Androgen Receptor CAG n Repeat Length Influences Phenotype of 47,XXY (Klinefelter) Syndrome

Department of Pediatrics, George Washington University, Washington, Washington, D.C., United States
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 10/2005; 90(9):5041-6. DOI: 10.1210/jc.2005-0432
Source: PubMed


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.
The objective of this study was to investigate the roles of these genetic factors in the variability of the KS phenotype.
This was a cross-sectional study.
The study was performed at a pediatric endocrinology referral clinic.
Thirty-five KS boys and men, aged 0.1-39 yr, were studied. Interventions: There were no interventions.
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.
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.
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.

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    • "Healthy men whose AR has a CAG repeat length of greater than 28 have an increased incidence of impaired spermatogenesis and infertility [47], whereas the expansion of the CAG repeat length of over 40 is related to SBMA, a rare neuromuscular disorder characterised by spinal and bulbar muscular atrophy and is associated with androgen insensitivity, decreased virilisation, testicular atrophy, reduced sperm production, and infertility [51]. Expanded CAGn repeat in the AR gene modulates other male-specific phenotypes, such as prostate growth under androgen substitution in hypogonadal men [52] or different phenotypic features in untreated patients with Klinefelter syndrome [53,54]. "
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    ABSTRACT: Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis. Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.
    Journal of medicine and life 03/2013; 6(1):18-25.
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    • "In adolescence and after puberty, KFS is characterized by varying symptoms of androgen defi- ciency. Zinn et al. (2005) opined that CAG repeat on AR gene, significantly influences the KFS phenotype especially on penile length, a biological indicator of androgen action. However, the authors opined, that KFS with mosaicism will not account for the phenotypic variability. "
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    ABSTRACT: Klinefelter syndrome phenotype is associated with hypogonadism and infertility that results from 47,XXY or 46,XY/47,XXY karyotype. Men with mosaic status show milder phenotype than those of non-mosaics. The present study aimed to report, a data profile on the observed phenotypic features in 72 cytogenetically confirmed Klinefelter syndrome male gathered from duly filled proforma. The reported phenotype from the literature were categorized into 14 groups (highly arched palate, winged scapula, thin long fingers, flat feet, prognathism, liver cirrohsis, seizures, mental illness, penis, gonads, axillary hair growth, and pubic hair growth, presence of gynaecomastia and semen analysis). The calculated total number of the 14 features multiplied for the 72 samples was 1,008. Of the 1,008 features (14X72), KFS male manifested only 16.56% of abnormal features (167/1,008). Scanty axillary hair growth (25%, 18), scanty pubic hair growth (26.38%, 19), small sized penis (25%, 18), small sized gonads (55.56%, 40), presence of gynaecomastia (45.83%, 33) were of highest percentage. It was noticed that, for the entire sample of 72, the manifestation of the 14 categorised features was only 16.56%, irrespective of the karyotype; out of which, with 47,XXY, the manifestation of the phenotypic features was observed to be highest (18.52%, 153/ 826). The findings confirmed the reported observations that in Klinefelter syndrome, there seemed to be a wide variability in the phenotype.
    International Journal of Human Genetics 09/2012; 12(3). · 0.37 Impact Factor
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    • "In adults, one study showed that the allele with the shortest CAG allele was preferentially inactivated and that the physiological mean CAG number could be correlated to a number of clinically significant parameters, including response to testosterone therapy, but also educational and marital status (Zitzmann et al., 2004). In paediatric KS patients, the CAG number was inversely associated with penile length in one study (Zinn et al., 2005) and to later pubertal reactivation of the pituitary–gonadal axis in another study (Wikstrom et al., 2006). Here, we investigate the distribution of skewed X-chromosome inactivation and CAG repeat length in 70 KS patients and 70 age-matched controls and correlate the findings to anthropometrical, hormonal, metabolic and bone-related variables already reported from the same cohort (Bojesen et al., 2006, 2011). "
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    ABSTRACT: The phenotypic variation of Klinefelter syndrome (KS) is wide and may by caused by various genetic and epigenetic effects. Skewed inactivation of the supra-numerical X chromosome and polymorphism in the androgen receptor (AR) have been suggested as plausible causes. We wanted to describe X-chromosome inactivation patterns and the AR polymorphism and correlate these to clinical findings in KS in a cross-sectional study. To that end, we studied 70 KS patients enrolled from fertility clinics and endocrine clinics and 70 age-matched control subjects. The main outcome was X-chromosome inactivation pattern (skewX), AR polymorphism (CAGn - repeat length) and correlation to anthropometrical, hormonal, metabolic and bone-related variables. Forty-six of 70 KS men were heterozygous for CAGn. The shortest and the longest alleles were equally frequent inactivated and the mean CAGn of the two alleles did not differ significantly from the CAGn from either KS men, homozygous for the CAGn, or from the control subjects (22 vs. 23 vs. 21). SkewX was found in 12 of the 46 informative KS men (26%). In KS, height and arm span correlated positively to CAGn, whereas total cholesterol and haematocrit correlated negatively to CAGn. In controls, bone mineral density at the spine and hip correlated positively with CAGn, whereas adiponectin correlated negatively with CAGn. SkewX did not correlate to any of the investigated parameters. We conclude that CAGn polymorphism in AR explain some of the phenotypic variation in KS, whereas skewed X-chromosome inactivation did not. The impact of CAGn on final height may be caused by later reactivation of the pituitary-gonadal axis.
    International Journal of Andrology 12/2011; 34(6 Pt 2):e642-8. DOI:10.1111/j.1365-2605.2011.01223.x · 3.70 Impact Factor
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