Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

Context: There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). Objectives: We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. Design and Patients: We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). Main Outcome Measures: AR gene methylation-weighted CAGn(mwCAGn) via CAGn length and X-chromosome inactivation analysis and clinical phenotype were determined. Setting: The study took place at a university hospital. Results: PA subjects had significantly shorter mwCAGn than controls [mean difference (95% confidence interval); 0.76 (0.14–1.38); P = 0.017]. AR gene mwCAGn did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAGn correlated positively with body mass index (BMI) (τ = 0.19; P = 0.02). The mean of mwCAGn was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38–1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). Conclusions: The AR gene CAGn polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.