Article

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: 6.31). 10/2005; 90(9):5041-6. DOI: 10.1210/jc.2005-0432
Source: PubMed

ABSTRACT 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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    • "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 · 3.21 Impact Factor
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    • "It has been suggested that the phenotype of a patient diagnosed with KS in childhood or at puberty is different from that of a patient diagnosed with KS in adulthood (Zinn et al., 2005; Bojesen and Gravholt, 2007). Our results indicate that even in adulthood, phenotypes may vary, especially in those patients visiting infertility clinics. "
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    ABSTRACT: This study aims to provide further insight into the phenotypic heterogeneity of Klinefelter syndrome (KS) by presenting clinical, hormonal, and genetic data from a large series of Egyptian infertile patients with KS. A retrospective case series of KS patients was studied over a period from January 2003 to April 2010. All patients underwent a complete history and physical examination; color duplex examination; semen analysis; measurement of total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin (PRL); and chromosomal typing. Mosaic KS diagnosis was confirmed by fluorescence in situ hybridization. The series included 216 KS patients (198 nonmosaic, 16 mosaic, and 2 KS variants). Typical clinical signs of hypoandrogenism were observed in 86% of patients. Gynecomastia affected 20.8% of the patients. Eunuchoidal body proportions, with arm span exceeding height and lower segment length exceeding upper segment length, were detected in 43.9% and 64.4% of the patients, respectively. In all patients, a reduction in testicular size and azoospermia were detected. Normal levels of T, FSH, LH, E2, and PRL were detected in 44.5%, 3.7%, 3.3%, 93.5%, and 91.2% of patients, respectively. Differences were not significant between patients with classic KS and those with mosaic KS in terms of the frequency of clinical signs of hypoandrogenism, gynecomastia, low T concentrations, or high concentrations of FSH, LH, E2, and PRL (all P > .05). The results of the current study emphasize the heterogeneous clinical, hormonal, and genetic phenotype of infertile KS patients. Our findings support the usefulness of cytogenetic studies in infertile patients showing small testicular size and azoospermia, regardless of the presence of other clinical or endocrine findings.
    Journal of Andrology 07/2011; 33(3):441-8. DOI:10.2164/jandrol.110.011536 · 1.69 Impact Factor
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    • "Experimentally, the number of repeats in the CAG tract was found to be inversely correlated with transcriptional activity of the AR protein (Chamberlain et al., 1994). In addition, AR-CAG repeat length was found to influence phenotype of Klinefelter syndrome (Zinn et al., 2005). "
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    ABSTRACT: The CAG repeat and its association with infertility has been debatable. Therefore, this study was planned to assess the distribution of CAG repeat expansion in Egyptian patients and to investigate its association with male infertility. Forty-five infertile men were eligible for the study in addition to 20 aged-matched fertile males as control. Semen analysis, scrotal sonography, assay of serum testosterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), and determination of the CAG repeat number within exon 1 of the androgen receptor (AR) gene were carried out. Statistically significant difference was found between infertile and control groups regarding sperm count, sperm motility, serum FSH level and CAG repeats (P < 0.05); statistically insignificant difference for the CAG repeats (P = 1.0) was found between oligozoospermic and asthenospermic groups; negative correlation was found between CAG repeat length and sperm count, and a positive correlation was found between CAG repeat length and serum FSH (P < 0.05). Our results validate the concept that long stretches of CAG repeat may be associated with lower AR function with derangement of sperm production, and this may contribute to male infertility in Egyptian men.
    Andrologia 04/2011; 44(1):26-33. DOI:10.1111/j.1439-0272.2010.01100.x · 1.17 Impact Factor
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