The etiology of XX sex reversal

The primary testis-determining function is exerted by a gene in the sex-determining region of the human Y chromosome. This gene is termed the sex-determining factor or TDF. A zinc finger gene, ZFY, residing in this region has been cloned and characterized. It is a candidate for TDF. A challenge to future molecular research is to clarify the function of a zinc finger gene on the X chromosome, ZFX, that shows high structural similarity to ZFY. Furthermore, the existence of other genes involved in sex determination is likely but so far unproven. Sex reversal leading to testes in apparently XX individuals (XX males) is most often due to the presence of TDF on the paternally derived X chromosome. The abnormality arises during meiosis in the father when an abnormal exchange leads to the transfer onto the X of the entire pseudoautosomal region plus a portion of the Y chromosome-specific region including TDF from the Y. An XX male resulting from such an exchange is described. 10-20% of XX males do not have Y DNA. Two major mechanisms to explain such Y(-) XX males are discussed. First, several published pedigrees show clear-cut dominant autosomal or X chromosomal inheritance of XX maleness. These patients are always Y(-) and usually have sexual ambiguity. This indicates the existence of other genes, obviously 'downstream' from TDF, that when mutated can trigger testis determination. Nothing concrete is presently known about these putative genes, but their phenotypic effect is slightly different from that of TDF. Second, mosaicism with a prevalent XX lineage and a hidden or scarce lineage containing a Y chromosome can explain some apparently Y(-) XX males. Two XX/XXY mosaic patients are described in detail. In one, only a combination of DNA hybridization and cytogenetic studies led to the discovery of the XXY cell line. In conclusion, XX sex reversal in man is caused by at least 3 mechanisms, viz. abnormal Y-X interchange, genes other than TDF, and mosaicism.