Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome

Objective To investigate how genetic features of the X chromosome influence growth, pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome (KS). Previous studies have suggested that genetic features of the X chromosome may contribute to the wide phenotypic variation in KS. Design A prospective clinical study. Patients Fourteen nonmosaic 47,XXY boys, aged 10-13.9 years. Measurements The relationship of genetic features of the X chromosome, including parental origin of X chromosomes, the CAG repeat length of the androgen receptor (AR) gene, and X inactivation with progression of pubertal development, growth and testicular function in KS boys. Results Paternal (47,(XXY)-X-m-Y-p, n = 3) as compared to maternal (47,(XXY)-X-m-Y-m, n = 11) origin of the supernumerary X chromosome was associated with a later onset of puberty. In 47,(XXY)-X-m-Y-p patients, serum LH concentrations increased above 1.0 IU/l at 12.5 +/- 0.6 years (mean +/- SD), Tanner stage P2 occurred at 12.5 +/- 0.7 years, and pubertal acceleration of growth was noted at 13.9 +/- 1.4 years and peak velocity at 14.5 +/- 0.8 years. All of these occurred 1.3-1.9 years later than in 47,(XXY)-X-m-Y-m patients (P = 0.01-0.09). In 47,(XXY)-X-m-Y-m subjects, CAG repeat length (range 17-26) correlated with age at which serum LH level first exceeded 1.0 IU/l (r(s) = 0.63, P = 0.06, n = 10) and testosterone 1.0 nmol/l (28.8 ng/dl) (r(s) = 0.78, P = 0.02, n = 10). Conclusions Paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the AR with later pubertal reactivation of the pituitary-testicular axis in KS boys. Identifying genetic factors that affect the phenotype may lead to a better understanding of the pathogenesis of KS.