The Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene

Author(s)

Moura-Massari, Vivian Oliveira ^[1] ; Cunha, Flavia Siqueira ^[1] ; Gomes, Larissa Garcia ^[1] ; Diniz Gomes, Diogo Bugano ^[2] ; Miguel Marcondes, Jose Antonio ^[1] ; Madureira, Guiomar ^[1] ; de Mendonca, Berenice Bilharinho ^[1] ; Sartori Sanchez Bachega, Tania A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM 42, Unidade Suprarrenal, Disciplina Endocrinol, Hosp Cl, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin, Dept Clin Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS One; v. 11, n. 2 FEB 5 2016.
• Web of Science Citations: 2

Abstract

Background In the nonclassical form (NC), good correlation has been observed between genotypes and 17OH-progesterone (17-OHP) levels. However, this correlation was not identified with regard to the severity of hyperandrogenic manifestations, which could depend on interindividual variability in peripheral androgen sensitivity. Androgen action is modulated by the polymorphic CAG tract (nCAG) of the androgen receptor (AR) gene and by polymorphisms in 5 alpha-reductase type 2 (SRD5A2) enzyme, both of which are involved in the severity of hyperandrogenic disorders. Objectives To analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype. Patients NC patients (n = 114) diagnosed by stimulated-17OHP >= 10 ng/mL were divided into groups according to the beginning of hyperandrogenic manifestations (pediatric and adolescent/adult) and CYP21A2 genotypes (C/C: homozygosis for mild mutations; A/C: compound heterozygosis for severe/mild mutations). Methods CYP21A2 mutations were screened by allelic-specific PCR, MLPA and/or sequencing. HpaII-digested and HpaII-undigested DNA samples underwent GeneScan analysis to study nCAG, and the SRD5A2 polymorphisms were screened by RLFP. Results Mean nCAG did not differ among pediatric, adolescent/adult and asymptomatic subjects. In the C/C genotype, we observed a significantly lower frequency of longer CAG alleles in pediatric patients than in adolescent/adults (p = 0.01). In patients carrying the A/C genotype, the frequencies of shorter and longer CAG alleles did not differ between pediatric patients and adolescent/adults (p>0.05). Patients with clitoromegaly had significantly lower weighted CAG biallelic mean than those without it: 19.1 +/- 2.7 and 21.6 +/- 2.5, respectively (p = 0.007), independent of the CYP21A2 genotype's severity. The SRD5A2 polymorphisms were not associated with the variability of hyperandrogenic NC phenotypes. Conclusions In this series, we observed a modulatory effect of the CAG-AR tract on clinical manifestations of the NC form. Although the NC form is a monogenic disorder, our preliminary data suggested that the interindividual variability of the hyperandrogenic phenotype could arise from polygenic interactions. (AU)

• FAPESP's process: 14/07878-4 - Improving the efficacy of congenital adrenal hyperplasia (CaH) diagnosis in the Brazilian newborn screening (NBs) program
• Grantee: Tania Aparecida Sartori Sanchez Bachega
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/51624-6 - Analysis of modulator genes in the nonclassical 21-hydroxylase deficiency phenotype
• Grantee: Vivian Moura Massari
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 05/04726-0 - Molecular characterization of congenital endocrine diseases that affect growth and development
• Grantee: Ana Claudia Latronico Xavier
• Support Opportunities: Research Projects - Thematic Grants