THE AROMATASE EXCESS SYNDROME IS ASSOCIATED WITH FEMINIZATION OF BOTHSEXES AND AUTOSOMAL-DOMINANT TRANSMISSION OF ABERRANT P450 AROMATASE GENE-TRANSCRIPTION

Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess i nherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had i sosexual precocity and/or macromastia. The propositus was a 9-yr-old b oy with gynecomastia. His 7.5-yr-old sister had precocious puberty, an d their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adr enal steroid hormones were determined before and after the administrat ion of corticotropin and/or hCG. Aromatase activity was determined by [H-3]Delta(4)-androstenedione to [H-3]estrone conversion by cultured, skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. Th e P450arom messenger ribonucleic acid was analyzed by rapid amplificat ion of complementary DNA (cDNA) ends, ribonuclease protection assay, a nd RT-PCR. hCG testing demonstrated a high rate of conversion of Delta (4)-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH a nalog, which successfully delayed skeletal and pubertal development In both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5'-splice variant was present in the patients' P450arom messenge r ribonucleic acid, thus identifying yet another first exon of this ge ne, which appears to be aberrantly expressed in this family. In conclu sion, a family with the aromatase excess syndrome is described, in whi ch the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.