What is Klinefelter (XXY) syndrome?

Most males are born with two sex chromosomes, an X chromosome and a Y chromosome, giving them an XY chromosomal configuration. A person with Klinefelter syndrome is born with an X and a Y chromosome, as well as an extra X chromosome, which results in an XXY configuration.

Klinefelter syndrome is sometimes referred to in other terms:

• KS
• 47,XXY
• XXY syndrome

Chromosomes house genetic information (DNA). Most humans have 23 pairs of chromosomes (46 chromosomes total) inside each cell. The sex chromosomes, typically XY or XX, make up one of these pairs and dictate either male sexual development or female sexual development.

A majority (80 to 90 percent) of males who have Klinefelter syndrome have the XXY chromosome configuration, giving them 47 total chromosomes instead of the usual 46 that the typical male possesses.ⁱ However, in 10 to 20 percent of cases, the genetic makeup is different and may be XXXY or XXYY, among other variations.ⁱⁱ These particular variants can have more severe impacts on development, and thus are sometimes viewed as separate conditions instead of KS variations.

Many cases of Klinefelter syndrome go undetected, with experts estimating that only around 25 percent of males with the syndrome will be diagnosed in their lifetime.ⁱⁱⁱ The vast majority of males with KS will not find out until adulthood when they begin to experience some symptoms associated with Klinefelter syndrome.

The genetic configuration associated with Klinefelter syndrome leads to the breakdown of the seminiferous tubules in the testes.^iv These tubules are the primary source of sperm production as well as a site of testosterone production; thus, this breakdown results in decreased testosterone production and testosterone deficiency, which affects multiple organ systems. While not always the case, it can also lead to infertility due to the testes producing little or no sperm.

The mean age of diagnosis of Klinefelter syndrome is in the mid-30s.^v Klinefelter syndrome affects an estimated 0.1 to 0.2 percent of newborn males, or approximately 150 males for every 100,000 born.^vi

What are the symptoms of Klinefelter syndrome?

According to Gravholt et al (2018), the symptoms of Klinefelter syndrome vary enough that there is not one set of physical, cognitive, or behavioral characteristics that would definitively or even strongly suggest that a male has this chromosome abnormality.^vii

Symptoms of Klinefelter syndrome

Here are some of the most common symptoms of Klinefelter syndrome, as well as the portion of patients who experience them:^{viii, ix}

• Infertility, which may be treatable (greater than 95 percent)
• Azoospermia, or lack of sperm in the semen (greater than 95 percent)
• Reduced testosterone production (greater than 75 percent)
• Decreased secondary sexual characteristics:
  • Decreased size of testes on both sides (95 percent)
  • Less facial and body hair (60 to 80 percent)
  • Decreased pubic hair (30 to 60 percent)
  • Excess belly fat (approximately 50 percent)
  • Decreased muscle mass and strength (approximately 40 percent)
• Metabolic changes:
  • Metabolic syndrome (46 percent)
  • Type 2 diabetes (10 to 30 percent)
  • Osteopenia, or decrease in bone mineral density (approximately 40 percent)
  • Osteoporosis, or severe decrease in bone mineral density and bone mass (5 to 10 percent)
• Heart conditions:
  • Mitral valve prolapse (0 to 50 percent)
  • Ischemic heart disease (1.5 times greater risk)
  • Blood clots (3 to 6 times greater risk)
• Tremor, or involuntary shaking movement caused by muscle contractions (greater than 25 percent)
• Gynecomastia, or enlarged breast tissue in a male (28 to 75 percent)
• Increased height (greater than 30 percent)
• Psychiatric issues, such as depression, anxiety, or schizophrenia (greater than 25 percent)
  

People with Klinefelter syndrome may also have an increased risk of breast cancer.^x One of the largest cohort studies examining this variable found an approximately 19 times greater risk of breast cancer in those with Klinefelter syndrome compared to males without Klinefelter syndrome. (Note: The risk is still low, and lower than for females).^xi

Children with Klinefelter syndrome are more likely to have the following symptoms, which can lead to early diagnosis of Klinefelter syndrome:

• Learning disability (greater than 75 percent), including slower social development
• Delayed speech development (greater than 40 percent)
• Decreased penis size (10 to 25 percent)

Klinefelter syndrome impacts physical appearance, but this impact is variable. For example, many males with Klinefelter syndrome are taller than average, have smaller testes, and have less facial hair and body hair, but not everyone will have these symptoms.^xii This variability in symptoms may explain why so many people with Klinefelter syndrome go undiagnosed or misdiagnosed. A boy with Klinefelter syndrome who has not yet gone through puberty may be diagnosed due to the symptoms of mild developmental delay or failure of the testes to descend into the scrotum.^xiii Adult males with Klinefelter syndrome are most likely to be diagnosed while undergoing tests for infertility treatment when trying to conceive.^xiv

^‍What causes Klinefelter syndrome? 

While the occurrence of Klinefelter syndrome is random, scientists know that the extra X chromosome is gained from an error during sperm or egg production in one of the biological parents.^xv During sperm and egg production, cells normally divide in a process called meiosis, which decreases the total number of chromosomes in each egg or sperm to 23. (Meiosis should not be confused with cellular mitosis, the cell division process in which a cell divides into two, duplicating itself.)

Because of meiosis, egg and sperm cells have 23 chromosomes instead of 46. This number is important, because when a sperm cell with 23 chromosomes combines with an egg cell with 23 chromosomes, the result is an embryo with 46 chromosomes. As those cells multiply to become a fetus, each cell of the developing fetus has 46 chromosomes, two of which are sex chromosomes.

When a chromosome does not separate correctly during meiosis, it is called a meiotic nondisjunction. When nondisjunction occurs with sex chromosomes, the XXY chromosome configuration of Klinefelter syndrome is one possible outcome. A meiotic nondisjunction can occur in either the egg or the sperm and does so at an equal rate. In other words, either a sperm or an egg with meiotic nondisjunction could produce offspring with Klinefelter syndrome.^xvi

In rarer cases, the nondisjunction can happen in the embryo instead of the egg or sperm. It leads to some cells with the typical XY male karyotype and other cells with the XXY karyotype, and is referred to as mosaic Klinefelter syndrome.^xvii

A case-control study by De Souza et al showed that a child's risk of developing Klinefelter syndrome goes up as the biological father's age rises.^xviii Therefore, it is possible that older fathers may be more likely to have offspring with Klinefelter syndrome.

How is Klinefelter syndrome diagnosed? 

Doctors use a blood test called chromosome karyotyping (chromosome analysis) to examine the chromosomes in cases of suspected Klinefelter syndrome.^xix It is the only way to formally diagnose someone as having Klinefelter syndrome. The patient may also undergo a non-invasive diagnostic ultrasound, which uses sound waves to measure testicular volume.

These other blood test results may indicate a possible case of Klinefelter syndrome:^xx

• Increased follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels
• Abnormally low testosterone levels
• Mild anemia (decreased red blood cells), which is usually related to low testosterone in males

Are Klinefelter males sterile?

Male infertility is common with Klinefelter syndrome because, in most cases, a male with this condition is azoospermic, meaning there is no sperm in their ejaculate. However, it does not mean that all people with Klinefelter syndrome do not have sperm.

A small study published in the Journal of Endocrinological Investigation found that seven of 84 males with Klinefelter syndrome had sperm in their ejaculate.^xxi In addition, 24 of the subjects underwent testicular sperm extraction (TESE), and successful sperm recovery was possible in nine of these individuals (37.5 percent).^xxii When analyzing the sperm retrieved, the researchers observed a higher percentage of chromosomally abnormal (aneuploid) sperm compared to males with non-genetic causes of infertility. The aneuploid sperm mainly had sex chromosome disomy, meaning that they had an extra sex chromosome (i.e., XY or XX, whereas normal sperm have only one X or one Y chromosome).^xxiii

At the same time, other studies have shown that as many as 50 percent of people with KS may have sperm that can be retrieved.^xxiv Given that sperm can be recovered in many individuals with KS, the scientific community does not consider males with KS to necessarily be sterile.^xxv Without interventions such as sperm extraction, however, the rate of infertility in KS is above 95 percent.^xxvi

Procedures such as TESE in combination with intracytoplasmic sperm injection (ICSI) — which involves injecting a carefully selected sperm directly into the egg for in vitro fertilization (IVF)  — can be effective interventions in some cases.^xxvii In a small study of 68 males with non-mosaic KS, sperm was retrieved in 45 males (66 percent) using a procedure called microdissection TESE. The subjects with low testosterone levels also received hormone therapy. For the 45 individuals with sperm recovered, the pregnancy rate following IVF using that sperm was 57 percent, with a live birth rate of 45 percent.^xxviii

For comparison, according to the Centers for Disease Control and Prevention (CDC), the live birth rate per IVF cycle in the general population of female patients under 35 years old was around 52 percent in 2018.^xxix

What are the treatment options, and how successful are they? 

Treatment of Klinefelter syndrome depends mostly on the age at which KS is first diagnosed. When doctors diagnose Klinefelter syndrome before puberty, interventions generally involve extra support for learning and social development. Testosterone replacement therapy at this age is controversial but might be considered.^xxx A child should always see an endocrinologist before testosterone therapy is prescribed.

If a male reaches adolescence before diagnosis, he may show signs of lower testosterone. At this point, doctors are likely to supplement testosterone to prevent incomplete puberty. If fertility issues become a concern, the doctor will run tests to confirm if the Klinefelter syndrome is causing low gonadotropin hormones (luteinizing hormone and follicle stimulating hormone). If it is, the doctor is likely to prescribe testosterone supplementation whether the male is trying to conceive or not.^xxxi,xxxii

If he is trying to conceive, a fertility doctor will likely suggest a TESE and ICSI after performing a semen analysis. Once completed, a fertility clinic can either freeze and store any embryos or transfer one into the uterus of the female partner or surrogate.

It has long been believed that males with Klinefelter syndrome could not use their own sperm for the purposes of conception, but the development of TESE and ICSI is changing fertility outcomes for many people trying to conceive. A study published in the Journal of Clinical Endocrinology & Metabolism found that sperm retrieval was successful approximately 50 percent of the time.^xxxiii The success of the sperm retrieval procedure did not decline with age of the male patient, although the oldest participant in the study was 39 years old. Previous testosterone treatment did not appear to influence the outcomes. It is good news for those first diagnosed during adulthood. In this study, the testicular sperm was frozen (cryopreserved) for potential future use in IVF with ICSI.

What are the other Klinefelter syndrome risks or complications? 

As seen in the symptoms of Klinefelter syndrome listed above, individuals with Klinefelter syndrome are at greater risk of several health conditions that could impact both quality of life and life expectancy.

The first among the risks is impaired sugar metabolism (insulin resistance), leaving males with Klinefelter syndrome at a greater risk of developing type 2 diabetes. However, testosterone therapy can both help prevent the development of diabetes and reduce its severity by increasing insulin sensitivity.

People with Klinefelter syndrome are also at greater risk of cardiovascular disease. They may develop dyslipidemia (changes in blood fats, such as high total cholesterol or low HDL cholesterol).^xxxiv There is currently no solid evidence that testosterone supplementation reduces these cardiovascular risks. However, hormone therapy can reduce blood pressure, which may reduce the impact of other cardiovascular disease symptoms.

Individuals with Klinefelter syndrome may also face an increased risk of bone fractures, directly related to poor muscle tone and decreased bone density associated with the condition. Vitamin D treatment plus testosterone supplementation can increase bone density, according to research.^xxxv One controlled study included 127 non-mosaic Klinefelter patients and 60 age-matched control subjects. The study found that vitamin D levels and bone density levels were significantly lower in patients with Klinefelter syndrome. More of the participants in the Klinefelter syndrome group with low vitamin D levels also had osteopenia or osteoporosis when compared to patients with normal vitamin D levels. The study found that supplementation with vitamin D plus testosterone increased bone density by 12.5 percent, but testosterone treatment alone did not.

Males with Klinefelter syndrome have an increased risk of early mortality from complications related to the above risks.^xxxvi The condition may result in a median loss of 10.4 years compared to males without the condition.^xxxvii However, multiple other studies have shown that testosterone can improve the health of people with KS, as well as reduce the risk of death.^xxxviii Hence, it is important to recognize that lifestyle and medical interventions can improve the outcomes for males with this condition.

Conclusion

Klinefelter syndrome can have a number of side effects and symptoms, in addition to an impact on male fertility. However, there are treatment options available, which mean that someone with this condition is not necessarily unable to have children and can modify some of the medical condition’s effects.

If a person suspects they may have Klinefelter syndrome, they should speak with their doctor. If they are diagnosed, lifestyle changes, and medical intervention can reduce the impact of the condition.