Placental Aromatase Deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Aromatase deficiency is an autosomal recessive disorder in which there is a decrease or absence in the level of aromatase in the body which leads to impairment in the conversion of androgens to estrogen. This is due to a genetic mutation in the CYP19A1, a subtype of [P450]. Patient affected by this disease typically presents with maternal virilization, amenorrhea in puberty in females. Males are rarely affected.

Historical Perspective

The evidence of the disease goes back to year 1991, when the first case of aromatase deficiency occurred . Most of the cases were that of women during the third trimester of pregnancy presenting with maternal virilization resulting in hirsutism and acne.

Pathophysiology

CYP19A1 gene is responsible for the production of enzyme aromatase, which converts androgens to different forms of estrogen . Estrogen is involved in sexual development in females prior to birth and the levels peak during pregnancy. Mutation in CYP19A1 gene leads to deficiency or absence of activity of aromatase . As a result, there is decrease in production of estrogen due to lack of conversion of androgens to estrogen and increase in testosterone and androstenedione levels. In pregnant women , excess androgens cross the placenta and enter into the maternal circulation leading to virilization. Female fetuses who are affected have ambiguous genitalia while males develop osteoporosis.

Causes

CYP19A1 gene mutation primarily causes Placental Aromatase Deficiency and the placenta is not capable of converting androgenic precursors of estrogen to estradiol. Mutations on exons 3,5 and 9 have been reported. Studies suggest that it is more prevalent in consanguinous marriages and both are heterozygous carriers of the mutation.

Differentiating Any Disease from other Diseases

Congenital adrenal hyperplasia can be considered as a differential in female patients. While, in male patients;

• 5 alpha reductase deficiency :The levels of testosterone and estrogen are normal.
• Estrogen resistance syndrome
• 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency
• Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
• Congenital hypogonadotropic hypogonadism

can be considered as the differentials.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Epidemiology and Demographics

Placental Aromatase Deficiency is a rare autosomal recessive disorder. The prevalence is unknown . Approximately 20 cases have been described in the literature.

Natural History , Complications and Prognosis

Placental aromatase deficiency is a rare entity.

As a result of defective synthesis of estrogen AD may result in :

• Delayed Puberty
• Insulin resistance
• Polycystic ovarian disorder
• Bone disorders

In patients with Aromatase deficiency lifetime hormone replacement therapy is mandatory. We can see osteoporosis as an outcome in male patients with late diagnosis, and these skeletal defects tend to remain even after hormonal treatment and sometimes require surgical correction. Moreover, the effects on glucose and lipid metabolism like adiposity and reproductive defects such as infertility are also not corrected by estradiol treatment.

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case #1