Overview

Klinefelter syndrome is a common genetic condition that affects people assigned male at birth (PAMAB). It results from the presence of an extra X chromosome, caused by random genetic errors during embryonic development. It can have a major impact on an individual’s life, however, there are treatment options available to those living with the condition.

What is Klinefelter syndrome?

Klinefelter syndrome is a genetic condition that affects people assigned male at birth (PAMAB). Whilst not inherited, it is caused by the presence of an extra X chromosome in a PAMAB’s genes. It is a common disorder, affecting around 1 in every 500 to 1000 PAMAB,¹ Klinefelter syndrome can sometimes also be referred to as XXY syndrome.

While most individuals with Klinefelter syndrome do not show any symptoms and lead normal lives, others may be impacted by a range of symptoms, which can have varying degrees of impact on their lives. Symptoms of triple X syndrome may include developmental issues that are not limited to difficulties in hand-eye coordination, speaking difficulties and weak muscle movement.

Causes of Klinefelter syndrome

In Klinefelter syndrome, a PAMAB is born with at least one additional X chromosome. Whilst not fully understood, this is thought to occur due to a random genetic error that occurs during the formation of the embryo. Klinefelter syndrome, however, is not inherited.

Chromosomes are structures found in most cells in our body that carry genetic information about ourselves. Most individuals typically exhibit 46 chromosomes in the form of 23 pairs. The final pair of chromosomes is known as sex chromosomes, and these determine the sex of a person. People assigned female at birth (PAFAB) generally have 2 X chromosomes, whilst PAMAB generally have an X and a Y chromosome.

PAMAB with Klinefelter syndrome have 2 X chromosomes and a Y chromosome (resulting in XXY), caused by the addition of an extra X chromosome during their embryonic development. This can occur in 2 main ways:

• Nondisjunction: Typically, sperm and egg cells undergo multiple rounds of cell divisions in their development, where chromosomes carrying similar information are separated equally among consequent cells. For example, whilst each egg cell receives an X chromosome, a sperm cell receives either an X or Y chromosome. However, in chromosomal nondisjunction, this process can go wrong, resulting in an egg or sperm cell with an additional X chromosome. These can then contribute towards an abnormal embryo that will exhibit XXY
• Mosaic Klinefelter syndrome: Following embryo formation by sperm and egg cells, a subset of cells in the embryo experience cell division errors. This results in some cells in the body that may have an additional X chromosome (XXY), whilst others are normal (XY). It is thought that the greater the proportion of cells that have an additional X chromosome, the more severe the symptoms exhibited by patients

Signs and symptoms of Klinefelter syndrome

A wide spectrum of symptoms can be exhibited by those with Klinefelter syndrome, though the type and severity of symptoms vary between individuals. Additionally, the proportion of cells in the body that consist of an extra X chromosome can also play a major part in symptoms.

Having a tall stature is a common symptom, which is a result of decreased testosterone production that normally inhibits long bone growth in PAMAB following puberty. Decreased testosterone levels can also be attributed to other symptoms such as reduced facial and body hair, small testes, lowered energy levels and a reduced sex drive. These observations may only be noticed following puberty.

In addition, there are cognitive and psychological impacts that can arise from Klinefelter syndrome. Following birth, many individuals exhibit difficulties in initial crawling and walking due to muscle weakness. Issues in speech, reading and problem solving are also important manifestations associated with the condition. This can develop into difficulties with social interactions in later life.²

There are reproductive implications for those with Klinefelter syndrome. In addition to a reduced sex drive, the majority of PAMAB will have a lowered sperm count, rendering them infertile. As such, many individuals are only diagnosed with Klinefelter syndrome in later life, upon experiencing fertility issues.³ Gynaecomastia (enlargement of the breasts) may also be seen in some individuals.

Complications

Many individuals with Klinefelter syndrome are able to lead normal, healthy lives, with fertility issues being the major problem.

However, those with Klinefelter syndrome are at an increased risk of other health conditions such as:

• Osteoporosis
• Obesity
• Type 2 Diabetes
• Anxiety
• Depression and other mental health related issues
• In rare cases, breast cancer⁴

Diagnosis

Whilst diagnosis may occur during teenage years upon observation of abnormal development, many individuals are only diagnosed with Klinefelter syndrome later in life as a result of fertility issues. A combination of both blood tests, karyotyping and analysis of semen can be carried out.

Karyotyping is a type of genetic test that looks at chromosomes in a sample of cells for any abnormalities, whilst semen analysis can determine the sperm count of an individual, which is lowered in individuals with Klinefelter syndrome.⁴

Furthermore, blood tests are performed to check the levels of varying hormones, such as testosterone levels, luteinizing hormone, follicle-stimulating hormone and oestrogen levels. Combined, the results from these tests, along with physical observations, can help to determine whether an individual has Klinefelter syndrome. 

Treatment options including testosterone replacement therapy

Whilst most individuals with Klinefelter syndrome can lead normal, healthy lives, a multidisciplinary approach can be used to help patients manage their symptoms. In addition to medications that can directly target symptoms, regular check-ups with a range of specialists can help individuals improve their personal growth and development. These doctors often work together to come up with a treatment plan that supports and suits the needs of the patient, and evaluate them consistently.

Testosterone replacement therapy is the mainstay treatment used to alleviate many of the symptoms. Medicines containing testosterone are either given in the form of gels or tablets in the case of children, or injections for adults. The hormone therapy can improve muscular growth, increase facial and body hair, as well as enhance energy levels and concentration. Improved mood and cognition have also been reported as an added benefit to testosterone replacement therapy.⁵

Other treatment options include:

• Activity-based therapy: Identifies and aims to work on the movement and hand-eye coordination issues of patients that may hinder their day-to-day activities
• Language therapy: Treats speech and language barrier difficulties
• Family-based therapy: Individuals and their families may choose to seek the advice of a genetic counsellor, for instance, who is able to provide information and educate individuals regarding the risk of giving birth to a child with Klinefelter syndrome for instance

FAQs

How can Klinefelter syndrome be prevented?

Klinefelter syndrome is not an inherited condition, but instead due to random genetic errors during fetal development. Nothing can be done to prevent its onset.

What is the life expectancy of Klinefelter syndrome?

Typically, most individuals have a normal life expectancy. However, there is some limited research that shows men with the condition may live for a year or two less, but this seems to be attributed to the health complications that are associated with Klinefelter syndrome.

Can people with Klinefelter syndrome have children?

Around 95 to 99% of individuals are infertile and are unable to produce sufficient sperm for an egg to be fertilised. However, recent developments in assisted reproductive technologies have improved the outlook for some individuals with Klinefelter syndrome to conceive. Intra-cytoplasmic sperm injection (ICSI) is one such novel technique developed, where a single sperm cell is injected into a single egg cell, as a way to increase the chance of fertilisation. Individuals with Klinefelter syndrome should speak to a healthcare professional to seek the appropriate steps for them.

Summary

Klinefelter syndrome is a common genetic condition caused by the possession of an additional X chromosome in individuals who are assigned male at birth. This occurs due to a random genetic error during embryo formation, but it is not inherited. Most individuals are able to lead normal, healthy lives with the disease, whilst symptoms vary in those who are more severely affected. Some of these symptoms can be managed through medication-based therapeutics, such as testosterone replacement therapy, whilst therapy-based solutions are able to deal with the psychological and social issues that arise due to the disorder.