Background: The rare 46, XX-male syndrome has to be distinguished from more frequent forms of hypogonadism, especially the Klinefelter syndrome (47, XXY). We report 11 cases of SRY-positive XX-males in comparison to 101 age-matched Klinefelter patients and 78 age-matched normal men in a case-control study.
Methods: The comparison included results from the physical examination, endocrinological data, semen analysis, cytogenetic and molecular genetic findings. X-chromosome inactivation analysis with inactivation of the androgen receptor (AR) alleles was performed in 10 heterozygous XX-male patients and the findings were compared to the X-chromosome inactivation pattern in Klinefelter patients and in women.
Results: The XX-males were significantly smaller than Klinefelter patients or normal men. The incidence of maldescended testes and gynecomastia was significantly higher than in both control groups. Most XX-male patients were hypogonadal and require testosterone replacement therapy. All investigated XX-males were infertile. The absolute X-chromosome inactivation in XX males was significantly different from random. Seven out of ten XX-male patients showed skewed X-chromosome inactivation ratios (<20% or >80%) with an equal proportion (distribution) of the X-inactivation on the short and on the long AR alleles. Two had highly skewed ratios of 2:98 and 99:1. There was no preference towards the longer or the shorter AR allele. The patients with skewed inactivation ratios showed no tendencies towards any special diseases.
Conclusions: Our study demonstrates that XX-males are distinct from other patients with hypogonadism due to chromosome disorders with two X chromosomes, such as Klinefelter patients. This is reflected by decreased body height and increased rate of maldescended testes. Two thirds of XX males in our group had non-random X-chromosome inactivation ratios. A reason for the skewed X-chromosome inactivation in these patients may be an X-chromosome abnormality, namely the translocated SRY gene.