title: 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.
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 5α-reductase type 2 (SRD5A2) enzyme, both of which are involved in the severity of hyperandrogenic disorders.
  
  
  OBJECTIVE
  To analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype.
  
  
  METHODS
  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.
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Vivian Oliveira
authors: VO
authors: Moura-Massari
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Flávia Siqueira
authors: FS
authors: Cunha
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Larissa Garcia
authors: LG
authors: Gomes
authors: Departamento de Clínica Médica, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Diogo
authors: D
authors: Bugano Diniz Gomes
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: José Antônio Miguel
authors: JA
authors: Marcondes
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Guiomar
authors: G
authors: Madureira
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Berenice Bilharinho
authors: BB
authors: de Mendonca
authors: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM 42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors: Tânia A Sartori Sanchez
authors: TA
authors: Bachega
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002987:Clitoris / Q000473:pathology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011944:Receptors, Androgen / Q000235:genetics*; D012720:Severity of Illness Index; D013255:Steroid 21-Hydroxylase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D011944:Receptors, Androgen; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human