Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.

[aromatase deficiency]

Aromatase deficiency in women is a rare 46 , XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens .To better understand this rare disorder , we searched for mutations in the CYP 19 A 1 gene of an affected girl and analysed their functional consequences .We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne ) during pregnancy .A genotype-phenotype correlation was found .By direct sequencing of the CYP 19 A 1 gene , we identified a heterozygous A >G mutation (c . A 1374 G ) mutation in exon IX , leading to the missense p .N 411 S in the P 450 A ro 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 .N 411 S protein was expressed in COS -1 cells . The placenta promoter variant had a significantly reduced (-50 %) transactivation ability compared to wild-type .Our data describe a novel loss -of-function missense mutation in CYP 19 A 1 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 .