Etiology

The additional X chromosome in the sperm or egg occurs randomly and hence Klinefelter syndrome (KS) is not an inherited or heritable disorder. The extra X chromosome arises from nondisjunction errors during either meiosis I or meiosis II divisions in spermatogenesis or oogenesis, with a roughly 50/50 split between disjunction of maternal versus paternal origin.[3]​ There is a weak association with increasing maternal age and this is attributable to increased maternal meiosis I errors.[3][5]​​

In mosaic KS, the error in the division of sex chromosomes occurs in the zygote post-fertilization.

Pathophysiology

The pathophysiology of KS is poorly understood, with the link between genotype and phenotype only partially explained.[4]​ Both hypogonadism and genetic effects are believed to contribute to the spectrum of clinical features associated with KS.[4] The androgen receptor (AR) gene is of interest regarding correlation between genotype and phenotypic variation as it contains a highly polymorphic trinucleotide repeat that is correlated with physiologic androgen effects and may be associated with androgen-dependent features of KS.[3]

Emerging evidence shows that the extra X chromosome leads to profound changes in methylation of DNA and transcriptomic changes, not only on the sex chromosomes but also on all the autosomes, with the phenotypic traits seen in KS explained by organ-specific genomic changes involving multiple genes.[5][11]

Testicular degeneration and abnormal testicular function begins in childhood (perhaps even in utero) and accelerates during puberty. From early- to mid-puberty onward, impairment of Leydig cells (the primary source of testosterone) results in hypergonadotropic hypogonadism, with extensive fibrosis and hyalinization of seminiferous tubules.​[1][2]​​​​[3][4]​​ Most adolescents and adults with KS have azoospermia in the ejaculate. However, pockets of normal spermatic tubular structure and focal spermatogenesis may be found within the highly disordered testicular architecture, perhaps due to a mechanism to eject the supernumerary X chromosome.​[1][2]​​​​[4]​​

The additional copy of the SHOX gene in the pseudoautosomal region of the X chromosome may contribute to faster childhood growth but the growth acceleration mechanism is not through increased growth hormone secretion and is therefore presumed to be through a direct genetic effect of the gene on the growth plate.[2]

The effect of an additional X chromosome on brain function and cognitive development has been well studied but the mechanisms of the chromosomal interference and any explanations for the nonspecific effects seen in KS are poorly understood.[12][13]

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