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What is Klinefelter syndrome?

Klinefelter syndrome, named after the Austrian/American endocrinologist Harry Klinefelter, is the most prevalent chromosomal disorder among males, typically characterised by an additional X chromosome in their genetic makeup.While between 80 – 90% of Klinefelter syndrome cases exhibit an extra 47^th X chromosome, a smaller fraction is present with other variations.^1,²^,⁷

Despite its frequency – affecting nearly 1 in 600 males – an estimated 64% of patients with Klinefelter syndrome will never be diagnosed.⁴^,⁷^,⁸ This underdiagnosis is often related to the inconclusive nature of the symptoms associated with Klinefelter syndrome and the degree how which these symptoms manifest over time.

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DNA, or deoxyribonucleic acid, is a long sequence of genetic molecules that contains the instructions needed for cells to grow, develop, function, and reproduce.⁹ Chromosomes can be thought of as X-shaped structures made from sections of DNA that have been cut down to make them more usable.

Rather than one long piece of DNA, chromosomes allow DNA to be organized into sections, like a library where books are divided into volumes for easier reference and management.

DNA within chromosomes is divided into sections called genes, each coding for specific proteins. Human cells typically contain 46 chromosomes, arranged in 23 pairs. Each pair contains one chromosome from each parent: 23 from mom, 23 from dad. The 23rd pair is known as the sex chromosomes, and they determine an individual's sex; females have two X chromosomes (XX), while males have one X and one Y chromosome (XY).¹⁰

Klinefelter syndrome happens when a male has an extra X chromosome, making the 23^rd pair XXY instead of the usual XY. This deviation from the normal XY arrangement leads to the various clinical manifestations associated with Klinefelter syndrome. Other chromosomal variations are found in 10 – 20% of Klinefelter syndrome patients and include:³^,⁸

Higher-grade aneuploidies - three or more X chromosomes (XXXY), or an additional X and Y chromosome (XXYY).²^,³^,⁷
Mosaicism - a combination of normal and abnormal cells. Some cells have the normal XY chromosome combination, and others have an abnormal combination (XXY, XXXY, XXYY. Etc).¹¹
Structurally abnormal X chromosomes - normal XY combination, but the X chromosome is defective in some way.

Symptoms of Klinefelter syndrome

As previously mentioned, the symptoms of Klinefelter syndrome are difficult to pinpoint given that they present in a variety of ways and different degrees of significance. Traditionally, people with Klinefelter syndrome may exhibit the following physical characteristics:³^,⁴

Taller than average height.
Smaller, firmer testicles.
Reduced facial and body hair.
Broader hips compared to shoulders.
Gynecomastia (breast tissue growth).

Beyond these physical symptoms, Klinefelter syndrome is also associated with social and cognitive challenges and fertility issues, as well as being a precursor for several health conditions, including type 2 diabetes, osteoporosis, cardiovascular diseases, blood clots, autoimmune disorders like lupus, hypothyroidism, anxiety, depression, and very rarely, male breast cancer.⁴^,⁵^,⁷^,⁸

It can be even more difficult to diagnose Klinefelter syndrome in younger adults and children due to the subtlety of the symptoms:²^,⁵^,⁸

For babies and toddlers, symptoms might include weaker muscles, very flexible joints, delayed milestones such as sitting up or walking, being quieter or more passive, having undescended or only one testicle, or a smaller penis.
During childhood, affected individuals may experience shyness, low self-confidence, difficulties with reading, writing, and attention, mild dyslexia or dyspraxia, low energy levels, and challenges in socializing or expressing emotions.
In teenage years, noticeable signs could be the unusually tall height for the family, long arms and legs, broad hips, poor muscle tone, delayed growth of facial and body hair, small and firm testes, and breast enlargement.
In adulthood, common issues include infertility, a lower sexual drive, small and firm testes, and erection problems.

It's important to emphasize that many people with Klinefelter syndrome only experience a few of these symptoms and lead healthy, normal lives. Symptoms can vary widely, making diagnosis difficult; some individuals may have very mild symptoms, while others might experience more significant challenges. For adults, infertility tends to be the principal concern and often prompts the investigation that leads to a diagnosis.

Diagnosis of Klinefelter syndrome

Diagnosing Klinefelter syndrome relies mainly on identifying the symptoms attributed to the disease. Diagnosis is confirmed through the detection of an extra X chromosome, which is often done using a karyotype test.⁵

This process involves collecting a small sample of blood or skin from the individual and examining it under a microscope. The advantage of a karyotype test is its reliability across any stage of a person's life, offering a definitive method for diagnosis.

While such a test is available and can diagnose chromosome disorders like Klinefelter syndrome before birth, due to the associated risks of miscarriage, these tests are usually reserved for pregnancies deemed at higher risk, for example, due to factors like the mother's age, medical history, or family history of chromosomal disorders.⁶

Without chromosomal testing, diagnosing Klinefelter syndrome remains a significant challenge due to its often mild and variable symptoms. It is estimated that only 10% of males with Klinefelter syndrome are diagnosed before puberty, and only 26% are identified in adulthood.³^,⁸

Sometimes, Klinefelter syndrome is found by accident. For instance, adults seeking treatment for fertility issues may prompt doctors to request a hormone test, as approximately 15% of men seeking help for infertility are found to have Klinefelter syndrome.⁶^,⁷

‍Hormone testing will typically reveal low testosterone and elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).⁷ Despite this, patients may be misdiagnosed with hypogonadism and never receive a Klinefelter syndrome diagnosis.

Hence, there is a need for heightened awareness and possibly more comprehensive screening strategies to ensure timely intervention and management of Klinefelter syndrome, given its subtle presentation in many cases.¹²

Causes of Klinefelter syndrome

If a family has one child with Klinefelter syndrome, the likelihood of having another child with the condition remains very small, indicating no significant inherited risk.⁴ Therefore, Klinefelter syndrome arises not from direct inheritance but due to a random anomaly, or mutation, that occurs during the formation of reproductive cells in either parent.²^,⁵

‍The occurrence of this random mutation can happen in the egg from the mother or the sperm from the father, with equal probability from both sides.³

Research has identified that the risk of giving birth to a child with Klinefelter syndrome is directly related to the age of the mother during birth.² In contrast, the influence of the father’s age on the risk of Klinefelter syndrome remains debatable.⁷

Treatment of Klinefelter syndrome

Treatment for KS isn’t quite straightforward. Its aim is to address various aspects of the condition, with the main focus of treatment being on Testosterone Replacement Therapy (TRT) and lifestyle modifications.⁴^,⁵

In those with KS, TRT is initiated around the time of puberty or when symptoms manifest in adulthood. TRT aims to normalize testosterone levels, which can help improve physical development, energy levels, mood, and bone density, although it does not address fertility issues.⁷

For children, testosterone can be administered in the form of gels or tablets, while adults may use gels or receive injections.
Starting at puberty, TRT may aid in developing a deeper voice, promoting the growth of facial and body hair, increasing muscle mass, reducing body fat, and enhancing energy levels. It's also linked to improvements in learning and behavioural issues.
TRT can offer benefits like improved mood and self-esteem, increased energy, and potentially reduced risk of osteoporosis.

For fertility concerns, options such as sperm retrieval techniques combined with assisted reproductive technologies might be explored.⁴^,⁸

Patients should also receive counselling on lifestyle modifications that can mitigate the risk of associated health conditions like diabetes, cardiovascular diseases, and osteoporosis. Regular exercise, a balanced diet, and avoiding smoking and excessive alcohol consumption are recommended.

Treating Klinefelter syndrome requires not only addressing the hormonal imbalance with TRT but also supporting the overall physical and mental well-being of the individual through a combination of medical interventions, lifestyle changes, and psychological support.

Mental health support is crucial, as individuals with KS may experience challenges such as depression and anxiety, which can go on to create larger problems in later life if left unattended.

Prognosis of Klinefelter syndrome

The prognosis for individuals with Klinefelter syndrome is generally favorable, particularly with early diagnosis and appropriate management. While the condition can lead to challenges such as infertility, learning disabilities, and increased risk for certain health issues like osteoporosis and cardiovascular disease, many individuals live healthy, productive lives.