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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) and 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.
- Mental retardation 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.
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.
- 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.
- XXY males may be diagnosed before birth, through amniocentesis or chorionic villus sampling.
- Later, serum testosterone is low or low normal. FSH and LH are elevated (FSH >LH).
- Diagnosis is confirmed by chromosomal analysis. The most common indications for karyotyping are hypogonadism and infertility.
- 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.
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.
- Intracytoplasmic injection of sperm has been reported and has proved to be successful.
- An alternative is artificial insemination by donor (AID).
Plastic surgery may be required for gynaecomastia.
The lifespan is normal.
Further reading & references
- Hutcheson J et al; Ambiguous genitalia and intersexuality, Medscape, Jan 2012
- Anonymous, Bhartia M, Ramachandran S; Klinefelter's syndrome--a diagnosis mislaid for 46 years. BMJ. 2012 Dec 3;345:e6938. doi: 10.1136/bmj.e6938.
- Klinefelter HF Jr, Reifenstein EC Jr, Albright F; Syndrome characterized by gynaecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle stimulating hormone. J Clin Endocrinol 1942 2:615-27.
- Blevins CH, Wilson ME; Klinefelter's syndrome. BMJ. 2012 Dec 3;345:e7558. doi: 10.1136/bmj.e7558.
- Chen H; Klinefelter Syndrome, Medscape, Jul 2011
- Groth KA, Skakkebaek A, Host C, et al; Klinefelter Syndrome--A Clinical Update. J Clin Endocrinol Metab. 2012 Nov 1.
- Paduch DA, Fine RG, Bolyakov A, et al; New concepts in Klinefelter syndrome. Curr Opin Urol. 2008 Nov;18(6):621-7. doi: 10.1097/MOU.0b013e32831367c7.
- Akashi T, Fuse H, Kojima Y, et al; Birth after intracytoplasmic sperm injection of ejaculated spermatozoa from a man with mosaic Klinefelter's syndrome. Asian J Androl. 2005 Jun;7(2):217-20.
- Brinton LA; Breast cancer risk among patients with Klinefelter syndrome. Acta Paediatr. 2011 Jun;100(6):814-8. doi: 10.1111/j.1651-2227.2010.02131.x. Epub 2011 Jan 18.
- Bruining H, Swaab H, Kas M, et al; Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics. 2009 May;123(5):e865-70. Epub 2009 Apr 13.
- Bojesen A, Gravholt CH; Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007 Apr;4(4):192-204.
- Yarali H, Polat M, Bozdag G, et al; TESE-ICSI in patients with non-mosaic Klinefelter syndrome: a comparative study. Reprod Biomed Online. 2009 Jun;18(6):756-60.
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Dr Hayley Willacy
Dr Colin Tidy
Dr Adrian Bonsall