Biology of DSDs: Klinefelter Syndrome

Description

Klinefelter syndrome is a sex chromosome condition which results in the presence of an extra X chromosome in males: a karyotype of 47,XXY instead of the typical 46,XY. The extra X chromosome commonly results in smaller than average testes, low testosterone levels, infertility, breast development, and decreased muscle mass and bone density.

If you want to help improve medical research and psychological support for individuals with these conditions, you can donate to DSDFamilies (https://dsdfamilies.org/donate).

Sources

[1] NIH. (2020). Klinefelter Syndrome. Genetics Home Reference, National Library of Medicine.

[2] DSDFamilies. (2019). The Story of Sex Development.

[3] LOCAH. (2018). The Intersex Masterpost. Medium.

[4] Sax, L. (2002). How common is intersex? A response to Anne Fausto‐Sterling.

[5] Brennan, D. (2019). Klinefelter Syndrome (XXY Syndrome), Treatments. WebMD.

[6] Bearelly, P., Oates, R. (2019). Recent advances in managing and understanding Klinefelter syndrome. Faculty Review, 112.

[7] Bhartia, M. (2012). Klinefelter's syndrome--a dialogue mislaid for 46 years. BMJ, 345.

[8] Nieschlag, E., et al. (2016). The Klinefelter syndrome, current management and research challenges. Andrology, 4, 545-549.

[9] Turriff, A., et al. (2017). The Impact of Living with Klinefelter Syndrome. Journal of Genetic Counseling, 26(4).

[10] Van Rijn, S., Swaab, H. (2019). Emotion regulation in adults with Klinefelter syndrome (47,XXY), neurocognitive underpinnings and associations with mental health problems. Journal of Clinical Psychology, 76, 228-238.

Transcript

Klinefelter syndrome is a sex chromosome condition which results in the presence of an extra X chromosome in males: a karyotype of 47,XXY instead of the typical 46,XY. The extra X chromosome (and the genes it carries) commonly results in smaller than average testes, low testosterone levels, infertility, breast development, and decreased muscle mass and bone density. It is one of the most common DSDs, affecting about 1 in 500 to 1 in 1000 newborn boys--a rate of around 0.1% of births, and it only affects males.

At conception, the chromosome set for Klinefelter's begins with 47,XXY, instead of 46,XY. This is because one of the parent's reproductive cells (eggs or sperm) experienced an error called nondisjunction, which prevents chromosomes from being distributed equally during cell division. During typical reproductive cell division, each egg gets a single X chromosome (leaving four egg cells each with an X), and each sperm gets either an X chromosome or a Y chromosome. However, with nondisjunction, an egg or sperm may end up with an extra X chromosome. If an egg with an extra X chromosome (XX) is fertilized by a sperm cell with a Y chromosome, the fetus will have Klinefelter syndrome. And if a sperm with both an X and a Y chromosome fertilizes an egg with an X chromosome, the fetus will also have Klinefelter syndrome.

Around the 8th week after conception, the 47,XXY fetus undergoes gonadal differentiation. The activation of the SRY gene on the Y chromosome causes the bipotential gonads to form into testes. As the gonads differentiate into testes, they produce two hormones: anti-Mullerian hormone (AMH) and the androgen known as testosterone.

Just like their 46,XY male counterparts, males with 47,XXY are fully exposed to AMH and testosterone. The production of anti-Mullerian hormone from the testes inhibits the development of the Mullerian structure (which would have formed the fallopian tubes, uterus, cervix, and upper part of the vagina). And the production of testosterone from the testes develops the Wolffian structure (which then forms the epididymis, vas deferens, and seminal vesicle). Because of a functioning SRY gene, anti-Mullerian hormone, and functioning androgen receptors, the fetus develops anatomy to support the production of small gametes. Thus, newborns with Klinefelter syndrome are males.

Most males with 47,XXY are not diagnosed at birth. Instead, many diagnoses of Klinefelter syndrome occur during puberty or adulthood. It is estimated that up to 75 percent of affected men and boys are never diagnosed. The diagnosis for Klinefelter syndrome uses karyotype testing, where an individual's chromosome composition is analyzed through a blood sample.

The extra copy of the X chromosome results in smaller testes, which leads to a reduced amount of testosterone. In the absence of hormone treatment, affected males may experience incomplete or delayed puberty, develop breast tissue, experience decreased muscle mass, decreased bone density, and a reduced amount of facial and body hair. Small testes and decreased hormone production means that most males with Klinefelter's are infertile. However, high-end reproductive technologies can help reduce the rates of infertility.

In terms of development and cognition, boys with Klinefelter's may exhibit problems with coordination that delay the development of motor skills. They often have learning disabilities, problems with reading, and mild delays in speech and language development. However, boys and men with Klinefelter's tend to have better receptive language skills (the ability to understand speech) than expressive language skills (the ability to produce speech). Because of this, some may experience difficulty communicating and yet, at the same time, excel at listening.

A variety of treatments are available to improve the life and health of males with Klinefelter's. The most common is testosterone replacement therapy: this can start at puberty and help the development of facial hair, a deeper voice, and stronger muscles and bones. Other than hormone therapy, occupational therapy and physical therapy combined with physical sports can help build muscles and develop better coordination; speech therapy can increase expressive language skills; counseling and support in school can help affected boys develop stronger learning skills; and finally, taking part in group activities can help build social skills.

In all, males with Klinefelter's have a unique set of developmental differences which arise from the presence of an extra X chromosome. Through the application of strong social support and appropriate therapies, males with 47,XXY can live happy and healthy lives.

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© 2020 Zachary A. Elliott, All Rights Reserved.