Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome.
BACKGROUND
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 (AR) polyglutamine repeat length may contribute to phenotypic variability in KS.


OBJECTIVE
The objective of this study was to investigate the roles of these genetic factors in the variability of the KS phenotype.


METHODS
This was a cross-sectional study.


METHODS
The study was performed at a pediatric endocrinology referral clinic.


METHODS
Thirty-five KS boys and men, aged 0.1-39 yr, were studied.


METHODS
There were no interventions.


METHODS
Auxological measurements, biological indices of testicular function, and clinical assessment of muscle tone were the main outcome measures. 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 AR polyglutamine (AR CAGn) repeat length and X inactivation ratio.


RESULTS
The only genetic factor that significantly influenced the KS phenotype was the AR CAGn repeat length, which was inversely correlated with penile length, a biological 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 AR coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occur in KS.
Zinn
Andrew R
AR
McDermott Center for Human Growth and Development, and Department of Internal Medicne, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8591, USA. andrew.zinn@utsouthwestern.edu
Ramos
Purita
P
Elder
Frederick F
FF
Kowal
Karen
K
Samango-Sprouse
Carole
C
Ross
Judith L
JL
D000293:Adolescent; D000328:Adult; D000886:Anthropometry; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D015331:Cohort Studies; D006579:Heterozygote; D006720:Homozygote; D006728:Hormones / Q000097:blood; D006801:Humans; D007223:Infant; D007713:Klinefelter Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics*; D018911:Trinucleotide Repeats
D006728:Hormones; D011944:Receptors, Androgen