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

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Abstract
Summary: 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,XmXpY,n = 3) as compared to maternal (47,XmXmY,n = 11) origin of the supernumerary X chromosome was associated with a later onset of puberty. In 47,XmXpY 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,XmXmY patients (P = 0·01–0·09). In 47,XmXmY subjects, CAG repeat length (range 17–26) correlated with age at which serum LH level first exceeded 1·0 IU/l (rs = 0·63,P = 0·06,n = 10) and testosterone 1·0 nmol/l (28·8 ng/dl) (rs = 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 theARwith 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.