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: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's 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's syndrome may be exaggerated, with low IQ 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

Epidemiology

• It is the most common sex chromosome disorder.
• It affects 1.72 per 1,000 male births,⁶ across all ethnic groups.⁷

Presentation

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.

Clinical features

• 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.

Investigations

• 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.

Associations

• Hypothyroidism.
• Adult-onset diabetes with insulin resistance.
• Taurodontism (abnormality of teeth - enlarged pulp chamber).
• Systemic lupus erythematosus.
• Germ cell tumours.
• Breast cancer - 50 x risk compared with normal men.⁹
• Lung disease, e.g. chronic bronchitis. It is particularly important not to smoke.
• Speech delay.
• Broad range of psychiatric disorders.¹⁰
• Autistic spectrum disorder.
• Varicose veins.

Management

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 Klinefelter's syndrome:¹¹

• 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 very successful.^12,13,14 This technique uses sperm aspirated from the testes of men with Klinefelter's syndrome - with a theoretical risk of passing on the extra chromosome.

An alternative is artificial insemination by donor (AID).

Surgical treatment

Plastic surgery may be required for gynaecomastia.

Prognosis

The lifespan is normal.

Document references

1. 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.
2. Lorda-Sanchez I, Binkert F, Maechler M, et al; Reduced recombination and paternal age effect in Klinefelter syndrome. Hum Genet. 1992 Jul;89(5):524-30. [abstract]
3. Jacobs PA, Hassold TJ, Whittington E, et al; Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet. 1988 May;52(Pt 2):93-109. [abstract]
4. Linden MG, Bender BG, Robinson A; Sex chromosome tetrasomy and pentasomy. Pediatrics. 1995 Oct;96(4 Pt 1):672-82. [abstract]
5. Borghgraef M, Fryns JP, Van den Berghe H; The 48,XXYY syndrome. Follow-up data on clinical characteristics and psychological findings in 4 patients. Genet Couns. 1991;2(2):103-8. [abstract]
6. Morris JK, Alberman E, Scott C, et al; Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet. 2008 Feb;16(2):163-70. Epub 2007 Nov 14. [abstract]
7. Amory JK, Anawalt BD, Paulsen CA, et al; Klinefelter's syndrome. Lancet. 2000 Jul 22;356(9226):333-5.
8. 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. [abstract]
9. Hultborn R, Hanson C, Kopf I, et al; Prevalence of Klinefelter's syndrome in male breast cancer patients. Anticancer Res. 1997 Nov-Dec;17(6D):4293-7. [abstract]
10. 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. [abstract]
11. Bojesen A, Gravholt CH; Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007 Apr;4(4):192-204. [abstract]
12. Palermo GD, Schlegel PN, Sills ES, et al; Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. 1998 Feb 26;338(9):588-90.
13. Lanfranco F, Kamischke A, Zitzmann M, et al; Klinefelter's syndrome. Lancet. 2004 Jul 17-23;364(9430):273-83. [abstract]
14. Schiff JD, Palermo GD, Veeck LL, et al; Success of testicular sperm extraction (corrected) and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005 Nov;90(11):6263-7. Epub 2005 Aug 30. [abstract]

Internet and further reading

• Chen H; Klinefelter syndrome, eMedicine, Mar 2010
• Hutcheson J; Ambigouous genitalia and intersexuality, eMedicine, Jul 2009
• Hughes IA, Houk C, Ahmed SF, et al; Consensus statement on management of intersex disorders. Arch Dis Child. 2006 Apr 19. [abstract]
• Wattendorf DJ, Muenke M; Klinefelter syndrome. Am Fam Physician. 2005 Dec 1;72(11):2259-62. [abstract]
• Genetics Home Reference; (A service of the U.S. National Library of Medicine). Klinefelter syndrome. Accessed August 2009
• Kathryn Leask, Klinefelter Syndrome. NHS Evidence - genetic conditions. Accessed August 2009

Acknowledgements