hormone, mosaic Klinefelter syndrome, mosaicism, sex chromosomes, testosterone, testosterone therapy, trisomy, X chromosome, XXXY syndrome, XXY male, XXY trisomy, Y chromosome.

Background

• The cells of a normal, healthy person contain two copies of each of 23 chromosomes, for a total of 46 chromosomes per cell. Everyone has two sex chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes. The X and Y chromosomes are called sex chromosomes because they contain the genetic information that determines male and female sexual characteristics. Klinefelter syndrome occurs when a male is born with an extra X chromosome in all or most of his cells. Sometimes people with this disorder are called XXY males. Even though a person with Klinefelter syndrome has an extra X chromosome, he is considered a male because he has a Y chromosome.

• The number of cells with an extra X chromosome varies among patients. When only some of the person's cells have an extra X chromosome, the condition is called mosaic Klinefelter syndrome. The severity of symptoms increases with the number of cells that have an extra chromosome. There are also several variants of Klinefelter syndrome, including 48 XXYY syndrome; 48 XXXY syndrome; 49 XXXXY syndrome; and XXXY syndrome.

• The most common symptom of Klinefelter syndrome is infertility because the genetic mutation causes males to produce less of the male hormone testosterone than healthy adult men. When the sex organs are underactive, it is called hypogonadism. Other symptoms may include reduced body and muscle tone (compared to males of the same age), enlarged breasts (called gynecomastia), difficulty communicating with others or expressing themselves, shyness, and intellectual and learning disabilities. In addition, males with this disorder have an increased risk of developing breast cancer and osteoporosis.

• It is estimated that Klinefelter syndrome affects about one out of 500-1,000 newborn males. The additional X chromosome occurs because of a random error during the development of sperm or egg cells. Mosaic Klinefelter syndrome is caused by a random mutation during fetal development. The risk for having a child with Klinefelter syndrome increases as the mother ages. Mothers who are 35 and older have the greatest risk of having children with this disorder.

• Most men with Klinefelter syndrome are able to live long, healthy lives. Although there is no cure for the disorder, treatment can effectively improve symptoms. Treatment with testosterone therapy, educational services, physical therapy, speech therapy, and/or occupational therapy helps most patients have normal sex lives, successful careers, and normal social relationships. Some males are able to have children, but they usually need the help of fertility treatments.

Risk Factors

• Maternal age: The risk for having a child with Klinefelter syndrome increases as the mother ages. In general, mothers who are 35 years of age and older have the greatest risk of having children with this disorder. Therefore, women older than 35 years of age are encouraged to talk to their doctors about potential risks and complications of pregnancy. There are no other known risk factors for Klinefelter syndrome.

Causes

• General: Healthy males have one X and one Y chromosome, while females have two X chromosomes. The X and Y chromosomes are called sex chromosomes because they contain the genetic information that determines male and female sexual characteristics. People with Klinefelter syndrome have an extra X chromosome in some or all of their cells.

• Random mutation: Klinefelter syndrome is not considered an inherited condition. Instead, the additional X chromosome occurs because of a random error that happens during the development of the sperm or egg cells. This error in cell division, called nondisjunction, results in an egg or sperm cell with an extra X chromosome. Mosaic Klinefelter syndrome is caused by a random mutation during fetal development.

• Because males with Klinefelter syndrome are typically infertile, there is little risk they will pass the disorder to their children.

• It is unknown what causes nondisjunction to occur. However, researchers have found that the risk of having a child with Klinefelter syndrome increases as the mother ages. In general, mothers who are 35 years of age and older have the greatest risk of having children with this disorder.

Signs and Symptoms

• General: The signs and symptoms of Klinefelter syndrome vary considerably among patients. This is because some people have mosaic Klinefelter syndrome or have an extra X chromosome in only some of their cells, while others have an extra copy in all of their cells.

• Physical development: Males with Klinefelter syndrome appear healthy at birth and have normal male genitalia.

• Most boys enter puberty normally, although some may reach puberty and start to develop secondary sex characteristics at a later age. About halfway through puberty, however, males with the condition produce about half as much testosterone as healthy boys of the same age. As a result, males with Klinefelter syndrome may have decreased facial and body hair and reduced muscle mass. About one-third of males with Klinefelter syndrome have gynecomastia, which is increased breast growth.

• This decrease in testosterone leads to an increase in two other hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). Normally, these two hormones are involved in the growth and development of immature sperm cells. However, since people with Klinefelter syndrome have only a few or no sperm cells, the extra FSH and LH causes excessive fibrous tissue to grow in the seminiferous tubules (where the sperm cells are normally located). The extra fibrous tissue inside the tubules increases the density of the testicles, causing them to become firmer and smaller than normal. Most males with Klinefelter disorder are infertile because they cannot produce enough sperm.

• Some people may also be taller than other males in their families and have abnormally long limbs and/or abnormal body proportions. This is because some of the genes inside the X chromosome regulate growth. Males with the disorder may also be thinner than average.

• Language development: During childhood and adolescence, many males with Klinefelter syndrome have some type of language problem, which may include difficulty learning to speak, difficulty expressing thoughts with language, reading trouble, and difficulty processing what they hear.

• Social development: Babies and young boys with Klinefelter syndrome may be quieter, less active, and more obedient than other children of the same age. During adolescence, males with the disorder are often more quiet and/or more shy than their peers. Some people with Klinefelter syndrome may experience anxiety, nervousness, and/or depression. However, most adults with the disorder appear to have healthy social relationships with friends and family members.

• Intellectual disabilities: Some males with Klinefelter syndrome may have intellectual disabilities (formerly called mental retardation) and/or learning disabilities. The severity of intellectual disability varies considerably among patients. Researchers typically use intelligence quotient (IQ) tests to measure the severity of a person's intellectual disabilities. Individuals who have 85-115 IQs are considered to have average intelligence.

• About half of males with Klinefelter syndrome are dyslexic. Dyslexia occurs when patients have difficulty translating written images into meaningful language. Patients may be unable to recognize written letters or words. Some may be reading at grade levels far below average. Therefore, adults with Klinefelter syndrome may have some difficulty doing work that involves reading and writing, but most are able to overcome these disabilities and live independently.

Diagnosis

• Karyotyping: If Klinefelter syndrome is suspected after puberty, a karyotype test is performed. This provides a picture of the person's chromosomes. A sample of the patient's blood is taken and analyzed for the presence of an extra X chromosome. This test analyzes at least 20 cells because patients may have mosaic Klinefelter syndrome and only have the extra X chromosome in some cells. If an extra X chromosome is detected in any of the cells, a positive diagnosis is made. In some cases, low-level mosaicism may be missed. Therefore, if the initial test results are negative, but Klinefelter syndrome is still suspected based on the patient's signs and symptoms (e.g. low testosterone levels with no other known cause), a repeat test may be performed.

Complications

• Cancer: Klinefelter syndrome is associated with an increased risk for breast cancer. Males with the disorder are also more likely to develop rare tumors called extragonadal germ cell tumors. This occurs when cells that are supposed to develop into sperm cells travel to other parts of the body and develop into tumors. Although these tumors can grow anywhere in the body, they are commonly found in the brain, lungs, or abdomen.

• Autoimmune disorders: Men who have Klinefelter syndrome also have an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjogren's syndrome. Autoimmune disorders occur when the immune system, which normally fights against diseases and infections, attacks the person's own body.

• Infertility: Males with Klinefelter syndrome typically produce less testosterone than healthy males. As a result, patients are often infertile. However, treatment with the male hormone testosterone may help some males have children.

• Osteoporosis: People with Klinefelter syndrome have an increased risk of developing osteoporosis, a condition that occurs when the bones become weak and brittle. This is because males with the disorder typically have low levels of testosterone and males convert testosterone into bone-preserving estrogen.

Treatment

• General: Most males with Klinefelter syndrome are able to live long, healthy lives. Although there is no cure for the disorder, treatment can effectively improve symptoms. Treatment with testosterone therapy, educational services, physical therapy, speech therapy, and/or occupational therapy helps most patients have normal sex lives, successful careers, and normal social relationships. Some males are able to have children with the help of fertility treatments. Early intervention and proper care helps ensure the best possible prognosis in terms of intellectual, social, and physical development.

• Education: If a child with Klinefelter syndrome has intellectual or learning disabilities, he must have access to education that is tailored to his specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities in the United States must receive free and appropriate education from age three until the end of high school or until the person is 21 years old (whichever occurs first).

• If a child has intellectual disabilities, members of the patient's school should consult with the patient's parents or caregivers to design an individualized education plan. The school faculty should document the child's progress in order to ensure that the child's needs are being met.

• Educational programs vary among patients depending on the severity of the person's intellectual and/or learning disabilities. In general, most experts believe that children with disabilities should be educated alongside their non-disabled peers. The idea is that normal students will help the patient learn appropriate behavioral, social, and language skills. Depending on the person's needs, patients with intellectual disabilities and Klinefelter syndrome may be educated in mainstream classrooms, attend public schools but take special education classes, or attend specialized schools that are designed to teach children with disabilities.

• Speech-language therapy: Patients with Klinefelter syndrome who have speech, language, and/or communication difficulties may benefit from speech-language therapy. During speech-language therapy, a qualified speech-language professional (SLP) works with the patient on a one-to-one basis, in a small group, or in a classroom to overcome speech and language problems. Programs are tailored to the patient's individual needs. On average, patients receive five or more hours of therapy per week for three months to several years.

• Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start off simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.

• Occupational therapy: Patients with moderate to severe intellectual disabilities may benefit from occupational therapy. During sessions, a therapist helps the child learn skills to help him/her perform basic daily tasks, such as feeding, dressing, and communicating with others. There are therapists who specialize in patients with specific disorders. Parents and caregivers can ask their children's pediatricians to recommend therapists.

• Physical therapy: Physical therapy may help patients with Klinefelter syndrome improve their physical strength and motor coordination. A variety of techniques, including exercises, stretches, traction, electrical stimulation, and massage are used during physical therapy sessions. A therapist may also teach parents or caregivers how to exercise a baby's muscles.

• Testosterone therapy: Testosterone replacement therapy has been shown to improve the testosterone levels of patients with Klinefelter syndrome. As a result, treatment helps males develop bigger muscles and deeper voices, grow facial and body hair, develop larger testicles, improve mood, improve self image, increase sex drive, and protect against osteoporosis. It may also help some males have children when they become adults.

• Treatment is typically started when the patient is about 12 years old. Doses of testosterone increase over time until it is high enough to maintain age-appropriate blood levels of testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH).

• Side effects may include salt and water retention with edema (swelling) and high blood pressure, high levels of red blood cells (called polycythemia), increased libido, and prostate enlargement. A rare side effect of testosterone therapy is priaprism, an erection that lasts longer than four hours. Although uncommon, testosterone may also cause excessive breast development. This is because testosterone can serve as substrate for extraglandular estrogen formation. As a result, it may lead to increases in estrogen levels.

• Breast reduction surgery: Some males with Klinefelter syndrome may develop excessive amounts of breast tissue. In such cases, cosmetic surgery may be performed to remove the extra breast tissue.

Integrative Therapies

• Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of Klinefelter syndrome.

• However, many herbs and supplements have been shown to have phytoestrogen properties, including agrimony, alfalfa, arginine, black cohosh, bloodroot, boron, burdock, chamomile, chasteberry, dong quai, Essiac®, fennel, fenugreek, fo-ti, ginseng, hops, kudzu, licorice, melatonin, niacin, oregano, pomegranate, pygeum, quercetin, red clover, resveratrol, soy, St. John's wort, thyme, white horehound, and yucca.

• Theoretically, the estrogen-like affects of phytoestrogens may interfere with testosterone therapy. Therefore, patients should talk to their doctors before taking any herbs or supplements.

Prevention

• Currently, there is no known method of prevention of Klinefelter syndrome because the condition is caused by a random genetic mutation.

• The risk for having a child with Klinefelter syndrome increases as the mother ages. In general, mothers who are 35 years of age and older have the greatest risk of having children with this disorder. Therefore, these women are encouraged to talk to their doctors about the potential risks and complications of pregnancy.

• People who have Klinefelter syndrome are encouraged to visit their doctors as soon as possible to confirm a diagnosis and start treatment. Early intervention and proper care helps ensure the best possible prognosis in terms of intellectual, social, and physical development.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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