CONTEXT: Klinefelter syndrome (KS; 47,XXY karyotype and variants) is characterized by tall stature and testicular failure, with marked variation in severity of the phenotype. Previous studies have proposed that genetic factors including mosaicism, parental origin of the supernumerary X chromosome, skewed X inactivation, and androgen receptor polyglutamine repeat length may contribute to phenotypic variability in KS.

OBJECTIVE. To investigate the role of these genetic factors in the variability of the KS phenotype.

DESIGN: Cross-sectional study.

SETTING: Pediatric endocrinology referral clinic.

PATIENTS: 35 KS boys and men, ages 0.1- 39 yr

INTERVENTIONS. None.

MAIN OUTCOME MEASURES: Auxologic measurements, biologic indices of testicular function, and clinical assessment of muscle tone. Genetic studies included karyotyping to detect mosaicism, genotyping of microsatellite markers to determine parental origin of the supernumerary X chromosome, and genotyping and methylation studies to measure androgen receptor polyglutamine (AR CAG_n) repeat length and X inactivation ratio.

RESULTS. The only genetic factor that significantly influenced the KS phenotype was the AR CAG_n repeat length, which was inversely correlated with penile length, a biologic indicator of early androgen action. Mosaicism, imprinting, and skewed X inactivation did not account for the variability of the KS phenotype.

CONCLUSIONS: Normal genetic variation in the androgen receptor coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occur in KS.