Klinefelter syndrome is a collection of signs and symptoms caused by an abnormal number of sex chromosomes in the cells of the body and its effects vary between males with the condition. Symptoms of Klinefelter syndrome can be so mild in some individuals that they, their parents, and their doctors may not even realise they have the condition. In many males it’s picked up when they try to start a family because even for those with mild symptoms, most men with Klinefelter syndrome produce very few or no sperm and are infertile.
However, some boys do show signs and symptoms in childhood and adolescence. Here’s what health professionals can keep an eye out for and what’s next when it comes to management of the condition.
What is Klinefelter syndrome?
People with Klinefelter syndrome can be affected in different ways, but they all share a common genetic characteristic: the cells of their bodies contain a different number of chromosomes than normal.
The collection of chromosomes in an organism’s cells is known as its karyotype. The usual human karyotype is made up of 22 pairs of chromosomes called autosomes (which are the same in males and females) and a pair of sex chromosomes (resulting in a total of 46 chromosomes). Normally, women have 44 autosomes and two X chromosomes (denoted 46,XX) and men have 44 autosomes and one X and one Y chromosome (46,XY).
The most common karyotype associated with Klinefelter syndrome is 47,XXY, which occurs in 80-90% of males with the condition . This is why the condition is sometimes referred to as ‘XXY syndrome’.
How does Klinefelter syndrome occur?
During development of eggs and sperm, the sex chromosomes might not separate properly, so a sperm or an egg can end up with 22 autosomes and 2 sex chromosomes (either XX from females or XY from males). After fertilisation, this can result in cells that are 47,XXY. People with this genotype have Klinefelter syndrome. Rarely, some people with Klinefelter syndrome have more than 2 X chromosomes (e.g., 48,XXXY or 49,XXXXY) or more than 1 Y chromosome (e.g., 48,XXYY).
The extra X chromosome in people with Klinefelter syndrome is responsible for effects on development and body function that vary from person to person. The ways in which the extra X chromosome causes these effects is unknown, but it might be because of the extra copies of some genes on the extra X chromosome.
Who does Klinefelter syndrome affect?
Somewhere around 1-2 per 1000 newborn boys is 47,XXY, making it the most common genetic disorder in men. However, only 25-50% of people with Klinefelter system are ever diagnosed, and most of these diagnoses are not made until adulthood.
Early detection of Klinefelter syndrome offers the best prospects for managing the condition and preventing complications.
Recognising the signs and symptoms of Klinefelter syndrome is difficult because they’re not the same for everyone.
What to look for and what to do in children with Klinefelter syndrome
- Sometimes, Klinefelter syndrome might be suspected from the results of prenatal testing. If that’s the case, a chromosome analysis after birth can provide a certain diagnosis. It’s valuable for parents of children with Klinefelter syndrome to see a genetic counsellor
- Measuring levels of luteinising hormone and testosterone at two to three months of age might be helpful to guide treatment of boys with Klinefelter syndrome. Testosterone treatment might be necessary for boys with Klinefelter syndrome who have a very small penis, but for others, testosterone treatment isn’t recommended
- Undescended testes can be a sign of Klinefelter syndrome, so a chromosome test might be a good idea for boys born with undescended testes that don’t move down into the scrotum by one year of age. Treatment of undescended testes is the same for boys with or without Klinefelter syndrome
- Young boys with Klinefelter syndrome usually grow normally. After five or six years of age they might start growing more quickly than what would be expected based on the height of their parents
- Boys with Klinefelter syndrome should have a physical examination every two years to track growth and testicular development
- Boys with Klinefelter syndrome should have their vitamin D levels measured, in case they need to take extra vitamin D or calcium, to help keep their bones strong
- Boys with Klinefelter syndrome who have low vitamin D levels should have a bone scan every couple of years
- Problems with speech, learning and behavioural problems in boys with Klinefelter syndrome should be discussed with your doctor, for referral to a specialist
What to look for and what to do around the time of puberty
- For people with Klinefelter syndrome, puberty starts around the same age as most other people
- Regular assessment of the progression of puberty, including measurement of testosterone and other reproductive hormones, and body size and proportions, should begin before puberty and regularly throughout
- People with Klinefelter syndrome, perhaps with their parents, should talk to their doctor or another specialist about fertility
- Using ultrasound to examine the testes might be useful during puberty
- Semen collection, to look for sperm, might be appropriate for some people with Klinefelter syndrome. Freezing sperm, if suitable, is a possibility for people who might want to have children later in life.
- Taking biopsies from the testes to collect sperm, for freezing and possible use in later life, might be suitable for some adolescents with Klinefelter syndrome, after specific counselling
- Testosterone treatment might be needed if puberty is delayed or if there are other symptoms of low testosterone
- Social and psychological support, speech therapy and educational support might be needed by some adolescents with Klinefelter syndrome
What to look for and what to do in adulthood
- Adults with Klinefelter syndrome should have their weight, waist circumference, blood pressure, blood sugar and fats measured every year, and get appropriate treatment if necessary
- Breast examinations (and perhaps an ultrasound examination or mammogram) should be performed by a doctor every two years, especially for people with Klinefelter syndrome and a family history of breast cancer
- An electrocardiogram (ECG) to assess heart function, at least once in adulthood, is suggested for people with Klinefelter syndrome
- Vitamin D and bone density measurements should be done for people with Klinefelter syndrome at intervals recommended by their doctors (and when they change doctor). Vitamin D and calcium supplements should be taken if necessary
- Adults with Klinefelter syndrome who want to become parents should have a semen test and sperm collection for freezing and use in artificial reproductive techniques
- For adults with Klinefelter syndrome who want to have children, if it’s not possible to get sperm from a semen sample, a biopsy of the testes to extract sperm should be done
- Adults with Klinefelter syndrome and low testosterone levels should receive testosterone treatment, just like other males with low levels
- Monitoring of testosterone treatment should be the same for people with Klinefelter syndrome as for other men
- Adults with Klinefelter syndrome who aren’t receiving testosterone treatment should have their testosterone levels measured every 12 months
- Testosterone treatment should not be started in people with Klinefelter syndrome until after collection of sperm (if possible) because of its negative effects on sperm production
- Concerns about mental health and sexuality for people with Klinefelter syndrome should be dealt with by specialists
- Eye problems, dental problems and autoimmune diseases seem to be more common than usual in people with Klinefelter syndrome, so specialist treatment might be needed for these conditions
 Zitzmann et al., 2021. European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology. Andrology