Klinefelter syndrome

Klinefelter syndrome usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells.

Most often, Klinefelter syndrome is caused by a single extra copy of the X chromosome, resulting in a total of 47 chromosomes per cell. Males normally have one X chromosome and one Y chromosome in each cell (46, XY), while females have two X chromosomes (46, XX). People with Klinefelter syndrome usually have two X chromosomes and one Y chromosome (47, XXY). Some people with Klinefelter syndrome have the extra X chromosome in only some of their cells; these people are said to have mosaic Klinefelter syndrome.

It is estimated that about half of the time, the cell division error occurs during development of the sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having offspring with this syndrome.

The features of Klinefelter syndrome are due to the extra copies of genes on the extra X chromosome, which can alter male sexual development.

Some people with features of Klinefelter syndrome have conditions known as "variants of Klinefelter syndrome" where there is more than one extra sex chromosome in each cell (48,XXXY, 48,XXYY and 49,XXXXY).

The cause of nondisjunction is unknown. Nondisjunction seems to be a chance event. Nothing that a person does or doesn't do during their reproductive years can cause these chromosomal changes. We do know that nondisjunction occurs more frequently in the eggs of women as they get older.

A diagnosis of Klinefelter syndrome is often suspected based on the presence of characteristic signs and symptoms. Additional testing can then be ordered to confirm the diagnosis. This generally includes a chromosomal analysis (called a karyotype).

It is also possible to diagnosis Klinefelter syndrome before birth through chorionic villous sampling or amniocentesis.

The vast majority of people with Klinefelter syndrome (KS) are azoospermic (have no sperm present in the ejaculate). However, motile sperms in the ejaculate and even spontaneous pregnancies resulting from fathers with KS have been described, although such cases are rare. In general, people with mosaic KS (those that also have a 46,XY cell line) are less severely affected so the chance of finding sperm in the ejaculate is significantly higher than in non-mosaic cases. In the past, the use of donor semen or adoption were the only possible ways of having a child. However, in recent years, testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection (ICSI) have helped more than 100 people with KS became biological parents.

People with KS should not automatically assume they are infertile without thorough testing.

Klinefelter syndrome is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these reproductive cells contributes to the genetic makeup of a child, the child will have one or several extra X chromosomes in each of the body's cells.

Approximately 15-20% of cases of Klinefelter syndrome are mosaic.The true prevalence is suspected to be greater as there could be cases missed given the varying levels of mosaicism that can be found in different tissues and the potential for males with mosaic Klinefelter syndrome to have more mild symptoms and miss diagnosis.

Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties. Adults with Klinefelter syndrome may also have primary hypogonadism (decreased testosterone production), small and/or undescendent testes (cryptorchidism), enlarged breast tissue (gynecomastia), tall stature, and/or inability to have biological children (infertility), as well as an abnormal opening of the penis (hypospadias), and an small penis (micropenis). KS is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm) that results in the presence of one extra copy of the X chromosome in each cell (47,XXY). KS treatment is based on the signs and symptoms present in each person. Life expectancy is usually normal and many people with KS have normal life. There is a very small risk of developing breast cancer and other conditions such as a chronic inflammatory disease called systemic lupus erythematosus.

In some cases, there is more than one X chromosome in each cell (for example, 48,XXXY or 49,XXXXY). These conditions, which are often called "variants of Klinefelter" syndrome usually have more serious problems (intellectual disability, skeletal problems, and poor coordination) than classic Klinefelter syndrome (47,XXY).

The U.S. National Institutes of Health, through the National Library of Medicine, developed ClinicalTrials.gov to provide patients, family members, and members of the public with current information on clinical research studies. You can find clinical trials for individuals with Klinefelter syndrome by clicking on the above link. Check this site often for regular updates.

You can also contact the Patient Recruitment and Public Liaison (PRPL) Office at the National Institutes of Health (NIH). We recommend calling the toll-free number listed below to speak with a specialist, who can help you determine if you are eligible for any clinical trials. If you are located outside the United States, and would like to be contacted via telephone, you will need to provide your telephone number in full, including area code and international dialing prefix.

Patient Recruitment and Public Liaison Office
NIH Clinical Center
Bethesda, Maryland 20892-2655
Toll-free: 800-411-1222
Fax: 301-480-9793
Email: prpl@mail.cc.nih.gov
Web site: http://clinicalcenter.nih.gov/

You can find helpful general information on clinical trials at the following ClinicalTrials.gov Web page.
http://clinicaltrials.gov/ct2/info/understand

A tutorial about clinical trials that can also help answer your questions can be found at the following link from the National Library of Medicine:
http://www.nlm.nih.gov/medlineplus/tutorials/cancerclinicaltrials/htm/lesson.htm

Studies of ejaculated or testicular mature sperm in people with Klinefelter syndrome (KS) have shown varying amounts of normal sperm. It has been proposed that adults with KS have a substantially higher proportion of sperm with an abnormal number of chromosomes than those without KS, giving these people a theoretically increased risk of fathering a child with conditions such as Klinefelter syndrome or 47 XXX syndrome. It has also been proposed that affected people may have an increased risk for sperm with an extra copy of chromosome 13, 18, or 21.

Preimplantation genetic diagnosis (PGD) is generally offered to people KS who have undergo successful testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). This technique allows for identifying chromosomally abnormal embryos in order to avoid transferring them into the uterus.

People interested in learning more about genetic risks and reproductive options should speak with a genetics professional.

About half of people with a 47, XXY chromosome finding have low testosterone levels, which can typically be raised by taking supplemental testosterone. However, not all males with a 47, XXY chromosome finding benefit from testosterone therapy. Furthermore, although the majority of people with a 47, XXY chromosome finding and/or Klinefelter syndrome grow up to identify as males, some develop atypical gender identities. For these people, supplemental testosterone may not be appropriate. Gender identity should be discussed with health care specialists before starting treatment.

In most cases, testosterone replacement therapy (sometimes referred to as androgen therapy), is started at puberty (around age 12 for males). The dose is gradually increased until it is enough to maintain age- appropriate serum concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). 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 early osteoporosis.

Limited information about the treatment of adults with Klinefelter syndrome is available; however, research has shown that continued testosterone injections, even if begun in adulthood, can be beneficial to those seeking treatment and may continue to help with hypogonadism, low libido (sex drive), and psychosocial issues. People with Klinefelter syndrome should consult their physicians regarding their personal course of treatment and to discuss the risks and benefits of testosterone replacement therapy.

Boys with Klinefelter syndrome (KS) are known to have an increased risk for psychosocial problems. While large studies of boys with KS are uncommon (only 10% of affected males are diagnosed during childhood), the time around puberty (peripubertal time) is presumed to be a susceptible time for the emergence of physical and psychosocial health issues.

Poor outcomes have been reported on measures of well-being, body image, self- esteem, mental health, social support, and general health for males with KS compared with the general male population. Studies have suggested that the majority of youth with KS report poor quality of life, with a risk for depression and/or suicidality. One study found that 68.8% of the affected males studied had clinically significant levels of depressive symptoms. Little is understood about the underlying cause, manifestations, and consequences of depression in affected males. However, depression is a leading cause of disability in adolescents and adults in the general population.

Research has also raised concerns that there is an increased risk for psychiatric disorders besides depression, including anxiety, schizophrenia, and other psychotic disorders.

For those who are diagnosed with KS, attention to self-esteem, self-concept, depression risk, and quality of life are important aspects of health care. Early neurocognitive and behavioral interventions for children who have psychosocial vulnerabilities are recommended.

Androgens (specifically testosterone) are known to have a broad influence on physical development, neurological development, cognitive functioning, and social behavior in males - beginning in utero and continuing through adulthood. Most adolescents with KS have enough circulating levels of serum testosterone to initiate puberty, but they often then fail to progress adequately. In these cases, testosterone supplementation can allow for normal pubertal development, increased muscle mass, and preservation of bone density. It may also improve mood, self-image, and behavior.

To our knowledge, there are no official guidelines for the best duration of therapy, or the best route of administration (e.g., injections, pills, or topical gel). It has been suggested that androgen therapy is the most important aspect of treatment and should begin at puberty (around age 12), with the dose increasing until it is enough to maintain age-appropriate serum concentrations of testosterone and other hormones. However, not all males with KS benefit from testosterone therapy. There have also been concerns about potential negative effects, such as aggressive behavior, hypercoagulability (excessive blood clotting) and the suppression of native testicular function.

The results of a 2014 study on the safety and tolerability of testosterone replacement therapy in a large group of adolescents with KS showed that early hormonal therapy in adolescents with KS can restore and maintain serum testosterone within the normal range. With close, appropriate followup, testosterone replacement therapy was not associated with any adverse effects. Topical testosterone gel was an acceptable choice of administration among adolescents, avoiding the anxiety and needle phobia associated with intramuscular testosterone injections.

People with questions about hormone therapy for themselves or family members should speak with their endocrinologist.

Mental health therapists or counselors, including psychologists and psychiatrists, can help males with Klinefelter syndrome (KS) find ways to cope with feelings of sadness, depression, self-doubt, and low self-esteem. These professionals can also help families deal with the emotions of having a son with KS.

People who are concerned about their child's behaviors should seek appropriate care:

• Talk to the child's doctor, school nurse, or another health care provider and seek further information about the behaviors or symptoms that are causing worry
• Ask the child's primary care physician or other health care provider for a referral to a specialist with experience in child emotional and/or behavioral problems

Many professional associations have listings of mental health providers, including:

• American Psychiatric Association
• American Psychological Association
• Association for Behavioral and Cognitive Therapies

Seek immediate assistance if you think your child is in danger of harming themselves or others. You can call a crisis line or the National Suicide Prevention Lifeline at 1.800.273.TALK (8255). The National Suicide Prevention Lifeline provides free and confidential emotional support to people in suicidal crisis or emotional distress, and can help you to find a therapist or support group near you. They also provide services to friends and loved ones of people thinking about suicide, and connect them to local resources.

Mosaicism occurs when an individual has more than one cell population with a different genetic make-up. This can include any cells within the body including blood cells, egg and sperm cells, and skin cells. Mosaicism is present from birth. The mosaicism present in Klinefelter syndrome is related to copies of the X and Y chromosomes (sex chromosomes). In Klinefelter syndrome, there is an error in cell division that occurs after fertilization, usually resulting in an additional copy of the X chromosome (46, XXY). Some people with Klinefelter syndrome have an extra X chromosome only in some of their cells (46, XY/46, XXY). Other rarer chromosomal complements resulting in mosaic Klinefelter syndrome include: 46, XX; 48, XXYY; 48, XXXY; 49, XXXYY; and 49, XXXXY.Individuals with mosaic Klinefelter syndrome may have more mild signs and symptoms, depending on how many cells have an additional copy of the X chromosome.

You can find relevant articles on mosaic Klinefelter syndrome through PubMed, a searchable database of biomedical journal articles. Although not all of the articles are available for free online, most articles listed in PubMed have a summary available. To obtain the full article, contact a medical/university library or your local library for interlibrary loan. You can also order articles online through the publisher’s Web site. Using "mosaic+Klinefelter syndrome" as your search term should help you locate articles. Use the advanced search feature to narrow your search results. Click here to view a search.
http://www.ncbi.nlm.nih.gov/PubMed

The National Library of Medicine (NLM) can help you find libraries in your area where you can get the full text of medical articles. The webpage also describes how you can get these articles through interlibrary loan and Loansome Doc (an NLM document-ordering service). You can search for libraries at the following link http://nnlm.gov/members/. You can also contact the NLM toll-free at 1-888-346-3656.

We were not able to find any published, successful ways to help males with KS lose the extra body fat. Some medical researchers support testosterone therapy, but as noted above, there is no evidence as of yet that this will help decrease weight. In addition, testosterone supplementation does not work for all males with KS.

However since this is a relatively common problem for men with KS, you may want to contact a nonprofit support and advocacy organization focused on KS for an answer to your question. Other members of an organization who have KS may be able to tell you what has worked for them and what has not. The medical advisory board may also know of unpublished information which may help you. We have several groups for KS listed under the Organization section.

Medical management of boys with Klinefelter syndrome (KS) is multidisciplinary and may involve several types of specialists. While there are age-specific recommendations for medical management, the specific signs and symptoms present in each affected person also play a role in treatment needs.

Management recommendations for boys during pubertal years include:

• Consideration of mild androgen supplementation in early or mid puberty if the affected male is lacking age-appropriate sexual characteristics, has tall stature, has hypogonadal appearance, or has gynecomastia (and when LH increases to supranormal levels)
• Semen collection and cryopreservation (sperm banking) if there are motile sperm in the ejaculate
• Exercise and lifestyle recommendations
• Bone density scan for bone mineralization and body composition every 2–3 years
• Supplementation with calcium/vitamin D if needed

Screening for associated diseases such as metabolic syndrome, autoimmune diseases, thyroid dysfunction, and malignancies is warranted during this period of life. Screening and/or intervention for psychosocial, behavioral, cognitive, or educational needs is also important.

People with questions about treatment for Klinefelter syndrome should speak with an endocrinologist or other healthcare provider with knowledge of the condition.

Recent research has shown that males with Klinefelter syndrome (KS) have increased body fat and reduced muscle mass. However at this time, the cause of the increased body fat, especially in the abdominal (stomach) area, is not known. Some medical researchers believe it may be caused by the hormone imbalance due to hypogonadism. Others believe the increased body fat may be caused by genetic factors due to having an extra X chromosome since the body fat begins to appear in childhood before the hormones of puberty would play a role. Still other medical researchers believe it is a combination of both testosterone levels and genetic factors. In a recent study of males with KS, testosterone therapy only partly corrected the unfavorable muscle/fat ratio, however some researches believe this may have been because the testosterone doses were too low. In addition, males with KS also have lower aerobic capacity (ability of lungs and heart to get oxygen to the muscles during exercise) and reduced muscle strength in both biceps and quadriceps muscles. This may decrease the amount of exercise a male with KS can do, which might increase the risk of weight gain. At present, no studies have studied the effects of testosterone treatment on muscle strength or other measures of physical fitness in males with KS.

Men with KS, especially those with increased weight in their abdominal area, are at an increased risk for type 2 diabetes and metabolic syndrome. Therefore if you are having difficulty losing weight, you should make certain your doctor is screening you for these conditions.

Nondisjunction is an error in cell division. The cells destined to become sperm and eggs undergo a process known as meiosis. In this process, the 46 chromosomes in the cell separate, ultimately producing two new cells having 23 chromosomes each. Before meiosis is completed, however, chromosomes pair with their corresponding chromosomes and exchange bits of genetic material. In women, X chromosomes pair; in men, the X and Y chromosome pair. After the exchange, the chromosomes separate, and meiosis continues.

In some cases, the two X chromosomes or the X chromosome and Y chromosome fail to pair and fail to exchange genetic material. Occasionally, this results in their moving independently to the same cell, producing either an egg with two Xs, or a sperm having both an X and a Y chromosome. When a sperm having both an X and a Y chromosome fertilizes an egg having a single X chromosome, or a normal Y- bearing sperm fertilizes an egg having two X chromosomes, an XXY male is conceived.

Babies with the 47, XXY form of Klinefelter differ little from healthy children. The results of one study on non-mosaic XXY infants younger than 2 years indicated that most XXY babies had normal external genitalia and facial features with height and weight in the normal range. Genetic testing had been performed due to a delay in walking and/or speech. Early diagnosis of Klinefelter syndrome is shown to be important to monitor potential developmental problems.

Boys with the 47, XXY karyotype may struggle through adolescence with academics, various frustrations, and, in a few instances, serious emotional or behavioral difficulties. However, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning. Lifespan is not affected by Klinefelter syndrome.

It is estimated that 1 in every 500 to 1,000 newborn males has an extra X chromosome, making Klinefelter syndrome one of the most common chromosomal disorders seen among newborns. Variants of Klinefelter syndrome (such as 48,XXXY, 49,XXXXY) are much rarer, occurring in 1 in 50,000 to 1 in 85,000 or fewer newborns.

It is suspected that Klinefelter syndrome is underdiagnosed because mild cases may not be identified. In addition, the features of this condition vary and can overlap significantly with those of other conditions.

Because symptoms of Klinefelter syndrome (KS) can sometimes be very mild, many people are never diagnosed or treated. When a diagnosis is made, treatment is based on the signs and symptoms present in each person, especially the problems related to hypogonadism, gynecomastia, and psychosocial problems. Treatment may include:

• Testosterone replacement: About half of people with SK have low testosterone levels, which may be raised by taking supplemental testosterone. Having a more normal testosterone level can help affected people develop bigger muscles, a deeper voice, and facial and body hair, and may also increase sexual desire, enlarge the testes, improve mood, self-image, and behavior; it may also protect against osteoporosis and decrease the risks of autoimmune disease and breast cancer.
• Breast removal or reduction surgery.
• Educational interventions: As children, many people with Klinefelter syndrome qualify for special services to help them in school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks into small steps.
• Several forms of therapy such as physical, speech, occupational, behavioral, mental health, and family therapy can often help reduce or eliminate some of the symptoms of Klinefelter syndrome such as poor muscle tone; speech and language problems; or low self-confidence.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development provides information about research activities and scientific advances relating to Klinefelter syndrome.