Overview

Klinefelter syndrome is a genetic condition. It is a syndrome where a genetically male is born with XXY chromosome instead of the regular XY chromosome, resulting in an extra copy of the X chromosome ,and a total of 47 chromosomes.¹ For some patients, the symptoms of this condition can be very mild, causing it to often go undiagnosed until adulthood. However, the degree of symptoms varies. One of the common symptoms of this condition is reduced testicular growth. This causes patients with Klinefelter syndrome to have smaller testicles, leading to a lower testosterone level.² 

Klinefelter syndrome and cancers

It is known that Klinefelter syndrome patients statistically have a higher mortality from certain types of cancers, like male breast cancer, lung cancer, prostate cancer and non-Hodgkin lymphoma.³ In this article, we are going to focus on the potential risk of testicular cancer in Klinefelter syndrome patients.⁴

In the following section, we will discuss the causes of Klinefelter syndrome, its symptoms in people at different stages, possible types of cancer and hormonal problems related to Klinefelter syndrome. Lastly, we will study the risks associated with the syndrome.

Causes of Klinefelter syndrome^2,5 

This syndrome is caused by a random error that causes biological males to have an extra X chromosome. Normally, Males have a set of XY sex chromosomes while females have a set of XX sex chromosomes. This causes the average person to have 46 chromosomes. In individuals with the Klinefelter syndrome, they possess one extra chromosome X, resulting in 47 total chromosomes. 

Some individuals may suffer from a less serious form of Klinefelter syndrome, mosaic Klinefelter syndrome. They may only have extra copies of X chromosomes in some of the cells but not all of them. These individuals experience fewer symptoms and are more likely to be undiagnosed. 

In contrast, more severe forms of Klinefelter syndromes are caused by extra X and Y chromosomes. This includes ,XXXY syndrome, 48,XXYY syndrome, and 49,XXXXY syndrome. The symptoms in these conditions tend to be more severe. 

Symptoms of Klinefelter syndrome^1,2

There are different known symptoms of the syndrome at different stages of life. 

 In infants, symptoms include:

• Weak muscles
• Difficulty learning to talk
• Passive and shy behaviour
• Having undescended or only one testicle (Cryptorchidism)
• Smaller penis
• Slower motor development
• Hypermobile joints

During childhood and teenage:

• Low self-esteem, struggling to self-express
• Low energy levels
• Dyslexia or dyspraxia 
• Growing taller than family 
• Gynecomastia(enlarged breast tissue)
• Low energy levels and weak bones 
• Broad hips
• Delayed or absent puberty

In adulthood:

• Erectile dysfunction
• Enlarged breast tissue
• Weak bones
• Low labido
• Infertility

Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations.⁶ This causes infertility problems due to low testosterone and low sperm count. 

Klinefelter syndrome and hormonal imbalance

Klinefelter syndrome patients are known to have a lower level of testosterone and a higher level of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)⁷. Some research argue that hormonal imbalance may be a potential cause of testicular cancer (hormonal carcinogenesis). It is said that the change in hormone metabolism genes might alter the hormonal environment linked to testicular cancer development.⁸

Klinefelter syndrome and higher risk of testicular cancer

Men with Klinefelter syndrome have a higher risk of developing extragonadal germ cell tumours (GCTs).⁹ It is found that people suffering from the syndrome are 19 times more likely to develop extragonadal germ cell tumours compared to a healthy biological male. In particular, mediastinal GCTs are the most commonly found.⁹ Cells that are destined to form sperm in the testicles sometimes travel to other parts of the body and grow in other organs to form extragonadal germ cell tumors. The tumours can grow in the brain, the lungs, back of abdomen and the testicles. The tumours can be benign or malignant. If the tumours are malignant, it is seen as a type of cancer. A common type of extragonadal germ cell tumours is testicular germ cell tumors (TGCTs). TGCTs are the origin of 90% of testicular cancer. There are two types of testicular cancer: nonseminoma and seminoma. The two types of cells can be identified visually through a microscope. In nonseminoma cancer, the cells grow and spread more quickly than seminomas. If untreated, the cancer can spread to other parts of the body. It is important to seek medical help as soon as possible if cancer is suspected, as the type of cancer may be nonseminoma. It is suggested that a possible explanation for the link may be due to the extra sex chromosome present in patients. Some also suggest that the increased risk may be due to the hormonal imbalances caused by Klinefelter syndrome.¹⁰

Possible lack of linkage between Klinefelter syndrome and testicular cancer

Multiple studies evaluating the risk of testicular cancer in Klinefelter syndrome often indicate a low correlation between Klinefelter syndrome and testicular cancer. In a study that follows up Klinefelter syndrome patients with testicular ultrasounds indicate that there is no statistical significance between Klinefelter syndrome and testicular cancer.¹¹ 

Cryptorchidism is a known condition found in Klinefelter syndrome. Additionally, it is known to be a factor causing testicular cancer.¹² However, large epidemiological research showed that there is a lack of correlation between cryptorchidism and testicular cancer when cryptorchidism is found in individuals with Klinefelter syndrome.

The theory of hormonal imbalance, although convincing, does not have enough scientific evidence and statistical significance to be proven as a medical fact. It is important for further research to be performed on this topic to improve our understanding of both conditions. 

Management of the possible risk of cancer in Klinefelter syndrome patients

Although the relationship between Klinefelter syndrome and testicular cancer is debated, it is still important to monitor possible cancer in the patient’s body as preventative measures are important for cancer recovery. 

As Klinefelter syndrome is known to be linked to different types of cancer, it is important for patients to regularly undergo body checks and scans to target possible sources of cancer.

​​Individuals with Klinefelter syndrome should still regularly check on the possibility of testicular cancer as a preventative measure, especially if a lump is found on the testicles. Testicular ultrasounds can be used to scan the testicles, allowing medical professionals to observe the location of the lump and predict the possibility of the lump being cancerous.  Additionally, tumour-marker blood tests can also be used to detect cancer cells. Indicators of testicle cancer include alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH). High levels of the indicators may be a sign of the presence of testicular cancer. If testicle cancer is discovered, a testicle may have to be removed.¹³ It is important to educate Klinefelter syndrome patients about the association of their condition with different types of cancer. It is important for them to be aware of the symptoms of cancer, to allow them to seek follow up medical evaluations if worrying symptoms arise.

Conclusion

Characterised by the presence of an extra X chromosome in males, the genetic disorder of Klinefelter syndrome causes patients to have XXY sex chromosomes. Due to its mild and variable symptoms, diagnosis usually occurs in adulthood. Reduced testicular growth and lower testosterone levels are common presenting features.

It is estimated that patients with Klinefelter syndrome have an increased risk of developing certain cancers, such as male breast cancer, lung cancer, prostate cancer, and Non-Hodgkin lymphoma. There is also an increased risk of extragonadal germ cell tumors. However, the relationship of the syndrome is not as clear with regard to testicular cancer. 

The absence of strong evidence of linkage does not disregard that Klinefelter's syndrome may be directly linked with testicular cancer. Therefore, It is important to monitor and utilise preventive measures. It is also important to ensure that Klinefelter syndrome patients are well educated on potential symptoms of associated cancers and the follow-up procedures. Regular body checks should also be undertaken. 

In terms of scientific advancement, there is a need for further research in the relationship between Klinefelter syndrome and risks of different cancer. This can allow better management and early intervention of cancer to ensure improved health conditions of Klinefelter syndrome patients.