Klinefelter syndrome

Published on 02/04/2015 by admin

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Last modified 22/04/2025

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245 Klinefelter syndrome

Instruction

Examine this patient and give us your diagnosis.

Salient features

History

• Infertility (commonest cause of male infertility)

• Mentally subnormal

• Ask about sensation of smell (to exclude Kallman syndrome).

Examination

• Male patient with eunuchoid body habitus with abnormally long legs (Fig. 245.1)

• Elongated body with an increase in length between the soles and pubic bone

• Lack of a beard, and the voice is not masculine.

image

Fig. 245.1 Patient with Klinefelter syndrome after several months of testosterone therapy. Note eunuchoidal body proportions, lack of muscular development and scant body hair after several months of testosterone therapy. Gynaecomastia has been surgically corrected.

(With permission from Rayman 2000.)

Proceed as follows:

• Tell the examiner that you would like to:

• examine the external genitalia (small atrophic testes, lack of male distribution of pubic hair)
• test the IQ: usually lower than normal, although mental disability is uncommon
• check for hypo-osmia (Kallman syndrome).

Diagnosis

This patient has Klinefelter syndrome (lesion) caused by an excess of X and Y chromosomes (aetiology), and has infertility (functional status).

Questions

How would you investigate such a patient?

• Plasma gonadotrophins: follicle-stimulating hormone is consistently raised

• Plasma testosterone concentration: variably reduced

• Plasma oestradiol: raised

• Chromosomal analysis (two or more X chromosomes and one or more Y chromosomes). Cytogenetic arrays (or genomewide assessment of copy-number alterations (deletions and duplications) by means of high-density array technologies) should allow identification of microdeletions.

What is the commonest karyotype?

Eighty-two per cent of patients have 47,XXY, which results from non-dysjunction during meiosis in one of the parents.

Are the patients fertile?

No. However, some men have chromosomal mosaicism (46,XY/47XXY) and are fertile. One report has suggested that in vitro fertilization using intracyoplasmic injection of sperm may be possible for men with non-mosaic Klinefelter syndrome (N Engl J Med 1998;338:588).

Advanced-level questions

What is Kallman syndrome?

It is idiopathic hypogonadotrophic hypogonadism with involvement of the hypothalamus. Patients have hypoosmia and other defects of the rhinencephalon (cleft lip/palate, congenital deafness and blindness). Replacement therapy with both gonadotrophins and gonadotrophin-releasing hormone (GnRH) ensures fertility in many of the affected individuals.

What do you know about the DAX1 gene?

DAX1 is linked to the X chromosome and encodes a member of the nuclear receptor family of proteins that inhibits testicular differentiation. It has been hypothesized that in Klinerfelter syndrome the presence of two X chromosomes, although in different cells (one from 45,XO and the other from 46,XY) may be sufficient to prevent sustained growth and differentiation of the testis by providing excessive DAX1 (or another inhibiting molecule), which suppresses testicular development.

Harry F Klinefelter (1912–1990), an American physician who worked at Johns Hopkins Hospital in Baltimore. He described this syndrome with Fuller Albright (1900–1969) and Edward Reifenstein while he was a visiting fellow at Massachusetts General Hospital and Harvard Medical School (Klinefelter HF Jr, Reifenstein EC Jr, Albright F. Syndrome characterized by gynaecomastia, aspermatogensis with a Leydigism and increased excretion of follicle stimulating hormone, J Clin Endocrinol 1942;2:615–27).

Albright described Albright syndrome and was stricken with Parkinson’s disease at the age of 36 years, and was rendered invalid in 1953 following surgical attempts to improve his Parkinson’s disease. 15 years after their description A Jacobs and JA Strong confirmed the association between the extra X-chromosome and Klinefelter syndrome (Nature 1959;183:302–03, Lancet 2000;356:333–35).

Information can be obtained from the Klinefelter Organisation (www.klinefelter.org.uk).

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