Klinefelter syndrome is a genetic syndrome that occurs when a male has an additional X chromosome, making them 47 XXY instead of 46 XY. Rarely, people with Klinefelter syndrome can have even more X chromosomes, such as 48 XXXY or 49 XXXXY. This is associated with more severe features. Life expectancy is close to normal, however.
Klinefelter syndrome is the most common congenital cause of primary hypogonadism.
It is thought to affect every 1 in 2000 live male births, but is underdiagnosed in many other men.
Pathophysiology
Normally, gonadotropin-releasing hormone (GnRH) increases the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH). LH stimulate Leydig cells in the interstitium of the testes into converting cholesterol to testosterone. This testosterone, along with FSH, then go on to activate the Sertoli cells in the seminiferous tubules into making more sperm (spermatogenesis). Negative feedback from testosterone causes inhibition of GnRH and LH, and Sertoli cells release inhibin which inhibits FSH.
In Klinefelter, the presence of the extra X chromosome inhibits the function of Leydig and Sertoli cells. The more X chromosomes present, the more severe this inhibition is. As Leydig and Sertoli cells are inhibited, testosterone and inhibin levels are going to be low, which means LH and FSH levels are going to increase (as they are not inhibited).
Low testosterone levels also mean that spermatogenesis, testicular maturation, development of secondary sexual characteristics will be impaired.
Klinefelter occurs from random genetic events. There is nothing that the parents can do to increase or decrease the risk.
😷 Presentation
The onset of symptoms depends mainly on age, but also on if the mutation is found in all cells or only some of them. This is known as mosaicism.
The male child will be normal until puberty. At this point, he will start to show features of primary hypogonadism:
- Small firm testes
- Gynaecomastia
- Tall stature - an increased leg length is seen as testosterone would normally stop long bone development.
- Psychological issues - including low self-esteem
- Wider hips
- Weaker muscles
- Subtle learning difficulties - particularly affecting speech and language.
- Higher-pitched voice
In adulthood, males show:
- Reduced libido
- Erectile dysfunction
- Gynaecomastia
- Reduced facial/body hair
- Infertility
- Increased adiposity or obesity
🔍 Investigations
- 🏆 Karyotyping - 47, XXY is seen in 80% of cases. There may be other chromosomal abnormalities such as 48, XXXY or 46,XY/47,XXY mosaicism (this is when some cells are 46, XY and some are 47, XXY).
- Bloods:
- Low testosterone - but sometimes we can get compensated hypogonadism, in which very high levels of FSH and LH are found with normal testosterone levels
- Raised GnRH, FSH and LH
- Raised sex hormone binding globulin (SHBG) - as there is no testosterone to bind to SHBG.
- Raised estradiol - due to the X chromosomes
- Azoospermia (no sperm in ejaculate)
🧰 Management
There is no way to treat the underlying genetic cause of Klinefelter syndrome. However, there are options for treating the symptoms and complications of Klinefelter syndrome.
Treatment involves:
- Testosterone injections improve many of the symptoms
- Advanced IVF techniques have the potential to allow fertility
- Breast reduction surgery for cosmetic purposes
- Multi-disciplinary team (MDT) aims to help patients with Klinefelter with their daily living and quality of life:
- Speech and language therapy to improve speech and language
- Occupational therapy to assist in day to day tasks
- Physiotherapy to strengthen muscles and joints
- Educational support where required, for dyslexia and other learning difficultie
🚨 Complications
- Osteoporosis
- Type 2 diabetes mellitus
- Thromboembolism
- Malignancy - such as germ cell tumours (form from developing sperm or egg cells that travel from the gonads to other parts of the body) or breast cancer.
- Anxiety and depression