Estrogen Excess Associated With Novel Gain-of-Function Mutations Affecting the Aromatase Gene

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When gynecomastia begins before puberty, increased estrogen resulting from excessive aromatase activity in extraglandular tissues could be responsible. A gene in chromosome 15q21, also known as CYP19, encodes aromatase, the critical enzyme for biosynthesis of estrogen. The expression of aromatase is regulated by several tissue-specific promoters. The result is a messenger RNA (mRNA) species having an identical coding region but tissue-specific 5'-untranslated regions in the placenta, gonads, brain, fat tissue, and skin. The investigators examined skin, fat, and blood samples from a man aged 36 years, his 7-year-old son, and an unrelated 17-year-old boy having severe gynecomastia starting before puberty. The father and unrelated boy had hypogonadotrophic hypogonadism resulting from markedly elevated circulating levels of estrone and estradiol. The increased estrogen levels were in turn a result of increased extraglandular aromatase activity. Aromatase activity and mRNA levels were markedly increased in fat and skin, as was the whole-body aromatization of androstenedione. Treatment with an aromatase inhibitor lowered serum estrogen levels and led to normal levels of gonadotropins and testosterone. The 5'-untranslated regions of aromatase mRNA contained the same sequence (FLJ) in the father and son and a different sequence (TMOD3) in the unrelated child. Control subjects lacked both of these sequences. In these cases, heterozygous inversions in chromosome 15q21.2-3 caused the coding region of the aromatase gene to lie adjacent to active cryptic promotors that normally transcribe other genes. The inversions led to markedly excessive estrogen resulting from the excessive expression of aromatase in many body tissues.