Beyond the Abstract - New Concepts in Klinefelter Syndrome Nov. 7, 2008

BERKELEY, CA (UroToday.com) - Klinefelter syndrome (47,XXY) is the most common numerical chromosomal aberration among men, with an estimated frequency of 1:500 – 1:1000 of live deliveries. Men with KS represent a broad spectrum of phenotypes, professions, incomes and socioeconomic status. Severe intellectual deficits are rare. Spermatogenic and steroidogenic dysfunction are cardinal and the most prevalent signs of Klinefelter syndrome.
The 47,XXY karyotype of Klinefelter syndrome arises spontaneously when paired X chromosomes fail to separate. Advanced maternal and paternal age have been linked to increased risk of Klinefelter syndrome. The X chromosome carries genes that regulate testis function, brain development and growth.
In the last decade, the combination of microsurgical testicular sperm extraction (TESE) and use of freshly retrieved sperm for in-vitro fertilization (IVF) resulted in life births of children from over 50% of patients with Klinefelter syndrome who attempted such a procedure . The fact that sperm can be found in the testes of men with Klinefelter syndrome has challenged the previous assumption that men with Klinefelter syndrome are always sterile. This has raised the hypothesis that children with Klinefelter syndrome are born with spermatogonia and later in life, most likely during early puberty, spermatogonia undergo massive apoptosis that results in depletion of spermatogonial population and subsequent azoospermia.
This hypothesis is based primarily on three observations: testicular sperm can be identified and recovered from at least half of adult men with Klinefelter syndrome; in rare cases, sperm can be found in ejaculates of men with Klinefelter syndrome; and data from boys with Klinefelter syndrome who were biopsied at different ages and development stages indicated that boys with Klinefelter syndrome have spermatogonia at birth but that damage to the germinal epithelium occurs early during puberty. Molecular mechanisms of spermatogonial loss are not known at this point. Sperm found in testes of men with Klinefelter syndrome have only a slightly increased frequency of sex chromosome polysomies, and most boys born from fathers with Klinefelter syndrome have a normal karyotype. These findings indicate that during early stem-cell proliferation or meiotic division, the checkpoint mechanisms are able to overcome X chromosome polysomy resulting in sperm with a single X (or Y) chromosome. We now have 3 boys when sperm was found in ejaculate early in puberty and subsequently lost, supporting that the damage to the testis occurs early during puberty.
The article we published in Current Opinions in Urology, summarizes our own experience in the fertility preservation program in adolescents with KS. It is based on often pioneering and out of the box thinking of our colleagues from around the world, who despite previous assumptions about sterility in men with KS, devoted time and resources to giving the hope and joy of fatherhood to thousands of men around the globe. KS brings tremendous opportunity to study how to best help our patients and potentially prevent progressive testicular failure. It also brings vast material for basic scientists to answer critical and broadly applicable questions about molecular mechanisms of how spermatogonia overcome presence of additional X chromosome-producing 23 X or 23 Y sperm, what are the underlying mechanisms of X chromosome inactivation in men with KS, and why despite high LH, a majority of men will become hypogonadal.
We hope this manuscript will result in renewed interest among clinicians and scientists in this common but under studied syndrome.
Written by: Darius A. Paduch, MD, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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