What Is Klinefelter Syndrome?

Klinefelter syndrome (also known as KS, Klinefelter’s, XXY syndrome, or 47, XXY) is a common genetic condition that causes males to be born with bigger breasts and wider hips but smaller undescended testicles, thus resulting in little to no testosterone and/or sperm production. It is mainly caused by an extra X chromosome copy in all somatic cells (47, XXY). 

Read on to find out how and why Klinefelter syndrome occurs, the different X and Y chromosome variations of Klinefelter syndrome, how it is diagnosed, managed, and treated, how common it is, whether it could be prevented or cured, its main signs, symptoms and risk factors, and when to see a doctor. 

Overview

With the exception of germ cells (egg and sperm cells), the very centre (nucleus) of each somatic (body) cell in every healthy human being contains a total of 46 chromosomes, 23 originating from each parent. ¹ Shaped like matchsticks, chromosomes carry deoxyribonucleic acid (DNA), the hereditary genetic material, and genes that determine important developmental factors including our height, the colour of our eyes and hair, the shape of our faces as well as our intelligence and risk of developing certain diseases. The 22nd pair of chromosomes are termed autosomes and are identical in both males and females.² The 23rd pair, the sex chromosomes or the X and Y chromosomes, however, differ and determine whether a person develops into a male or female. Healthy females normally inherit two copies of the X chromosome (XX), one from each parent.³ Males, on the other hand, normally inherit one copy of the X chromosome from the mother and one copy of the Y chromosome from the father (XY). 

Unfortunately, ‘’mistakes’’ often occur during development and an egg cell or sperm can carry an extra chromosome.³ This is what happens in Klinefelter syndrome. Named after its discoverer, Dr. Harry Klinefelter, Klinefelter syndrome (KS) is a genetic condition that mainly occurs when males inherit an extra copy of the X chromosome, therefore typically ending up with a karyotype (chromosome pattern) of 47, XXY instead of 46, XY.  Consequently, Klinefelter syndrome is sometimes also referred to as the ‘’XXY syndrome’’,  ‘’XXY condition’’, ‘’47, XXY’’, ‘’XXY male’’, and/or ‘’KS/XXY’’. 

People with Klinefelter syndrome develop as males despite having two copies of the X chromosome because the Y chromosome is very distinctive.⁴ 

Causes of klinefelter syndrome

As stated above, Klinefelter syndrome is mainly caused by the presence of an extra X chromosome.³ The first study to demonstrate this was published in 1959.⁵

The extra X chromosome can either be:³

• Present in every somatic cell: this serves as the most common cause of Klinefelter syndrome (47, XXY)
• Present in some, but not all, somatic cells: This variation of Klinefelter’s is referred to as mosaic Klinefelter syndrome. It occurs when some cells have the extra X chromosome, whilst others have the normal 46, XY karyotype (47, XXY/46, XY). It is less common and gives rise to more mild symptoms

Klinefelter syndrome can also be caused by more than one extra X chromosome (e.g. 48, XXXY, 48, XXYY, and 49, XXXXY). ³ These X and Y chromosome variations or syndromes of Klinefelter’s are often more severe but thankfully, less common and relatively rare. 

In the typical XXY form of Klinefelter syndrome, the extra X chromosome can come from either the mother’s egg cell or the father’s sperm.¹ Scientists believe that this mistake occurs randomly, by chance rather than as a result of something the parent/s ‘’have or - haven’t done’’.⁶ Klinefelter syndrome is not an inherited but a congenital condition, meaning that it occurs before or during birth. ⁴

Signs and symptoms of klinefelter syndrome

Unfortunately, the signs and symptoms of Klinefelter syndrome can be very subtle.⁷ Most men go years without being diagnosed or even knowing that they have the condition. In fact, according to the Klinefelter’s Syndrome Association, 75% of males live with the congenital condition without having the diagnosis.⁸

The signs and symptoms vary widely depending on the X and Y chromosome variations of Klinefelter syndrome and age, with babies, boys, and teenagers often experiencing fewer and more mild symptoms than adult males (men).⁷ 

For each age group with the typical 47, XXY variation, the following signs and symptoms may include:⁷

• Babies: 

1. Muscle weakness (myotonic dystrophy)
2. Speaking, walking, sitting up, talking and/or crawling later than usual
3. Undescended testicles

• Boys and teenagers: 

1. Enlarged breast tissue (gynecomastia)
2. Small penis 
3. Small, firm testes
4. Decreased facial and body hair 
5. Tall stature 
6. Broad hips and short torso 
7. Delayed puberty 
8. Low energy levels (fatigue)
9. Bone weakness
10.  Learning, social, behavioural, mental and/or emotional difficulties 
11.  Shyness and sensitivity

• Adult males (men): 

1. Low to no testosterone levels/sperm count (infertility)
2. Small penis and testicles 
3. Low sex drive 
4. Gynecomastia
5. Decreased facial and body hair
6. Decreased muscle mass 
7. Increased belly fat 

Visootsak J and Graham JM Jr. suggest that other signs and symptoms may develop in the X and Y variations of Klinefelter syndrome with more than one extra X chromosome including:⁹

• 48, XXXY:

1. Widely spaced eyes (ocular hypertelorism)
2. Flat nasal bridge
3. Abnormal connection of the radius and ulna bones in the forearm (radioulnar synostosis)
4. Curving of the pinky finger (fifth-finger clinodactyly)

• 49, XXXXY (most severe):

1. Small head in a baby (microcephaly)
2. Splitting of the tissue at the back of the throat (bifid uvula)
3. Splitting in the roof of the mouth and/or upper lip (cleft palate)
4. Radioulnar synostosis
5. Fifth-finger clinodactyly
6. Heart defects 

Management and treatment for Klinefelter syndrome

Unfortunately, to date, no cure for Klinefelter syndrome exists. However, there are some treatments available that can help modify and better manage the signs and symptoms including: ⁴ 

1. Testosterone replacement therapy (or testosterone therapy): this treatment involves taking testosterone in the form of tablets, gels or injections.⁴ By increasing testosterone levels, it helps males with delayed puberty or absent puberty develop secondary male sex characteristics including a deeper voice, more sparse facial and body hair, higher muscle mass and sexual drive (libido). ¹⁰ Testosterone therapy may also improve bone density, mood and behaviour. It, however, does not improve infertility
2. Breast tissue removal surgery: via a plastic surgeon¹⁰
3.  Fertility treatment: Men who have a very low sperm count may find intracytoplasmic sperm injection (ICSI) especially helpful.¹⁰ ICSI works quite similarly to IVF (in-vitro fertilisation), but rather than mixing the sperm with the eggs and leaving them to fertilise, an embryologist injects a single sperm into the egg to improve the chances of fertilisation¹¹
4. Speech and physical therapy: especially during childhood¹⁰
5. Educational and behavioural support at school: this is particularly helpful for children who struggle with socialisation, learning and/or find it hard to express their feelings and emotions. Talk to your son’s teacher, school counsellor and/or school nurse for extra assistance¹⁰
6. Psychological counselling: to help manage and support mental health¹⁰
7. Physiotherapy: to help build muscle and bone strength⁴
8. Occupational therapy: to help with coordination problems (dyspraxia)⁴ 

FAQs

How is Klinefelter syndrome diagnosed?

Because the complications of Klinefelter syndrome are severe and can increase the risk of developing certain diseases including breast cancer, cardiovascular disease, osteoporosis and type 2 diabetes (amongst others), early diagnosis is key.  A doctor or general practitioner (GP) will typically diagnose a suspected KS patient by conducting the following tests in this particular order:¹⁰

1. Physical examination: this may include asking for personal information, examining the chest and genital area as well as assessing reflexes, development and functioning
2. Hormone testing: the KS patient may be asked to give a blood or urine sample to look for any abnormal changes in hormone levels, particularly testosterone
3. Chromosome analysis (or karyotype analysis): in this ‘’gold-standard’’ genetic test, the KS patient’s blood sample will be sent to the lab and checked for the presence of the extra X chromosome. This type of test helps confirm the diagnosis of Klinefelter syndrome

Although less common, Klinefelter syndrome may also be diagnosed before birth by performing a prenatal screening blood test_. The diagnosis is then confirmed by examining foetal cells in the amniotic fluid (amniocentesis).¹⁰

Can klinefelter syndrome be prevented?

Unfortunately, no, at least not to date. Klinefelter syndrome cannot be prevented because not only does it occur before or during birth, but the sex chromosome abnormality also becomes part of the genetic material (DNA) of the baby boy.¹²

Who is at risk of Klinefelter syndrome?

The risk of having a baby boy born with Klinefelter syndrome is highest in mothers that are over 35 years of age, with studies showing that 40-year-old  women are 4 times more likely to have a boy born with the condition compared to 24-year old women.¹³

Thankfully, once a mother gives birth to a son with Klinefelter syndrome, the risk of it happening again is very low.⁴

How common is klinefelter syndrome?

Despite being rarely diagnosed and considered by many medical professionals to be a rare disease, Klinefelter syndrome is a common sex chromosome abnormality, with a frequency demonstrated to occur in about 1 in every 600 live male births. ⁸ In Britain, approximately 300 baby boys are born with this life-long condition every year. ¹

When should I see a doctor?

See a doctor immediately if your son has: 

• Slow growth and physical and/or mental development during infancy and childhood
• Male infertility⁷

Summary

Klinefelter syndrome is a genetic condition that causes men to be born mainly with one (47, XXY) or more (48, XXYY, 48, XXXY or 49, XXXXY) extra X chromosomes in either some, (mosaic Klinefelter’s syndrome: 47, XXY/46, XY), or, all somatic cells in their bodies. As a result, boys and men develop as males but with: 1) low to no testosterone levels/sperm count and 2) secondary female sex characteristics including decreased facial and body hair, enlarged breast tissue, small penis and testicles, broader hips etc. 

Despite being rarely diagnosed and considered by many to be a rare disease, Klinefelter syndrome is quite common, with an incidence of 1 in every 600 male live births. 

Advanced maternal age (older than 35 years) is one of the main and only known risk factors for Klinefelter syndrome. 

Klinefelter syndrome cannot be prevented or cured and predisposes males to many chronic diseases including breast cancer. Its signs and symptoms vary widely depending on both the X and Y chromosome variations and age. Often, the older the male and the larger the number of extra X chromosomes, the more severe the signs and symptoms tend to be.  

Klinefelter syndrome is mainly diagnosed via hormone and/or genetic tests (e.g. chromosome analysis). Intracytoplasmic sperm injection, breast tissue removal surgery, and different forms of therapy including testosterone therapy, occupational therapy, physiotherapy, and speech and language therapy (to name a few) act as the main current treatments for Klinefelter syndrome. 

If your son is showing signs of slow development and/or is struggling with infertility, see a doctor immediately. 

Haajar Dafiri

Bachelor of Science with Honours – BSc (Hons), Biochemistry, University of
Wolverhampton, UK


Haajar Dafiri is a recent First Class BSc (Hons) Biochemistry graduate from the University of Wolverhampton with over 4 years of academic writing experience.
She has professional experience working in both labs and hospitals such as LabMedExpert and the NHS, respectively. Due to her ‘’outstanding undergraduate’’ academic achievements, she was awarded both the Biosciences Project Prize and the Biochemical Society Undergraduate Recognition Award.

From a young age, whenever words and science were involved, Haajar eagerly followed. Haajar particularly enjoys diving deep into intricate research articles and interpreting, analysing and communicating the scientificfindings to the general public in an easy, fun and organised manner – hence, why she joined Klarity. She hopes her unique, creative and quirky writing style will ignite the love of science in many whilst putting a smile on their faces.

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