Klinefelter Syndrome and Other Sex Chromosome Variations: Cellular Manifestations and Clinical Implications

Dear Colleagues,

Overall management of patients with disorders of sex chromosomes has changed dramatically in recent years. Advances in genetic diagnosis, pathophysiologic mechanisms and clinical management of these conditions have led to significant improvement in their quality of life. At the same time, dramatic advances in assisted reproductive techniques have now enabled these patients to have their own offspring, whereas previously infertility and sterility were the usual conditions.

Changes involving Klinefelter Syndrome patients are the most well-described. KS results from the presence of a supernumerary X chromosome (47 XXY) and is the most common genetic cause of male infertility, occurring in 70-90% of adults with this condition. Thanks to advances in genetic diagnosis, KS is now diagnosed much more frequently at early ages. This allows for earlier counseling and life planning for this condition, as well as specific treatment plans to maximize fertility potential. As an example, optimization of hormonal management throughout puberty and later has led to a better quality of life and for significantly improved likelihood of success for those desiring paternity. However, randomized placebo-controlled clinical trials are still needed to find answers to frequent questions derived from current clinical practice. 

Despite inherent testicular fibrosis and hyalinization noted at puberty approximately half of adult Klinefelter syndrome (KS) patients are now known to have retrievable sperm obtainable by microsurgical testicular sperm extraction (TESE). Additional azoospermic others are now identified resulting from refinements in histological analysis and immunohistochemical staining as having residual spermatogonial stem cells in the absence of sperm, offering an additional potential resource for fertility.

Recent advances in spermatogonial stem cell (SSC) characterization, cryopreservation and propagation in vitro have opened the doors for future applications in advanced reproductive techniques for selected Klinefelter Syndrome patients. Newer fertility treatment options being currently investigated include: cryo-banking of pre- or peri-pubertal testicular tissue from testicular biopsies or TESE; spermatogonial stem cell transplantation; in vitro differentiation of sperm; testicular tissue grafting for in vivo maturation; and ex vivo maturation of testicular tissue. Currently occurring identification and understanding of fibrosis mechanisms in the Klinefelter testis may allow also for the development of inhibitory treatments in the future as another means to diminish male infertility.

Similar advances are described in other sex chromosome variation syndromes, where a better understanding of these conditions has led to more precise and improved management. As an example, newer assisted reproductive techniques offering the potential for fertility are available for girls with Turner Syndrome (45 XO) who previously have been universally considered to be sterile.

These major advances in basic science research have opened the doors for further improvements in this field. Genetic advances including a better understanding of the processes leading to these sex chromosome abnormalities, gene actions and gene expressions and pre-natal genetic screening as well as refinements and enhancements in hormonal management and clinical reproductive management are occurring.

In this Special Issue, we seek to identify and review these advances and changes affecting the diagnosis and management of these conditions now occurring. We aim to elucidate the most current pertinent insights, with the hope that this issue will be a stimulus for further enhancements and refinements in this field. 

Similarly, this review outlines that treatment for this infertility must also be tailored to each patient’s individual case. Though biological paternity in PBS is rare, assisted reproductive technology has led to live births. By examining and understanding the testicular histology of PBS, further scientific research may expand the repertoire of assisted reproductive technology to advance fertility rates and increase the number of successful cases of paternity in patients with PBS.

AXYS Clinical & Research Consortium was founded in 2015 and exists to:

• Make life easier for those seeking evaluation and treatment.
• Bring consistency to treatment that is consensus and/or evidence-based.
• Advance the overall X&Y variation field through coordinated efforts including research.
• Bring clinical excellence to the field of X&Y variations.

However, providers should not initiate testosterone treatment for induction of puberty without consideration of its potential negative effects on later fertility, taking into account an evaluation of an individual’s overall fertility status.

Dr. Stanley J. Kogan
Dr. Guillermo Galdon
Guest Editors

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• klinefelter syndrome
• sex chromosome variations
• fertility status