No Correlation between Androgen Receptor CAG and GGN Repeat Length and the Degree of Genital Virilization in Females with 21-Hydroxylase Deficiency

• Published in: The journal of clinical endocrinology and metabolism 2010-05, Vol.95 (5), p.2443-2450
• Main Authors: Welzel, M., Schwarz, H.-P., Hedderich, J., Dörr, H. G., Binder, G., Brämswig, J. H., Krude, H., Richter-Unruh, A., Niedziela, M., Gromoll, J., Krone, N., Riepe, F. G., Holterhus, P.-M.
• Format: Article
• Language: English
• Subjects: Adrenal Hyperplasia, Congenital - classification; Adrenal Hyperplasia, Congenital - genetics; Adrenal Hyperplasia, Congenital - pathology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Alleles; Biological and medical sciences; DNA Primers; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Amplification; Genotype; Humans; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Polymerase Chain Reaction; Receptors, Androgen - genetics; Sequence Deletion; Steroid 21-Hydroxylase - genetics; Trinucleotide Repeats - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Virilism - classification; Virilism - genetics; Virilism - pathology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-1338

Context: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. Objective: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. Design and Patients: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. Outcome Measurements: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. Results: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I–V (median IV); A, Prader I–V (median IV); B, Prader I–V (median III); C, 0–III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0–I), intermediate (II–III), or severe (IV–V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71–1.35). In contrast, patients with Prader 0–I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65–1.02). Conclusion: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD. Neither CAG nor GGn repeat lengths of the androgen receptor gene are significant modifiers of genital virilization in 21OHD females.