5 Alpha Reductase Deficiency Flashcards
A 15-year-old individual with a history of ambiguous genitalia at birth presents for evaluation of recent pubertal changes. The patient was raised as female but reports clitoral enlargement and deepening of the voice over the past year. Examination reveals phallic growth, bilateral descended testes, and no breast development. Laboratory studies show elevated testosterone levels with a high testosterone-to-DHT ratio (>20). Karyotype analysis reveals 46,XY. Genetic testing confirms a mutation in the SRD5A2 gene. Which of the following is the most likely diagnosis?
A) Congenital adrenal hyperplasia
B) 5-Alpha-reductase deficiency
C) Androgen insensitivity syndrome
D) Turner syndrome
E) Aromatase deficiency
Answer: B) 5-Alpha-reductase deficiency
Explanation: 5-Alpha-reductase deficiency is an autosomal recessive condition caused by mutations in the SRD5A2 gene, resulting in decreased conversion of testosterone to dihydrotestosterone (DHT). This impairs DHT-dependent masculinization of the external genitalia and prostate during fetal development, leading to ambiguous or female-appearing genitalia at birth in 46,XY individuals. At puberty, high testosterone levels drive the development of secondary male sexual characteristics, including phallic growth, testicular descent, and virilization. The elevated testosterone-to-DHT ratio (>20) is a hallmark diagnostic finding. Genetic testing confirms the diagnosis.
Incorrect Answers:
A) Congenital adrenal hyperplasia: CAH causes ambiguous genitalia in 46,XX individuals and is associated with adrenal insufficiency and salt-wasting crises, which are not features here.
C) Androgen insensitivity syndrome: AIS presents with a female phenotype in 46,XY individuals, including normal breast development and absence of pubic hair, due to androgen receptor dysfunction.
D) Turner syndrome: Turner syndrome affects 45,X individuals and is associated with short stature and ovarian dysgenesis, not virilization or a 46,XY karyotype.
E) Aromatase deficiency: This condition causes virilization in 46,XX individuals and maternal virilization during pregnancy, not the ambiguous genitalia or pubertal changes described in 5-alpha-reductase deficiency.
What is the prevalence of 5-alpha-reductase deficiency?
Rare (exact incidence unknown)
What is the etiology of 5-alpha-reductase deficiency?
Rare autosomal recessive loss-of-function mutation of the SRD5A2 gene on chromosome 2
What karyotype is associated with 5-alpha-reductase deficiency?
46,XY
What is the pathophysiology of 5-alpha-reductase deficiency?
Defective 5-alpha-reductase leads to decreased conversion of testosterone to dihydrotestosterone (DHT), impairing DHT-dependent masculinization of external genitalia and the prostate, despite normal testosterone production.
What are the clinical features of 5-alpha-reductase deficiency at birth?
Female external genitalia or ambiguous genitalia (e.g., pseudovaginal perineoscrotal hypospadias, micropenis resembling a clitoris).
Normal internal male genitalia and urogenital tract.
What are the pubertal changes seen in 5-alpha-reductase deficiency?
Development of secondary male sexual characteristics (e.g., phallic growth, testicular descent) due to high testosterone levels.
Breast will not develop (as opposed to AIS) because the androgen receptors on the breasts are functional and activate with binding to testosterone.
What are the characteristic hormone levels in 5-alpha-reductase deficiency?
Normal or increased testosterone, decreased DHT (testosterone:DHT ratio > 20).
normal estrogen.
normal or increased LH.
What diagnostic test confirms 5-alpha-reductase deficiency?
karyotype, T:DHT ratio, genetic evaluation of gene mutation.
What is the treatment approach for individuals with a female gender identity in 5-alpha-reductase deficiency?
Gonadectomy and estrogen substitution therapy to prevent virilization and optimize longitudinal growth.
What is the treatment approach for individuals with a male gender identity in 5-alpha-reductase deficiency?
Testosterone substitution and surgical correction of hypospadias and cryptorchidism
