What is Klinefelter (XXY) syndrome?

Most males are born with two sex chromosomes, namely an X chromosome and a Y chromosome, giving them an XY chromosomal configuration. If a male is born with both X and Y chromosomes as well as an extra X chromosome (XXY), he would have Klinefelter syndrome.

Klinefelter is also sometimes known as:  

• KS  
• 47, XXY
• XXY syndrome  

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

A majority (80-90 percent) of males who have KS have the XXY chromosome configuration,ⁱ giving them 47 total chromosomes instead of the usual 46 that the typical male possesses. However, in 10-20 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 rather than KS variations. Many cases of KS go undetected, with experts estimating that only around 25 percent of males with this syndrome will be diagnosed in their lifetime.ⁱⁱⁱ The vast majority of males who are diagnosed with KS will not find out until adulthood, when they begin to experience some symptoms associated with KS.

The genetic configuration associated with KS leads to the breakdown of the seminiferous tubules in the testes.^iv These tubules are the primary source of sperm production in a male 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 lower sperm production.

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

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What are the symptoms of Klinefelter syndrome?

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

However, some common symptoms of KS include:^viii

• Infertility occurs in over 99 percent of cases but may be treatable
• Azoospermia occurs in over 95 percent of cases
• Lessened testosterone production (>75 percent)
• Decreased secondary sexual characteristics
• Decreased size of testes on both sides (95 percent)
• Less facial hair and body hair (60-80 percent)
• Decreased pubic hair (30-60 percent)
• Excess belly fat (~50 percent)
• Decreased muscle mass and strength (~40 percent)
• Tremor (>25 percent) is an involuntary shaking movement caused by muscle contractions.
  
• Gynecomastia is enlarged breast tissue in a male (28-75 percent). Breast tissue is a fibrous and glandular tissue distinctly different from the fatty tissue that can build up around breast tissue when a person accumulates excess fat on the chest.
  
• Increased height (>30 percent)
  
• Psychiatric issues (>25 percent), such as depression, anxiety, or schizophrenia
• Increased risk of breast cancer.^ix One of the largest cohort studies examining this variable found an approximately 19x greater risk of breast cancer in those with KS compared to males without KS (note that the risk is still low, and lower than for females).^x
  

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Metabolic changes:

• Metabolic syndrome (46 percent) includes several symptoms that often occur together such as insulin resistance, high blood pressure, high triglycerides (a type of fat in the blood), and low HDL cholesterol (good cholesterol).
• Type 2 diabetes (10-39 percent) is a condition in which the body does not respond effectively to insulin. Insulin is a hormone produced by the pancreas that primarily transfers unused glucose into the cells for storage and later usage, thus avoiding hyperglycemia (high blood sugar), and ensuring people have stored energy to release in between meals.
• Osteopenia (~40 percent) is a loss of bone mass and bone density. It is normally associated with aging and may advance to osteoporosis.
• Osteoporosis (5-10 percent) is a severe loss of bone mass resulting in porous bones and a higher risk of fractures and falls.
  

Heart conditions:

• Mitral valve prolapse (0-50 percent), which occurs when blood leaks backward into the left atrium from the left ventricle because the valves are unable to close properly.
• A 1.5 times greater risk of ischemic heart disease, which is associated with frequent chest pain and discomfort and can lead to heart attacks.
• A 3-6 times greater risk of blood clots

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

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

One typical symptom for men with an XXY karyotype is the decreased size of their testes, also called testicular volume.^xi If a male has lower testicular volume, this is something he should speak with his doctor about.

KS impacts physical appearance, known as phenotype, but the impact on appearance is variable. For example, while many men with KS are taller than average, have smaller testes, and less facial/body hair, not all will have these symptoms.^xii This may also explain why so many people with KS go undiagnosed or misdiagnosed. A boy with KS 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 men with Klinefelter’s syndrome are most likely to be diagnosed while undergoing tests for infertility treatment when trying to conceive.^xiv

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What causes Klinefelter syndrome? 

While the occurrence of KS is random, scientists know that the extra X chromosome is gained from an error during sperm or egg production in the biological parents.^xv During sperm/egg production, cells normally experience a cell division called meiosis, which decreases the number of chromosomes to 23. This 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 will have 23 chromosomes instead of 46. This is important because when a sperm cell with 23 chromosomes combines with an egg cell with 23, the result is an embryo with 46 chromosomes. As those cells multiply to become a fetus with two sex chromosomes, each cell of the developing baby would have 46 chromosomes, two of which are sex chromosomes.  

However, when a meiotic nondisjunction happens, the chromosome does not separate correctly during meiosis. When non-disjunction occurs with sex chromosomes, XXY Klinefelter's 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, male sperm or the female eggs could both produce offspring with KS.^xvi

In rarer cases, the non-disjunction can happen in the embryo instead of the egg or sperm. This leads to some cells with the typical XY male karyotype and other cells with the XXY KS Karotype. This is referred to as “mosaicism” or mosaic Klinefelter syndrome.^xvii

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

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How is Klinefelter syndrome diagnosed? 

Doctors will use a blood test called chromosome karyotyping (chromosome analysis) to examine the chromosomes in cases of suspected KS.^xix This 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.

Other blood test results may indicate a possible case of KS, such as:^xx

• Increased follicular stimulating hormone (FSH) and luteinizing hormone (LH) levels

• Abnormally low testosterone levels  

• Low testosterone levels  

• Mild anemia (decreased red blood cells), which is usually related to low testosterone in males

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Are Klinefelter males sterile?

Infertility is common with KS because, in most cases, a male with this condition is azoospermic, meaning there is no sperm in their ejaculate. This does not, however, mean that all people with KS do not have sperm.  

A small study published in the Journal of Endocrinological Investigation found that seven of 84 (8.3 percent) men with KS 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, they observed a higher percentage of chromosomally abnormal (aneuploid) sperm compared to males with non-genetic infertility. The aneuploid sperm mainly had sex chromosome disomy,^xxiii meaning that they had an extra sex chromosome (i.e., XY or XX, whereas normal sperm have only one X or one Y chromosome).^xxiv

At the same time, other studies have shown that as many as 50 percent of men with KS may have sperm that can be retrieved.^xxv Given that sperm can be recovered in many individuals with KS, the scientific community does not consider those with KS to necessarily be sterile.^xxvi Regardless of the variance in sperm recovery rates, the rate of infertility in KS is 97 percent without intervention.^xxvii

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 in some cases.^xxviii In a small study of 68 males with non-mosaic KS, sperm was retrieved in 45 males (66 percent) using microdissection TESE. The subjects with low testosterone levels also received hormone therapy. For the 45 individuals with sperm recovered, it was used for IVF and the pregnancy rate was 57 percent, with a live birth rate of 45 percent.^xxix

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

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

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

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 KS is causing low gonadotropin hormones (luteinizing hormone and follicular stimulating hormone). If it is, the doctor is likely to prescribe testosterone supplementation whether the male is trying to conceive or not.^xxxii,^xxxiii 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 place transfer one into the uterus of the female partner or surrogate.

It has long been believed that men with KS could not use their own sperm for the purposes of conception, but the development of TESE/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.^xxxiv The success of the sperm retrieval procedure did not decline with age of the male patient, although the oldest participant in the study was 39yr of age. Previous testosterone treatment did not appear to influence the numbers. This is good news for those males who may be getting this diagnosis during adulthood. In this study, the testicular sperm was frozen (cryopreserved) for future potential use in IVF with ICSI.

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What are the other Klinefelter syndrome risks or complications? 

As seen in the symptoms of KS listed previously, those with KS 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 men with KS at a greater risk of developing Type 2 Diabetes. However, studies have shown that testosterone therapy can both prevent the development of diabetes and reduce its severity by increasing insulin sensitivity.

Those with KS are also at greater risk of cardiovascular disease. They may develop dyslipidemia (changes in blood fats, such as high total cholesterol or low HD).^xxxv 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.

Those with Klinefelter 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.^xxxvi One controlled study included 127 nonmosaic Klinefelter patients and 60 age-matched control subjects. The study found that Vitamin D levels and bone density levels were significantly lower in those with KS. More of the participants in the KS group with low D levels also had osteopenia or osteoporosis when compared to those 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.

As for life expectancy, men with KS have an increased risk of early mortality from complications related to the above risks. This may result in a median loss of 10.4 years compared to men without the condition.^xxxvii However, multiple other studies have shown that testosterone can improve the health of those with KS, as well as reduce the risk of dying.^xxxviii Hence, as always, it is important to recognize that lifestyle and medical interventions can improve the outcomes for men with this condition.  

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Conclusion

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

If a person suspects he may have KS, he should speak with his doctor. If a diagnosis is made, some lifestyle changes and medical intervention can reduce the impact of the condition on his life.