Klinefelter Syndrome

Klinefelter Syndrome: The Complete Guide


Hassan Thwaini, MPharm, GPC
May 17, 2024
Take-home points
  • Klinefelter syndrome (KS) is the most common sex chromosome abnormality in men, affecting somewhere between 1 in 500 (0.16%) and 1 in 1,000 (0.2%) of males.14  
  • Boys and men with Klinefelter syndrome are still genetically male, and often will not realise they have a chromosomal deviation, but occasionally it can cause problems that may require treatment.5
  • 10% of males with KS are diagnosed before puberty and only 26% are identified in adulthood. The majority never receive a diagnosis.3
  • 15% of men seeking help for infertility are found to have KS; low testosterone is a common symptom.6

What is Klinefelter Syndrome?

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

A crash course in chromosomes

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 organised 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 mum, 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 23rd 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.

Signs and 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 in 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, 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 socialising or expressing emotions.
  • In teenage years, noticeable signs could be 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 sex drive, small and firm testes, and erection problems.

It’s important to stress that many with Klinefelter syndrome are burdened by few of these symptoms and lead normal healthy 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 what prompts the investigation that leads to a diagnosis.

Causes and risk factors for 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 father’s age on the risk of Klinefelter syndrome remains debatable.7  

Diagnosing 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 luteinising 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

Klinefelter Syndrome Treatment

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 normalise 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.

Learn more about testosterone replacement therapy

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.

Do I have Klinefelter Syndrome?

Early detection and intervention can significantly improve quality of life and outcomes for those with Klinefelter syndrome.4 Therefore, taking proactive steps towards diagnosis and treatment is essential for anyone with concerns about this condition.

If you're concerned that you or your child may have Klinefelter syndrome, the first and most crucial step is to consult with a healthcare provider. A detailed discussion about the symptoms, medical history, and any concerns will guide the next steps.  

For expectant parents with concerns about prenatal exposure to risk factors or a family history of chromosomal disorders, discussing the possibility of prenatal testing with a healthcare provider is advisable.  

Interested in our other disease guides?

  1. Bojesen A, Juul S, Gravholt CH. Prenatal and Postnatal Prevalence of Klinefelter Syndrome: A National Registry Study. J Clin Endocrinol Metab. 2003;88(2):622-626. doi:10.1210/jc.2002-02149  
  2. Crawford D, Dearmun A. Klinefelter syndrome. Nurs Child Young People. 2017;29(6):19. doi:10.7748/ncyp.29.6.19.s21
  3. Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest. 2017;40(2):123-134. doi:10.1007/s40618-016-0541-6
  4. Lizarazo AH, McLoughlin M, Vogiatzi MG. Endocrine aspects of Klinefelter syndrome. Curr Opin Endocrinol Diabetes Obes. 2019;26(1):60. doi:10.1097/MED.0000000000000454
  5. Klinefelter syndrome. nhs.uk. Published October 18, 2017. Accessed March 24, 2024. https://www.nhs.uk/conditions/klinefelters-syndrome/
  6. How do health care providers diagnose Klinefelter syndrome (KS)? | NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development. Published January 9, 2024. Accessed March 25, 2024. https://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/diagnosed
  7. Kanakis GA, Nieschlag E. Klinefelter syndrome: more than hypogonadism. Metabolism. 2018;86:135-144. doi:10.1016/j.metabol.2017.09.017
  8. Bearelly P, Oates R. Recent advances in managing and understanding Klinefelter syndrome. F1000Research. 2019;8:F1000 Faculty Rev-112. doi:10.12688/f1000research.16747.1
  9. Genetics, Chromosomes - PubMed. Accessed March 25, 2024. https://pubmed.ncbi.nlm.nih.gov/32491716/
  10. Chromosomes and DNA - Cell division - AQA - GCSE Combined Science Revision - AQA Trilogy - BBC Bitesize. Accessed March 25, 2024. https://www.bbc.co.uk/bitesize/guides/z2kmk2p/revision/1
  11. Nieschlag E. Klinefelter Syndrome. Dtsch Ärztebl Int. 2013;110(20):347-353. doi:10.3238/arztebl.2013.0347
  12. Nieschlag E, Ferlin A, Gravholt CH, et al. The Klinefelter syndrome: current management and research challenges. Andrology. 2016;4(3):545-549. doi:10.1111/andr.12208

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