Wednesday, 27 October 2010

Klinefelter’s syndrome

Klinefelter’s syndrome was named after Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, USA in 1942 who thought it was an endocrine disorder due to lack of a second testicular hormone that he postulated but was unable to identify. The postulated hormone, inhibin, was isolated later.

There are two inhibins (inhibin A and inhibin B), both of which inhibit FSH release by direct action on the pituitary though inhibin B appears to be the FSH regulating inhibin. Inhibin B is a marker of spermatogenesis and Sertoli cell function and is produced by the Sertoli cells and it is the major negative feedback regulator of FSH release. It is undetectable in patients with Klinefelter’s syndrome hence the elevated FSH.  Inhibin B correlates positively with sperm concentration and testicular volume and it correlates negatively with the degree of testicular damage.

The 47, XXY karyotype characteristic of Klinefelter syndrome was first described in Scotland, UK in 1959. XXY karyotype of maternal origin arises by an error at either meiosis I (MI) [commonest source of maternal nondisjunction - ? advanced maternal age] or meiosis II (MII). XXY karyotype of paternal origin arises by an MI error with the formation of XY sperm (? advanced paternal age) because, error at MII forms XX sperm or YY sperm rather than XY sperm.

Klinefelter’s syndrome is the commonest sex chromosome abnormality.

Klinefelter’s syndrome is a classic example of seminiferous tubular sclerosis (where germ cells and Sertoli cells are not identified lining  many sclerotic seminiferous tubules that reveal hyalinising fibrosis with absent spermatogenesis, seminiferous tubules can be completely obliterated). In isolated cases several tubules may show intact spermatogenesis with elongated spermatids and sperms. 

Germ cell presence and sperm production are variable in men with Klinefelter’s mosaicism. The term mosaic describes an art form in which pictures are produced by joining together tiny pieces of different coloured stone or glass. The term is used in genetics to describe individuals composed of cells of different genotypes, such as  Klinefelter’s mosaicism patients and patients with Turner syndrome who have both 45, XO and 46, XX cells. The pattern may vary according to cell type and timing of mosaicism. Mosaic forms of Klinefelter's syndrome represent mitotic nondisjunction within the developing zygote and are thought to occur in approximately 10% of individuals with this condition. The commonest form observed is 46, XY / 47, XXY mosaicism.

A nonmosaic Klinefelter’s syndrome patient was able to impregnate his wife without assisted reproductive technology then showed severe oligoasthenozoospermia followed by azoospermia*. This and other studies suggest that early (before the age of 35 years) sperm (if detected) retrieval and cryopreservation for future management of infertility in Klinefelter's syndrome should be considered.

The mechanism by which an extra X chromosome renders patients infertile is not known. Usually azoospermia is established. In some patients few sperm or severe oligoasthenoteratospermia can be found. Spontaneous pregnancies are extremely rare.

The phenotype is normal (there might be disproportionately long legs, clinodactyly and learning difficulties) before puberty, which starts at the normal age but as a process fails to progress normally.

Adult men with Klinefelter’s syndrome have small firm testicles (testicular volume is rarely over 4 ml). The phenotype can vary from a normally virilised man to one with stigmata of androgen deficiency (Leydig cell function is commonly impaired but Leydig cells are present in normal or increased numbers), including female hair distribution, scanty body hair and long legs (usually tall patients) because of late epiphyseal closure. Patients may develop gynaecomastia (with risk of breast cancer). Ultrasound findings of testicular microlithiasis can be seen in men with Klinefelter’s syndrome. There are some Klinefelter's syndrome variants that were reported e.g. 49 , XXXXY variant with several additional features such as microcephaly, mental retardation, facial dysmorphism, radioulnar synostosis, micropenis, and muscular hypotonia. As the number of X chromosomes increases, the severity of mental retardation and of malformations also increases. Each extra X is associated with a 15- to 16-point reduction in IQ, with language most affected, particularly expressive language skills. Compared with their classmates, patients may notice differences and become socially alienated (social maladjustment). This may explain the fact that some patients become criminals on trying to prove one's manhood!

FSH and LH levels increase to hypergonadotropic levels, inhibin B decreases to undetectable levels, testosterone levels are low or low-normal (thus libido can be normal) and oestradiol levels are normal or elevated. The diagnosis is confirmed by chromosome studies.


Reported associated features include e.g. osteoporosis, psychiatric disorders, leg ulcers especially in combination with hyperpigmentation or atrophie blanche (androgens may protect against their development), incontinentia pigmenti (as incontinentia pigmenti trait is usually lethal in males, it has been proposed that the second X chromosome protects against foetal death), and systemic lupus erythematosus [SLE](androgens may normalise SLE haematological and serological abnormalities with clinical remission).

Due to the significant increase of sex chromosomal and autosomal abnormalities in the embryos of Klinefelter patients generated through ICSI, pre-implantation genetic diagnosis (PGD) is strongly advised.

Testosterone replacement is needed as the patient ages and it should be noted that a threshold serum testosterone level is required to achieve full efficacy with PDE5i (phosphodiesterase-5 inhibitors) when required. There is controversy over the indication for testosterone treatment of children with Klinefelter's syndrome (? might improve learning ability). As stated before, compared with their classmates, patients may notice differences and become socially alienated (social maladjustment). This may explain the fact that some patients become criminals on trying to prove one's manhood! Thus testosterone replacement should not lead to exceeding the upper normal values.  

Yearly follow up of men with Klinefelter’s syndrome is required and androgen replacement therapy should be started when testosterone level is in the range of hypoandrogenism. All men with Klinefelter’s syndrome who undergo testicular biopsy procedures for sperm retrieval need long-term endocrine follow-up.

*Ichioka K, Utsunomiya N, Kohei N, Ueda N, Inoue K, Terai A. Adult onset of declining spermatogenesis in a man with nonmosaic Klinefelter’s syndrome. Fertil Steril 2006; 85(5): 1511.e1-2.

This page was last updated in April 2013

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Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
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  • Bailey and Love's Short Practice of Surgery
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  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
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  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
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  • Practical Dermatopathology (R Rapini)
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