title: The effect of fetal androgen metabolism-related gene variants on external genitalia virilization in congenital adrenal hyperplasia.
abstract: The 21-hydroxylase deficiency (21OHD) is caused by CYP21A2 mutations resulting in severe or moderate enzymatic impairments. 21OHD females carrying similar genotypes present different degrees of external genitalia virilization, suggesting the influence of other genetic factors. Single nucleotide variants (SNVs) in the CYP3A7 gene and in its transcription factors, related to fetal 19-carbon steroid metabolism, could modulate the genital phenotype. To evaluate the influence of the 21OHD genotypes and the CYP3A7, PXR and CAR SNVs on the genital phenotype in 21OHD females. Prader scores were evaluated in 183 patients. The CYP3A7, PXR and CAR SNVs were screened and the 21OHD genotypes were classified according to their severity: severe and moderate groups. Patients with severe genotype showed higher degree of genital virilization (Prader median III, IQR III-IV) than those with moderate genotype (III, IQR II-III) (p < 0.001). However, a great overlap was observed between genotype groups. Among all the SNVs tested, only the CAR rs2307424 variant correlated with Prader scores (r(2)  = 0.253; p = 0.023). The CYP21A2 genotypes influence the severity of genital virilization in 21OHD females. We also suggest that the CAR variant, which results in a poor metabolizer phenotype, could account for a higher degree of external genitalia virilization.
authors.affiliation: Laboratório de Hormônios e Genética Molecular- LIM/42, Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: L C
authors.initials: LC
authors.lastname: Kaupert
authors.forename: S H V
authors.initials: SH
authors.lastname: Lemos-Marini
authors.forename: M P
authors.initials: MP
authors.lastname: De Mello
authors.forename: R P
authors.initials: RP
authors.lastname: Moreira
authors.forename: V N
authors.initials: VN
authors.lastname: Brito
authors.forename: A A L
authors.initials: AA
authors.lastname: Jorge
authors.forename: C A
authors.initials: CA
authors.lastname: Longui
authors.forename: G
authors.initials: G
authors.lastname: Guerra
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: T A
authors.initials: TA
authors.lastname: Bachega
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D005260:Female; D005787:Gene Frequency; D005835:Genitalia / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D014770:Virilism / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase