Increased extraglandular aromatization has been reported as the cause of
familial gynecomastia. We studied a kindred with
aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or
gynecomastia, and affected females had isosexual precocity and/or macromastia. The propositus was a 9-yr-old boy with
gynecomastia. His 7.5-yr-old sister had
precocious puberty, and their father and paternal grandmother had peripubertal
gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal
steroid hormones were determined before and after the administration of
corticotropin and/or hCG.
Aromatase activity was determined by [3H]delta4-
androstenedione to [3H]
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. The
P450arom messenger
ribonucleic acid was analyzed by rapid amplification of
complementary DNA (
cDNA) ends,
ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate of conversion of delta4-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 analog, 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 messenger
ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family. In conclusion, a family with the
aromatase excess syndrome is described, in which 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.