Context: Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens.
Objective: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.
Design and patient: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.
Main outcome measurement: A genotype-phenotype correlation was found.
Results: By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type.
Conclusion: Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.
© 2011 Blackwell Publishing Ltd.