General Medical Information

Aromatase Mutations

Joe Leigh Simpson

Conversion of androgens (D4-androstenedione) to estrogens (estrone) requires cytochrome P450 aromatase, an enzyme that is the gene product of a single 40-kb gene located on chromosome 15q21.1. The gene consists of ten exons. Although Ito reported a mutation in this CYP19 (P450 arom) gene in a 18-year-old 46,XX woman with primary amenorrhea and cystic ovaries, deficiency of the aromatase enzyme more often is associated with genital ambiguity. Shozu detected placental aromatase deficiency manifesting as maternal virilization during the third trimester. The 46,XX infant was born with genital ambiguity (female pseudohermaphroditism). Adrenal enzyme defects were not evident. The molecular basis of the mutation was a 87-bp insert in exon 6 of the aromatase gene, altering the splice junction site to produce a novel protein with 29 additional amino acids. Aromatase mutations in 46,XX female infants have been associated with genital ambiguity or clitoromegaly. Clitoral enlargement occurred at puberty, but breast development did not. Multiple ovarian follicular cysts were evident. FSH was elevated; estrone and estradiol were low. Estrogen and progesterone therapy resulted in a growth spurt, decreased FSH, decreased androstenedione and testosterone, breast development, menarche, and fewer follicular cysts. Molecular studies demonstrated compound heterozygosity for CYP19 point mutations.