Klinefelter syndrome

Klinefelter syndrome (KS) is a chromosome variation affecting around 1 in 660 males in which an extra X chromosome is present, resulting in a genetic karyotype of 47,XXY. Karyotype analysis is required for definitive diagnosis.

The extra X chromosome leads to testicular hypofunction and testosterone deficiency, which can result in small testes, infertility, and other symptoms/signs of hypogonadism (e.g., reduced facial/pubic hair, gynaecomastia). Developmental delay in childhood is common, particularly affecting speech.

Symptoms and signs of KS may be subtle and the majority of affected individuals function fairly normally and are never diagnosed. Among those who are diagnosed, this most commonly happens following evaluation for male infertility, although antenatal diagnosis is becoming increasingly common.

Treatment focuses on testosterone therapy, typically starting in adolescence and continuing lifelong, together with neuropsychological and educational support tailored to the individual’s age and symptoms. Assisted reproductive technologies such as testicular sperm extraction have improved the prospects for men with KS to father biological children, although use of donor sperm or adoption remains a common alternative for many affected individuals.

Men with KS have a significantly increased risk of many long-term health conditions, including diabetes, cardiovascular disease, osteoporosis, and breast cancer.

Klinefelter syndrome (KS) is a sex chromosome aneuploidy (abnormal chromosome number) that is defined by the presence of an extra X chromosome.[1]Groth KA, Skakkebæk A, Høst C, et al. Clinical review: Klinefelter syndrome - a clinical update. J Clin Endocrinol Metab. 2013 Jan;98(1):20-30. https://www.doi.org/10.1210/jc.2012-2382 http://www.ncbi.nlm.nih.gov/pubmed/23118429?tool=bestpractice.com ​[2]Butler G, Srirangalingam U, Faithfull J, et al. Klinefelter syndrome: going beyond the diagnosis. Arch Dis Child. 2023 Mar;108(3):166-71. http://www.ncbi.nlm.nih.gov/pubmed/35948402?tool=bestpractice.com ​[3]Zitzmann M, Aksglaede L, Corona G, et al. European Academy of Andrology guidelines on Klinefelter syndrome. Endorsing organization: European Society of Endocrinology. Andrology. 2021 Jan;9(1):145-67. https://www.doi.org/10.1111/andr.12909 http://www.ncbi.nlm.nih.gov/pubmed/32959490?tool=bestpractice.com ​ Around 90% of individuals with KS have the 47,XXY karyotype (47 chromosomes, with an extra X), with the remainder having mosaic karyotypes such as 46,XY/47,XXY (i.e., the extra X chromosome is present in some cells but other cells have the typical male karyotype of 46,XY).[4]Gravholt CH, Chang S, Wallentin M, et al. Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology. Endocr Rev. 2018 Aug 1;39(4):389-423. https://www.doi.org/10.1210/er.2017-00212 http://www.ncbi.nlm.nih.gov/pubmed/29438472?tool=bestpractice.com ​ ​