Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination

Abstract

Clinical, chromosomal and molecular studies of a group of 15 XX males confirm the presence of two main groups. A Y + ve group of ten patients exhibit sex reversal as the result of transfer of the distal end of the short arm of the Y chromosome, including testis determining factors, to the short arm of one X-chromosome, presumably by accidental crossing-over in paternal meiosis. The ten patients have Klinefelter's syndrome but differ from XXY cases in that they are short and shown no impairment of intelligence. The four Y-ve XX males have no demonstrable Y sequences and differ from Y + ve cases in abnormality of the external genitalia and invariable gynaecomastia; in this, they more closely resemble XX true hermaphrodites than XY males. These observations on Y - ve XX males and an additional exceptional Y + patients suggest that the ZFY locus is not essential for male differentiation and is not the primary testis determining factor. Male sex determination in sporadic, and familial Y-ve XX males and true hermaphrodites is likely to be the result of mutation in an X-linked TDF gene and its consequent escape from the constraints of X-inactivation. It seems premature to abandon the dosage model of sex determination on the recent evidence that ZFX does not show dosage compensation.