Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disorder resulting from various mutations of the gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males, and virilization in mothers carrying fetuses with the disorder. , fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.
The deficiency causes the virilization of XX fetuses. The onset of symptoms usually occurs in adolescence or early adulthood. The lack of estrogen results in the presentation of primary amenorrhea and tall stature. The taller than expected height occurs because estrogen normally causes fusion of the epiphyseal growth plates in the bones, and, in its absence, the growth plates will not fuse and the patient will keep growing taller. The gonadotropins LH and FSH will both be elevated and female patients present with polycystic ovaries. Furthermore, the low estrogen will predispose those with the condition to osteoporosis.
Symptoms are generally manifested in adulthood:
During gestation, a fetus with aromatase deficiency can cause the mother to become virilized, causing deepening of the voice, cystic acne, more hair growth than normal, clitoromegaly, and hirsutism. The mother also has an increased level of circulating testosterone. However, the symptoms normally regress post-partum.
Aromatase is an estrogen synthase that synthesizes estrone (E1) and estradiol (E2) from Androstenedione and Testosterone respectively. During pregnancy, the placenta, which is fetal tissue, synthesizes large amounts of androstenedione and testosterone, intermediates in the biosynthesis of estrogens, but cannot convert them to estrogens due to the absence of aromatase. The level of accumulated androgens in the mother can elevate to 100 times higher than normal cycling levels, which subsequently virilizes both the mother and the fetus. The mother will experience cystic acne, deepening of the voice and hirsutism. However, these symptoms are normally resolved following parturition.
If the fetus is a male, it will develop normal male genitalia and will proceed to grow normally and exhibit secondary male sex characteristics. If the fetus is a female, it will be born with ambiguous genitalia including labioscrotal fusion and a greatly enlarged phallus.
Aromatase deficient females cannot synthesize estrone or estradiol in the absence of aromatase. The amount of androgens will accumulate at a very high rate in the blood, disrupting the LHRH-LH/FSH axis, which can potentially lead to polycystic ovaries in adulthood. In the absence of estrogen, high levels of circulating LH and FSH can result in Hypergonadotropic hypogonadism.
While females begin to virilize and grow hair in various places during adolescence, they are unable to undergo normal female puberty without the presence of estradiol, subsequently causing primary amenorrhea, clitoromegaly, and absence of breast development. As puberty fails, the growth spurt is absent and bone age is delayed. Without treatment, the collection of excess androgens in the blood can lead to the development of polycystic ovaries.
Aromatase deficient males experience normal growth into adulthood. A very low level of circulating estrogen (<7pg/mL) results in a higher level of FSH and LH in the blood. Elevated levels of androgens do not contribute to harmonic skeletal muscle growth like estrogen does, thus patients exhibit eunuchoid body habitus.
Patients are generally tall in stature and have a pattern of persistent linear bone growth into adulthood. Without estrogen, the epiphyseal plates cannot fuse together properly, resulting in continuous height growth. Since estrogen is a necessary steroid to maintain bone homeostasis, low levels of estrogen also result in osteopenia and osteoporosis of the lumbar spine and cortical bone. Low estrogen is also thought to be linked to abnormal lipid profile and hyperinsulinemia in men, though the mechanism is unknown.
Aromatase deficiency is an autosomal recessive disease with most of the mutations occurring along the highly conservative regions of the gene. Both homozygous and heterozygous mutations have been identified along various locations of the exon on the P450 arom (CYP19) gene localized on chromosome15p21.1. In addition, mutations in cytochrome P450 oxidoreductase (POR), which is required for enzymatic activity of aromatase, can also cause aromatase deficiency.
Aromatase deficiency in a fetus can be predicted when the pregnant mother displays virilization. A female infant can be physically diagnosed due to the abnormal genitalia along with hormonal blood test. The diagnosis can be considered for any virilized 46,XX child when congenital adrenal hyperplasia is excluded. The condition can be suspected for males in their late teens or twenties who have continued linear growth and bone pain. Excessively low level of estrogen and elevated levels of androgens are diagnostic markers for aromatase deficiency in both males and females. Testosterone level in the urine may be normal or elevated.
In males, transdermal estradiol replacement enables closure of the epiphyseal plates, increases bone density, promotes skeletal maturation, lowers FSH and LH level to normal, and decreases insulin blood concentration.
In females, hormonal replacement therapy, such as cyclic oral therapy of conjugated estrogen, leads to breast development, menses, pubertal growth spurt, resolution of ovarian cysts, suppression of elevated FSH and LH levels in the blood, and proper bone growth. Ambiguous genitalia, clitoromegaly, and ovarian cysts can be removed surgically.
Aromatase deficiency was first recorded in literature in 1991 by Shouz and colleagues. The pregnant mother had low estrogen serum level and high androgen level in the third trimester along with signs of progressive virilization. Upon delivery, the female infant exhibited ambiguous genitalia. Aromatase activity of the placenta was approximately ten times less than the normal range.