What Is Klinefelter's Syndrome?

Klinefelter's Syndrome - A Genetic Condition Affecting Males

An illustration of chromosomes.
What are the symptoms, causes, genetics, and treatments for Klinefelter's syndrome?. Science Photo Library - SCIEPRO/Getty Images

Klinefelter's syndrome is a genetic condition that affects only males. Here's what you should know about the causes, symptoms and treatment options for the condition.

What Is Klinefelter's Syndrome?

Klinefelter's syndrome is a genetic abnormality that affects only males. Named after the American physician Harry Klinefelter in 1942, Klinefelter's syndrome affects approximately one in 500 newborn males, making it a very common genetic abnormality.

At the current time, the average time of diagnosis is in the mid 30s, and it's thought that only around a fourth of men who have the syndrome are ever officially diagnosed. The most common signs of Klinefelter's syndrome involve sexual development and fertility, though for individual men, the severity of symptoms can vary widely. The incidence of Klinefelter's syndrome is thought to be increasing.

The Genetics of Klinefelter's Syndrome

Klinefelter's syndrome is characterized by an abnormality in the chromosomes or genetic material which make up our DNA.

Ordinarily we have 46 chromosomes, 23 from our mothers and 23 from our father. Of these, 44 are autosomes and 2 are sex chromosomes. A person's sex is determined by the X and Y chromosomes with males having one X and one Y chromosome (an XY arrangement) and females having two X chromosomes (an XX arrangement.) In males, the Y chromosome comes from the father and either an X or Y chromosome comes from the mother.

Putting this together, 46, XX refers to a female an 46, XY defines a male.

Klinefelter syndrome is a trisomy condition, referring to a condition in which three, rather than two of the autosomal chromosomes or sex chromosomes are present. Instead of having 46 chromosomes, those who have a trisomy have 47 chromosomes (though there are other possibilities with Klinefelter syndrome discussed below.)

Many people are familiar with Down syndrome. Down syndrome is a trisomy in which there are three 21st chromosomes. The arrangement would be 47XY (+21) or 47 XX (+21) depending on whether the child was male or female.

Klinefelter syndrome is a trisomy of the sex chromsomes. Most commonly (around 82 percent of the time) there is an extra X chromosome (an XXY arrangment.)

In 10 to 15 percent of men with Klinefelter's syndrome, however, there is a mosaic pattern, in which more than one combinations of sex chromosomes are present, such as 46XY/47XXY. (There are also people who have mosaic Down syndrome.)

Less common are other combinations of sex chromosomes such as 48XXXY or 49XXXXY.

With mosaic Klinefelter's syndrome, the signs and symptoms may be milder, whereas other combinations, such as 49XXXXY usually result in more profound symptoms.

In addition to Klinefelter's syndrome and Down syndrome there are other human trisomies.

Genetic Causes of Klinefelter's Syndrome - Nondisjunction and Accidents in Replication in the Embryo

Klinefelter's syndrome is caused by a random genetic error that occurs during the formation of the egg or sperm, or after conception.

Most commonly, Klinefelter's syndrome occurs due to a process referred to as nondisjunction in the egg or the sperm during meiosis. Meiosis is the process by which genetic material is multiplied and then divided to supply a copy of genetic material to an egg or a sperm. In a nondisjunction, the genetic material is improperly separated. For example, when the cell divides to create two cells (eggs) each with one copy of an X chromosome, the separation process goes askew so that two X chromosomes arrive in one egg and the other egg does not receive an X chromosome.

(A condition in which there is an absence of a sex chromosome in the egg or the sperm may result in conditions such as Turner syndrome, a "monosomy" which has the arrangement 45, XO.)

Nondisjunction during meiosis in the egg or sperm is the most common cause of Klinefelter's syndrome, but the condition may also occur due to errors in the division (replication) of the zygote following fertilization.

Risk Factors for Klinefelter's Syndrome

Klinefelter's syndrome appears to occur more frequently with both older maternal and paternal age (over the age of 35.) A mother who gives birth over the age of 40 is two to three times more likely to have a baby with Klinefelter's syndrome than a mother who is age 30 at birth. We currently do not know of any risk factors for Klinefelter's syndrome which occurs due to errors in division after fertilization.

It's important to note again that while Klinefelter's is a genetic syndrome, it is not usually "inherited" and therefore does not "fun in families." Instead, it is caused by a random accident during the formation of the egg or the sperm, or shortly after conception occurs. An exception may be when sperm from a man with Klinefelter's syndrome are used for in vitro fertilization (see below.)

Symptoms of Klinefelter's Syndrome

Many men can live with an extra X chromosome and experience no symptoms. In fact, men may be first diagnosed when they are in their 20s, 30s, or older, when an infertility workup discovers the syndrome.

For men who have signs and symptoms, these often develop during puberty when the testes do not develop as they should. Signs and symptoms of Klinefelter's syndrome may include:

  • Enlarged breasts (gynecomastia.)
  • Small, firm testicles.
  • Small penis.
  • Sparse facial and body hair.
  • Abnormal body proportions (usually the tendency to have long legs and a short trunk.)
  • Intellectual disability - Learning disabilities, especially language based concerns are more common than in those without the syndrome, though intelligence tests are usually normal.
  • Decreased libido.
  • Infertility - As noted, many men do not realize they have Klinefelter's until they are trying to start a family of their own, as men with the condition do not produce sperm and are therefore infertile. Genetic tests will show the presence of an extra X chromosome and are the most effective way to diagnose Klinefelter's.

Diagnosis of Klinefelter's Syndrome

The diagnosis of Klinefelter's syndrome, as noted above, is often made when a man presents with infertility and a lack of sperm is found on a sperm sample. A genetic karyotype test can then be used to confirm the diagnosis.

On lab tests, a low testosterone level is common, and is usually 50 to 75 percent lower than in men without Klinefelter's syndrome. Keep in mind that there are many causes of low testosterone levels in men in addition to Klinefelter's syndrome.

Gonadotropins, particularly follicle stimulating hormone (FSH) and luteinizing hormone (LH) are elevated, and plasma estradiol levels are usually increased (for unknown reasons.)

Treatment Options for Klinefelter's Syndrome

Androgen therapy (types of testosterone) is the most common form of treatment for Klinefelter's syndrome and can have a number of positive effects, including improving sex drive, promoting hair growth,  increasing muscle strength and energy levels, and reducing the likelihood of osteoporosis. While treatment may improve several of the signs and symptoms of the syndrome, it does not usually restore fertility (see below.)

Surgery (breast reduction) may be needed for significant breast enlargement (gynecomastia) and can be very helpful from an emotional standpoint.

Klinefelter's Syndrome and Infertility

Men with Klinefelter's syndrome are most often infertile, although some men with mosaic Klinefelter's syndrome are less likely to experience infertility.

Using stimulatory methods, such as gonadotropic or androgenic stimulation as is done for some types of male infertility does not work due to the lack of development of the testes in males with Klinefelter's syndrome.

Fertility may be possible by surgically withdrawing sperm from the testes, and then using in vitro fertilization. Unfortunately, it's been found that using IVF with sperm from men with Klinefelter's syndrome can increase the risk of what is called aneuploidy. If men do wish to consider this option, they should have a thorough understanding on how an analysis of the genomics of the sperm can be done prior to implantation.

Infertility in men with Klinefelter's syndrome opens up emotional, ethical, and moral concerns for couples which were not present before the advent of in vitro fertilization. Talking with a genetic counselor so that you understand the risks, as well as the options to test prior to implantation, is critical for anyone considering these treatments. You may also wish to learn more about preimplantation genetic diagnosis.

Klinefelter's Syndrome and Other Health Issues 

Men with Klinefelter's syndrome tend to have more than the average number of chronic health conditions and a shorter life expectancy than men who do not have the syndrome. That said, it's important to note that treatments such as testosterone replacement are being studied which may change these "statistics" in the future. Some conditions which are more common in men with Klinefelter's syndrome include:

  • Breast cancer - Breast cancer in men with Klinefelter syndrome is 20 times more common than in men without Klinefelter synrome
  • Osteoporosis
  • Germ cell tumors
  • Strokes
  • Autoimmune conditions such as systemic lupus erythematosis
  • Congenital heart disease
  • Varicose veins
  • Deep vein thrombosis
  • Obesity
  • Metabolic syndrome
  • Type 2 diabetes

Klinefelter's Syndrome - An Underdiagnosed Condition

It's thought that Klinefelter's syndrome is underdiagnosed, with an estimate that only 25 percent of men with the syndrome receiving a diagnosis (since it is often diagnosed during an infertility examination.) This may initially not seem to be a problem, but many men who are suffering from the signs and symptoms of the condition could be treated, improving their quality of life. Making a diagnosis is important as well with regard to screening and careful management of medical conditions for which these men are at an increased risk.

Sources:

Calogero, A., Giaqulli, V., Mongioi, L. et al. Klinefelter Syndrome: Cardiovascular Abnormalities and Metabolic Disorders. Journal of Endocrinological Investigation. 2017 Mar 3. (Epub ahead of print).

Groth, K., Skakebaek, A., Host, C., Gravholt, C., and A. Bojesen. Clinical Review: Klinefelter Syndrome – A Clinical Update. The Journal of Clinical Endocrinology and Metabolism. 2013. 98(1):20-30.

Kasper, Dennis L.., Anthony S. Fauci, and Stephen L.. Hauser. Harrison's Principles of Internal Medicine. New York: Mc Graw Hill education, 2015. Print.

Kliegman, Robert M., Bonita Stanton, St Geme III Joseph W., Nina Felice. Schor, Richard E. Behrman, and Waldo E. Nelson. Nelson Textbook of Pediatrics. 20th Edition. Philadelphia, PA: Elsevier, 2015. Print.

McEleny, K., Cheetham, T., and R. Quinton. Should We Be Offering Fertility Preservation By Surgical Sperm Retrieval to Men with Klinefelter Syndrome?. Clinical Endocrinology (Oxford). 2017. 86(4):463-466.

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