Klinefelter's Syndrome

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. He described a series of men who:¹

• 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 (47XXY, 48XXYY polysomy or a mosaic 47XXY/46XY) and this extra chromosome material forms a dense chromatin mass in the nuclei of somatic cells - the Barr body.

• Advanced maternal or paternal age increases the risk for the XXY chromosome, but only slightly.²
• Half the time the extra chromosome comes from the father.³

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.
• A few instances of males having two or even three additional X chromosomes have also been reported in the medical literature.⁴
• In these individuals, the classic features of Klinefelter syndrome may be exaggerated, with low I.Q. or moderate to severe learning difficulties also occurring.

Rarely an individual may possess both an additional X and an additional Y chromosome. XXYY males are described as having slight to moderate learning difficulties. They may sometimes be aggressive or even violent.⁵

• It is the most common sex chromosome disorder.
• It affects 1.72 per 1000 male births,⁶ across all ethnic groups.⁷

This can be variable and often delayed; children may present with delayed speech or learning difficulties, unusually rapid growth in mid childhood or truncal obesity. Adults may present with hypogonadism or subfertility. There may also be failure of sexual maturation.

Although the majority have normal intelligence, they may also tend to have minor developmental and learning disabilities, or some degree of difficulty with language throughout their lives. If untreated this impairment can lead to school failure and loss of confidence.

• Arm span may exceed the body length by 4 inches
• Loss of libido
• 10-33% of XXY males in all will develop breasts large enough to embarrass them; a few XXY males are diagnosed at adolescence, when excessive breast development forces them to seek medical attention
• Impotence
• Most cases have impaired spermatogenesis (azoospermia) and hypogonadism leading to infertility. Although some XY/XXY mosaics may have enough normally functioning cells in the testes to allow them to father children.⁸
• Reduced facial hair
• Reduced muscle power and stamina
• Tiredness
• Different body shape with increased fat
• Osteoporosis
• Depression
• Premature heart disease

• Many XXY males are diagnosed before birth, through amniocentesis or chorionic villus sampling (CVS).
• Later serum testosterone is low or low normal. FSH and LH are elevated (FSH>LH).
• Diagnosis is confirmed by chromosomal analysis.

• Hypothyroidism
• Adult onset diabetes with insulin resistance
• Taurodontism (abnormality of teeth - enlarged pulp chamber)
• Systemic lupus erythematosus
• Germ cell tumours
• Breast cancer - 50x risk compared with normal men.⁹
• Lung disease eg chronic bronchitis. It is particularly important not to smoke.
• Varicose veins

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

Testosterone replacement

This reduces the risks of most of the long-term complications associated with Klinefelters:

• 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 proven to be very successful.^10,11,12 This technique uses sperm aspirated from the testis of men with Klinefelter's - with a theoretical risk of passing on the extra chromosome.
An alternative is insemination by donor (AID).

Surgical treatment

Plastic surgery may be required for gynaecomastia.

The life span is normal.