Klinefelter syndrome

The signs and symptoms of Klinefelter syndrome (KS) vary among affected people. Some men with KS have no symptoms of the condition or are only mildy affected. In these cases, they may not even know that they are affected by KS. When present, symptoms may include:^[1][2][3]

• Small, firm testicles
• Delayed or incomplete puberty with lack of secondary sexual characteristics resulting in sparse facial, body, or sexual hair a high-pitched voice and body fat distribution resulting in a rounder, lower half of the body, with more fat deposited in the hips, buttocks and thigh instead of around the chest and abdomen
• Breast growth (gynecomastia)
• Reduced facial and body hair
• Infertility
• Tall stature
• Abnormal body proportions (long legs, short trunk, shoulder equal to hip size)
• Learning disability
• Speech delay
• Crypthochirdism
• Opening (meatus) of the urethra (the tube that carries urine and sperm through the penis to the outside) on the underside of the penis (hypospadias) instead of the tip of the head of the penis
• Social, psychologic and behavioral problems  

Whether or not a male with KS has visible symptoms depends on many factors, including how much testosterone his body makes, if he is mosaic (with both XY and XXY cells), and his age when the condition is diagnosed and treated.^[1] Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis as well as some autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.^[2][4] 

Some people with features of Klinefelter syndrome have more than one extra X chromosome in each cell (such as 48,XXXY or 49,XXXXY). In these cases, known as "variants of Klinefelter syndrome", the signs and symptoms can be more severe and may include:^[1][2][4]

• Intellectual disability
• Distinctive facial features
• Skeletal abnormalities
• Poor coordination
• Severe speech difficulties
• Behavioral problems
• Heart defects
• Teeth problems.

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.^[2]

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.^[2]

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.^[5]

The features of Klinefelter syndrome are due to the extra copies of genes on the extra X chromosome, which can alter male sexual development.^[3]

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).^[5]

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.^[2]

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).^[3][6] 

It is also possible to diagnosis Klinefelter syndrome before birth through chorionic villous sampling or amniocentesis.^[6]

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:^[1][3][4]

• 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.

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.^[4]

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.^[4]

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.^[1][7]

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.^[7]