Aromatase deficiency

Question 1

A 16-year-old female presents for evaluation of primary amenorrhea and severe acne. Physical examination reveals ambiguous external genitalia with clitoromegaly and normal internal genital organs. She has tall stature, significant hirsutism, and no breast development. Her parents report that her mother experienced significant virilization during pregnancy. Laboratory studies show elevated testosterone and androstenedione levels with decreased estrogen. Karyotype analysis reveals 46,XX. Which of the following is the most likely diagnosis?

A) Congenital adrenal hyperplasia
B) Aromatase deficiency
C) Androgen insensitivity syndrome
D) Turner syndrome
E) Polycystic ovary syndrome

Answer 1

Answer: B) Aromatase deficiency

Explanation: Aromatase deficiency is an autosomal recessive condition caused by mutations in the CYP19A1 gene, leading to defective or absent aromatase, the enzyme responsible for converting testosterone to estrogen. In 46,XX individuals, this results in ambiguous genitalia at birth, impaired breast development, primary amenorrhea, and virilization during puberty (e.g., hirsutism, severe acne). Maternal virilization during pregnancy is a hallmark feature caused by excess fetal androgens crossing the placenta. Hormonal studies show increased testosterone and androstenedione levels with low estrogen. Diagnosis is confirmed with karyotype analysis and hormone levels.

Incorrect Answers:

A) Congenital adrenal hyperplasia: This condition involves enzyme defects in cortisol biosynthesis, typically presenting with adrenal insufficiency and salt-wasting crises.
C) Androgen insensitivity syndrome: This occurs in 46,XY individuals with normal external female genitalia and sparse pubic hair due to androgen receptor resistance.
D) Turner syndrome: Characterized by a 45,X karyotype and features such as short stature, webbed neck, and ovarian dysgenesis, not virilization or tall stature.
E) Polycystic ovary syndrome: Typically presents with irregular menses, hyperandrogenism, and polycystic ovaries in 46,XX females, but does not cause ambiguous genitalia or maternal virilization.

Question 2

What is the prevalence of aromatase deficiency?

Answer 2

Rare

Question 3

What is the etiology of aromatase deficiency?

Answer 3

Autosomal recessive mutations in the CYP19A1 gene encoding the aromatase enzyme

Question 4

What karyotypes are associated with aromatase deficiency?

Answer 4

46,XX or 46,XY (normal sexual development in males)

Question 5

What is the pathophysiology of aromatase deficiency?

Answer 5

Defective/absent aromatase leads to decreased conversion of testosterone to estrogen, resulting in low estrogen and high testosterone levels

Question 6

What are the clinical features of aromatase deficiency in 46,XX individuals at birth?

Answer 6

Ambiguous external genitalia, normal internal genital organs

Question 7

What are the clinical features of aromatase deficiency in 46,XX individuals during puberty?

Answer 7

Impaired breast development, primary amenorrhea, virilization (e.g., hirsutism, severe acne)

Question 8

What are the clinical features of aromatase deficiency in 46,XY individuals?

Answer 8

Abnormal sperm production, small or undescended testes, decreased sex drive

Question 9

What features are shared by both 46,XX and 46,XY individuals with aromatase deficiency?

Answer 9

Tall stature, osteoporosis, hyperglycemia, weight gain, and fatty liver

Question 10

What diagnostic findings might indicate aromatase deficiency before birth?

Answer 10

Maternal virilization during pregnancy due to fetal androgens crossing into maternal circulation

Question 11

What are the hormone level abnormalities in aromatase deficiency after birth?

Answer 11

Increased testosterone, increased androstenedione, decreased estrogen

Question 12

What are the main treatment options for aromatase deficiency?

Answer 12

Estrogen and progesterone replacement therapy, calcium and vitamin D supplementation, surgical correction of ambiguous genitalia