CONTEXT The 46,XX male syndrome represents a rare, poorly characterised form of male hypogonadism.

OBJECTIVE To distinguish the 46,XX male syndrome from the more frequent 47,XXY-Klinefelter syndrome in regard to clinical, hormonal and epigenetic features.

DESIGN Case-control study.

SETTING University-based reproductive medicine and andrology institution.

PATIENTS 11 SRY-positive 46,XX males were compared to age-matched controls: 101 47,XXY Klinefelter patients, 78 healthy men and 157 healthy women (latter all heterozygous for androgen receptor [AR] alleles).

INTERVENTIONS None.

MAIN OUTCOME MEASURES Comparison of phenotype, endocrine profiles and X-chromosomal inactivation patterns of AR alleles.

RESULTS The 46,XX males were significantly smaller than Klinefelter patients or healthy men, resembling female controls in height and weight. The incidence of maldescended testes was significantly higher than that in Klinefelter patients and controls. Gynecomastia was more frequent in comparison to controls, while there was a non-significant trend in comparison to Klinefelter patients. All XX males were infertile and most were hypogonadal. The inactivation patterns of AR alleles in XX males were significantly more skewed than in Klinefelter patients and women. Seven of ten heterozygous XX male patients displayed an extreme skewing of >80% with no preference towards the shorter or longer AR allele. The length of the AR CAG repeat polymorphism was positively related to traits of hypogonadism.

CONCLUSIONS XX males are distinctly different from Klinefelter patients in terms of clinical and epigenetic features. Non-random X chromosome inactivation ratios are common in XX males, possibly due to the translocated SRY gene. The existence of a Y-chromosomal, growth-related gene is discussed.