Klinefelter Syndrome

Klinefelter Syndrome (KS) is a Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) caused by the presence of one or more extra X chromosomes in individuals with XY chromosomes. It is one of the most common causes of insufficient testosterone production and infertility in XY individuals, with an incidence of approximately 1:500-1:700. It is estimated to affect about 10-12% of individuals with azoospermia (absence of sperm in the ejaculate).
The extra X chromosome leads to a progressive degeneration and fibrosis (hyalinisation) of the seminiferous tubules, starting during puberty and resulting in smaller and firmer testicles. Newborns with KS typically have male external genitalia. Individuals experience puberty spontaneously and at the usual age, although some may face hypogonadism (reduced testosterone production) and signs of undermasculinisation (e.g., limited facial and body hair development) during adolescence. There is often a discrepancy between the progression of pubertal development –such as penis growth and the development of secondary sexual characteristics (e.g., facial hair growth and body fat distribution)– and the increase in testicular volume, which reaches a plateau and may even regress. In adulthood, individuals with KS may be tall, have broad hips, narrow shoulders, reduced body and facial hair, and gynaecomastia (increased breast volume in XY individuals).
Individuals with KS have an increased risk of developing osteoporosis, type 2 diabetes, cardiovascular diseases, thyroid disorders, autoimmune diseases (e.g., systemic lupus erythematosus), and malignant neoplasms such as breast carcinoma. Their overall intelligence quotient (IQ) is typically normal or close to normal, while the verbal IQ may be reduced during the prepubertal period, but tends to normal during puberty.

Genetic traits
Klinefelter syndrome (KS) is caused by the presence of one or more extra X chromosomes, which can result from a non-disjunction event during either maternal or paternal meiosis. In about 90% of cases, the karyotype is 47,XXY, but more rarely, karyotypes such as 48,XXXY or 49,XXXXY are found, as well as mosaicism (coexistence of different chromosomal populations within the same individual). Karyotypes 48,XXXY, and 49,XXXXY are associated with severe mental retardation and physical abnormalities, such as skeletal deformities and underdeveloped external genitalia.

Identification
This condition is typically suspected in adulthood because of its clinical features. It should be considered for all individuals who appear typically male but exhibit smaller and firmer testicles than expected, gynaecomastia, tall stature, reduced upper-to-lower body segment ratio, broad hips, narrow shoulders, and reduced body and facial hair. Additionally, azoospermia (absence of sperm in the ejaculate) with elevated levels of gonadotropins, specifically follicle-stimulating hormone (FSH), can be indicative of Klinefelter Syndrome. Occasionally, the diagnosis in adulthood occurs incidentally during investigations for infertility.
Confirmation of KS is obtained through karyotype analysis, which reveals the abnormal number of X chromosomes. Less frequently, this condition may be recognized prenatally during amniocentesis or chorionic villus sampling, or in childhood/adolescence.

Medical options
There are usually no hormonal deficits at birth or in childhood, and sufficient testosterone is generally produced to start and progress through pubertal development. In most individuals with Klinefelter Syndrome, however, testosterone levels in adulthood are reduced or at the lower end of the normal range. When testosterone deficiency becomes evident, hormone replacement therapy with testosterone should be initiated. The principles of hormone replacement therapy are similar to the treatment of other forms of hypogonadism, and use testosterone in gels or intramuscular injections.
KS is characterised by testicular damage, leading to impaired fertility, and in most cases, azoospermia (absence of sperm in the ejaculate). For individuals wishing to have children, assisted reproductive techniques may be necessary. Sperm retrieval through multiple testicular biopsy samples (TESE or microscope-assisted TESE) is recommended, followed by cryopreservation of the retrieved material. If these procedures are planned, it is better to delay the beginning of testosterone replacement therapy, as reducing gonadotropin levels may interfere with sperm production. Approximately 16% of all azoospermic individuals with KS will successfully have children using these techniques, as indicated in scientific literature.

Bibliography
Liang B, Cheung AS, Nolan BJ. Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review. Clinical endocrinology. 2022 Jul;97(1):3-12
Zitzmann M et al. European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology. Andrology. 2021 Jan;9(1):145-167

Further Links
NHS. Klinefelter syndrome