Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome.
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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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.
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ABSTRACT: Gynaecomastia (enlargement of the male breast tissue) is a common finding in the general population. Most cases of gynaecomastia are benign and of cosmetic, rather than clinical, importance. However, the condition might cause local pain and tenderness, could occasionally be the result of a serious underlying illness or a medication, or be inherited. Breast cancer in men is much less common than benign gynaecomastia, and the two conditions can usually be distinguished by a careful physical examination. Estrogens are known to stimulate the growth of breast tissue, whereas androgens inhibit it; most cases of gynaecomastia result from deficient androgen action or excessive estrogen action in the breast tissue. In some cases, such as pubertal gynaecomastia, the breast enlargement resolves spontaneously. In other situations, more active treatment might be required to correct an underlying condition (such as hyperthyroidism or a benign Leydig cell tumour of the testis) or medications that could cause breast enlargement (such as spironolactone) might need to be discontinued. For men with hypogonadism, administration of androgens might be helpful, as might antiestrogen therapy in men with endogenous overproduction of estrogens. Surgery to remove the enlarged breast tissue might be necessary when gynaecomastia does not resolve spontaneously or with medical therapy.Nature Reviews Endocrinology 08/2014; · 11.03 Impact Factor
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ABSTRACT: Klinefelter Syndrome (KS) is the most common sex chromosome disorder in males. Key findings in older adolescents and young men are small testes with variable hypo-androgenism but almost universal azoospermia, most frequently in combination with a history of learning difficulties and behavior problems. KS males may come to medical attention through different medical presentations, given its association with several congenital malformations, psychiatric, endocrine and metabolic disorders. Preventive care is to be provided from diagnosis, preferentially through a multidisciplinary approach, including that from an endocrinologist, clinical psychologist or psychiatrist, neurologist, urologist, sexologist and a fertility team. Accurate information about the condition and assessment of associated medical conditions should be offered at diagnosis and should be followed by psychological counseling. Medical treatment during transition into adulthood is focused on fertility preservation and testosterone replacement therapy in the case of hypo-androgenism, and alleviation of current or future consequences of testicular fibrosis. However, more research is needed to determine the need for pro-active testosterone treatment in adolescence, as well as the conditions for an optimal testosterone replacement and sperm retrieval in KS adolescents and young men. Furthermore, screening for associated diseases such as metabolic syndrome, auto-immune diseases, thyroid dysfunction and malignancies, is warranted during this period of life. The practical medical management during transition and more specifically the role of the endocrinologist is discussed in this article.European Journal of Endocrinology 05/2014; · 3.69 Impact Factor