Clinical, Endocrinological, and Epigenetic Features of the 46,XX Male Syndrome, Compared with 47,XXY Klinefelter Patients

CONTEXT: The 46,XX male syndrome represents a rare, poorly characterized form of male hypogonadism. OBJECTIVE: The objective of the study was to distinguish the 46,XX male syndrome from the more frequent 47,XXY-Klinefelter syndrome in regard to clinical, hormonal, and epigenetic features. DESIGN: This was a case-control study. SETTING: The study was conducted at a university-based reproductive medicine and andrology institution. PATIENTS: Eleven SRY-positive 46,XX males were compared with age-matched controls: 101 47,XXY Klinefelter patients, 78 healthy men, and 157 healthy women latter all heterozygous for androgen receptor (AR) alleles. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: There was a 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 with controls, whereas there was a nonsignificant trend in comparison with 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 10 heterozygous XX male patients displayed an extreme skewing of more than 80% with no preference toward 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. Nonrandom 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.