Klinefelter’s syndrome

This condition was first described in 1942 by Dr Harry Klinefelter Jnr (1912-90), a Baltimore endocrinologist who was working at the Massachusetts General Hospital with Fuller Albright. There are alternative earlier attributions to Richard Altmann in 1895 and Walther Berblinger in 1934. They all described a series of men who:

  • Were tall (around six feet).
  • Had small testes or hypogonadism.
  • Were unable to produce sperm.
  • Had sparse facial and body hair.
  • Had gynaecomastia.

Those affected have an extra X chromosome (47,XXY, 48,XXYY polysomy or a mosaic 47,XXY/46,XY).[1] This extra chromosome material forms a dense chromatin mass in the nuclei of somatic cells – the Barr’s body.

Occasionally, variations of the XXY chromosome count may occur, the most common being the XY/XXY mosaic:

  • In mosaicism some of the cells in the male’s body have an additional X chromosome and the rest have the normal XY chromosome. The percentage of cells with the extra chromosome varies in each patient.
  • Chromosome abnormalities other than 47,XXY (eg, 46,XY/47,XXY mosaicism; 48,XXXY; 49,XXXXY) account for 10-20% of cases.
  • General learning disability and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY.
  • Rarely, an individual may possess both an additional X and an additional Y chromosome (48,XXYY).
  • It is the most common sex chromosome disorder, affecting 1 in 660 men.
  • Klinefelter’s syndrome often goes undiagnosed in affected males. Many with known Klinefelter’s syndrome are not diagnosed until they are adults.

What are the symptoms of Klinefelter’s syndrome?

Symptoms of Klinefelter’s syndrome vary between individuals. Some symptoms, particularly the learning and behavioural problems in young boys, may also happen in other medical conditions. Small testes are present in almost all men with Klinefelter’s syndrome.

Childhood Puberty and adulthood
    • difficulties with speech and reading
    • delayed motor development
    • lower attention span
    • poor muscle tone
    • behavioural problems
    • undescended testes at birth (uncommon)
    • small testes
    • gynaecomastia (breast enlargement)
    • taller than average height
    • fat accumulation on abdomen and hips
    • less facial and body hair/decreased shaving frequency
    • low libido (sex drive)
    • poor erections
    • fatigue
    • infertility
    • osteoporosis (thinning of the bones)
  • depression
  • The classic clinical description includes:
    • Infertility; small firm testes; decreased facial and pubic hair; loss of libido; impotence.
    • Tall and slender, with long legs, narrow shoulders and wide hips.
    • Gynaecomastia or history of gynaecomastia during puberty; decreased libido; history of undescended testes.
    • Learning disability; delayed speech development; behavioural problems; psychosocial disturbances.
  • Other features may include tiredness, reduced muscle power and stamina, and truncal obesity (which may be associated with metabolic syndrome).
  • Infertility and small testes are present in about 99% of individuals but other clinical features vary and many individuals may have only subtle clinical features.
  • Sperm can be found in over 50% of men with Klinefelter’s syndrome.
  • Some XY/XXY mosaics may have enough normally functioning cells in the testes to allow them to father children.

Klinefelter’s syndrome

How is Klinefelter’s syndrome diagnosed?

Small testes (1–4 mL, about the size of a sultana grape) after puberty are an indication of Klinefelter’s syndrome in most cases.

A diagnosis of Klinefelter’s syndrome is confirmed using a blood test called a karyotype that checks the number and structure of chromosomes in cells.

A blood test is also carried out to look at levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH is needed for the cells in the testes to make testosterone. Testosterone and FSH act together on the seminiferous tubules (sperm-producing tubes) in the testes to make sperm.

In many men with Klinefelter’s syndrome, levels of LH are raised, but testosterone levels are borderline or below normal. FSH levels are also raised, which can be a sign of damage to the seminiferous tubules in the testes.

When is Klinefelter’s syndrome diagnosed?

With the increase in use of prenatal (before birth) testing (such as amniocentesis, chorionic villus sampling (CVS) or more recently maternal blood testing in early pregnancy), Klinefelter’s syndrome may be diagnosed before birth. If not, a paediatrician may diagnose Klinefelter’s syndrome immediately after birth (postnatally).

In other cases Klinefelter’s syndrome is identified during childhood when learning or behavioural difficulties may be occur, or around the time of puberty when expected physical changes are delayed or do not happen. Because the symptoms are not always obvious, the diagnosis of Klinefelter’s syndrome might not be made until the man seeks medical help for infertility, a loss of sex drive or a bone fracture, or is not diagnosed at all.

Why is Klinefelter’s syndrome under-diagnosed?

It is suspected that as many as three quarters of the men with Klinefelter’s syndrome are not diagnosed and remain untreated for life. This could be because doctors do not routinely check testes size.

Some symptoms of Klinefelter’s syndrome during childhood and puberty, such as learning difficulties and behavioural problems, can be due to other conditions and so doctors may not think about Klinefelter’s syndrome.

A lack of knowledge about their own body is another reason that men with undiagnosed Klinefelter’s syndrome may not visit a doctor. These men may be unaware of how small their testes are and they may not think anything is wrong. Other men may be too shy or embarrassed to approach a doctor if they are concerned about the size of their testes.

  • Endocrine diseases – eg, diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism and precocious puberty.
  • Osteoporosis, which may cause vertebral collapse.
  • Taurodontism (abnormality of teeth – enlarged pulp chamber).
  • Autoimmune diseases – eg, systemic lupus erythematosus, rheumatoid arthritis and Sjögren’s syndrome.
  • Germ cell tumours.
  • Male breast cancer – studies have shown an increased incidence, especially among 47XXY mosaics.
  • Increased risk of leukaemias, Hodgkin’s lymphoma, non-Hodgkin’s lymphomas and other myeloproliferative diseases.
  • Increased risk of cardiovascular disease.
  • Increased incidence of deep vein thrombosis, pulmonary embolism, venous ulcers and varicose veins.
  • Increased incidence of mitral valve prolapse.
  • Lung disease – eg, chronic bronchitis.
  • Speech delay.
  • A broad range of psychiatric disorders.
  • Autistic spectrum disorder.

Multidisciplinary team follow-up is required to monitor for long-term problems. The team may need to include an endocrinologist, geneticist (genetic counselling), psychologist, physiotherapist and speech therapist.

Testosterone replacement

This reduces the risks of most of the long-term complications associated with Klinefelter’s syndrome:

  • Treatment should begin as they enter puberty.
  • XXY males diagnosed in adulthood are also likely to benefit from the hormone.
  • A regular schedule of testosterone injections will increase strength and muscle size and promote the growth of facial and body hair.
  • In addition to these physical changes, testosterone injections often bring on psychological changes as well.

Although the risk of breast cancer is markedly increased, there is currently no screening programme.

Fertility treatment

  • Intracytoplasmic injection of sperm has been reported and has proved to be successful.
  • An alternative is artificial insemination by donor (AID).

The condition is associated with an increased morbidity, resulting in the loss of approximately a two-year lifespan, with an increased mortality from many different diseases


More information

Genetic causes of male infertility