Aromatase deficiency

Did You Know?

• Mutations in cytochrome P450 oxidoreductase (POR), required for aromatase enzymatic activity, can also cause aromatase deficiency.
• Aromatase deficiency was first recorded in literature in 1991 by Shouz and colleagues.
• In the first reported case, the mother had low estrogen and high androgen in the third trimester with progressive virilization, and the infant's placental aromatase activity was about ten times less than normal.

Signs and symptoms

In XX fetuses, aromatase deficiency causes virilization. After birth, female infants typically show ambiguous genitalia such as labioscrotal fusion, clitoromegaly, and phallic genitalia, with normal internal female structures. Prader scale ratings in known cases range from II to V, most commonly IV (11 of 23 cases) or III (7 of 23 cases). Some 46,XX individuals are assigned male at birth due to sufficiently virilized genitalia, and a male gender identity persisted in a subset. During puberty, progressive virilization occurs, including body hair growth, while normal female puberty fails due to lack of estradiol action. Bone aging is delayed, and there is no growth spurt. In adulthood, symptoms include virilization, absent breast development, primary amenorrhea, infertility, and polycystic ovaries. Other adult manifestations include tall stature, osteopenia, osteoporosis, type II diabetes, hyperinsulinemia, acanthosis nigricans, lipid metabolism disorders, and liver function impairment. During gestation, the mother may become virilized, with deepening voice, cystic acne, increased hair growth, clitoromegaly, and hirsutism, along with elevated circulating testosterone; these symptoms usually regress postpartum.

Diagnosis

Aromatase deficiency may be suspected before birth if the mother shows signs of virilization. In a newborn girl, the condition is identified by atypical genitalia and confirmed with a blood hormone test. For any virilized 46,XX child, this diagnosis should be considered once congenital adrenal hyperplasia is ruled out. In males, the condition often appears in late adolescence or young adulthood with ongoing height growth and bone pain. Both sexes show very low estrogen and high androgen levels on lab tests. Urinary testosterone can be normal or high.

Treatment

In males, transdermal estradiol replacement closes the epiphyseal plates, increases bone density, promotes skeletal maturation, normalizes FSH and LH levels, and decreases insulin blood concentration. In females, hormonal replacement therapy with cyclic oral conjugated estrogen leads to breast development, menses, pubertal growth spurt, resolution of ovarian cysts, suppression of elevated FSH and LH, and proper bone growth. Ambiguous genitalia, clitoromegaly, and ovarian cysts can be surgically removed.