Aromatase deficiency: a novel compound heterozygous mutation identified in a Chinese girl with severe phenotype and obvious maternal virilization.

Abstract Background Aromatase deficiency is a rare autosomal recessive disorder that is caused by an impairment of androgen conversion to estrogens. Affected 46, XX individuals generally present with virilization of external genitalia at birth and mutations in CYP19A1 g ene. Objective This study described the clinical features and molecular basis of a Chinese 46, XX girl born with ambiguous genitalia and investigated the functional alteration of two novel mutations of the CYP19A1 gene. Methods and results Obvious prepartum virilization and remarkably elevated testosterone were observed in the mother, who was initially suspected to have a testosterone-producing ovarian tumor. Clinical phenotypes and hormone profiles of the patient and her mother were investigated. Genotyping analyses of the CYP19A1 gene were performed in the patient and her parents. Functional impairment of the mutations was explored using three-dimensional computer model and mutagenesises in vitro transfection assays. A compound heterozygous mutation of the CYP19A1 gene was revealed in the patient, with a G deletion in nucleotide 264 of exon 3 in one allele and a 23-bp insertion in exon 9 in another allele; both mutations resulted in reading frame-shifts that led to truncated proteins of 87 and 360 amino acids, respectively. Molecular modeling analysis suggested that the two renascent truncated proteins lacked crucial amino acids that were involved in substrate access and catalysis as well as heme-binding region. Functional studies in transfected HEK-293T cells exhibited a nearly complete abolishment of enzyme activity, which may underlie the phenotype and hormone profile. Conclusions Two novel CYP19A1 mutations were identified in a Chinese girl born with ambiguous genitalia and severe maternal virilization during pregnancy. Maternal virilization should prompt consideration of aromatase deficiency, preventing unnecessary interventions in pregnancy. This study broadens the spectrum of phenotype and genetic mutations of this rare disorder.