5α-Reductase 2 deficiency

5α-Reductase deficiency
Synonyms	5-ARD
Pronounce	N/A
Field	N/A
Symptoms	Ambiguous genitalia, lack of androgen-driven development
Complications	Cryptorchidism, risk of testicular cancer
Onset	Prenatal, visible at birth or puberty
Duration	Lifelong
Types
Causes	Genetic mutation in SRD5A2
Risks	Family history of 5-ARD, consanguinity
Diagnosis	Genetic testing, hormone analysis, physical examination
Differential diagnosis	Androgen insensitivity syndrome, Congenital adrenal hyperplasia
Prevention	Genetic counseling
Treatment	Hormone replacement therapy, surgical intervention in some cases
Medication	Testosterone therapy in some cases
Prognosis	Varies, good with appropriate management
Frequency	Rare
Deaths	None directly related

5α-Reductase deficiency is an autosomal recessive intersex genetic disorder caused by a mutation in the SRD5A2 gene, which encodes the enzyme 5α-reductase type 2. This enzyme is responsible for converting testosterone into the more potent androgen dihydrotestosterone (DHT), which is crucial for the development of male external genitalia in utero.

Signs and Symptoms

Individuals with 5-ARD typically have an XY karyotype and develop testes, but due to impaired DHT production, their external genitalia may appear ambiguous, ranging from a micropenis to a macroclitoris. Some individuals may be assigned female at birth due to the underdeveloped male phenotype.

Common features include:

• Ambiguous genitalia at birth
• Small prostate gland
• Hypospadias (abnormal urethral opening)
• Cryptorchidism (undescended testes)
• Absence of male pattern baldness
• Virilization at puberty, including:
  • Voice deepening
  • Growth of facial hair and body hair
  • Increased muscle mass
  • Possible testicular descent

Pathophysiology

The enzyme 5α-reductase type 2 is crucial for converting testosterone into dihydrotestosterone (DHT). DHT is required for the normal development of male external genitalia during fetal development. Without sufficient DHT, individuals with 5-ARD may have incomplete masculinization at birth. However, at puberty, increased testosterone production may induce secondary male sexual characteristics due to the partial conversion of testosterone by 5α-reductase type 1.

Diagnosis

Diagnosis is based on:

• Physical examination revealing ambiguous genitalia
• Karyotype analysis confirming 46,XY
• Hormonal analysis showing normal/high testosterone with low DHT levels
• Genetic testing identifying mutations in the SRD5A2 gene

Treatment and Management

Management varies depending on gender identity and clinical presentation. Options include:

• Hormonal therapy – Testosterone may be administered if a male gender identity is chosen
• Surgical intervention – Hypospadias repair or genital reconstruction surgery may be performed depending on the individual's needs
• Psychosocial support – Counseling and support groups for affected individuals and families

Fertility

Individuals with 5-ARD have functional testes that may produce sperm, but fertility may be compromised due to underdeveloped seminal vesicles and prostate gland. Fertility potential depends on the degree of testicular function and medical intervention.

Epidemiology

The condition is rare but has been documented in:

• The Dominican Republic, where affected individuals are called "Güevedoces"
• Papua New Guinea
• Some regions of Turkey and Egypt

These cases suggest a possible founder effect or genetic bottleneck in certain populations.

Society and Culture

Sports

The presence of 5-ARD has raised concerns in competitive sports, particularly in women's sports, due to variations in natural androgen levels. Cases of intersex athletes undergoing medical examinations have sparked ethical debates regarding sex verification in sports.

Popular Culture

• The condition is a central theme in Jeffrey Eugenides' Pulitzer Prize-winning novel Middlesex.
• It is mentioned in the TV series Nip/Tuck in the episode "Quentin Costa."

See Also

• Intersex variations
• Disorders of sex development
• Androgen insensitivity syndrome
• 5α-Reductase inhibitors
• Ambiguous genitalia
• Hormone replacement therapy
• Genetic counseling

External Links

• OMIM entry on 5α-Reductase Deficiency
• MedlinePlus Article on 5-ARD