5-alpha-reductase Deficiency

5-alpha-reductase deficiency is an autosomal recessive intersex or “disorder of sex development” (DSD) condition caused by a loss-of-function mutation in a gene on chromosome 2. The affected subjects have a 46,XY karyotype, bilateral testes, and normal testosterone production but have impaired virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone (DHT), which is a significantly more potent androgen. This leads to male pseudohermaphroditism or ambiguous genitalia in males. Also known as pseudovaginal perineoscrotal hypospadias, these patients present with a clitoris-like phallus, cryptorchidism, bifid scrotum, and a rudimentary prostate. No Müllerian structures are present.

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Epidemiology and Etiology

Synonyms

  • Steroid 5-alpha-reductase 2 deficiency
  • Pseudovaginal perineoscrotal hypospadias (PPSH) 
  • Familial incomplete male pseudohermaphroditism type 2

Epidemiology

  • Extremely rare, prevalence remains unknown
  • High incidence has been reported in isolated villages in the Dominican Republic, Papua New Guinea, Turkey, and Egypt

Etiology

  • Karyotype of an individual with 5-alpha-reductase deficiency is 46,XY DSD (disorders of sex development)
  • Caused by a loss-of-function mutation of the SRD5A2 gene of chromosome 2
  • Autosomal recessive inheritance pattern

Pathophysiology

  • Three different steroid 5-alpha-reductases exist
    • Having distinct and separate genes distributed over 3 different chromosomes
    • Only types 1 and 2 are involved in human sex development
  • A mutation in the SRD5A2 gene on the short arm of chromosome 2 causes a deficiency of steroid 5-alpha-reductase deficiency type 2 enzyme, but the type 1 enzyme is normal (it is expressed at lower levels and in different tissues than type 2). 
  • During embryogenesis, defective steroid 5α-reductase type 2 enzyme → lack of conversion of testosterone into the more potent dihydrotestosterone (DHT) → poorly developed external male genitalia
  • During puberty, virilization to some extent occurs, caused by the normal increase in serum testosterone and/or by an increase in DHT concentrations through increased activity of 5-alpha-reductase type 1.
  • Testosterone and estrogen levels are normal.
  • Luteinizing hormone may be normal or increased.
  • No Müllerian structures are present because they regress when exposed to anti-Müllerian hormone (AMH), a glycoprotein formed by Sertoli cells of the fetal testis beginning at approximately 6 weeks of development.
5-alpha-reductase deficiency

Diagram displaying the role of 5α-Reductase in the development of male genitalia

Image by Lecturio.

Clinical Presentation

Table: Clinical presentation of 5-alpha-reductase deficiency
Clinical phenotype
  • Feminized external genitalia at birth
    • Micropenis that resembles a clitoris
    • Blind perineal pouch that resembles a vagina
  • Hypospadia (congenital malformation in which the opening of the penile urethra is abnormally located on the ventral side of the penis, scrotum, or perineum)
  • Puberty → ↑ testosterone levels leads to virilization
    • Testicular descent
    • Phallic growth
    • Male secondary sexual characteristics
    • Development of male gender identity
Cognition/intelligenceNormal
Behavioral phenotypeNormal
AssociationsNormal internal male urogenital organs

Diagnosis and Management

Diagnosis

  • Clinical diagnosis by physical examination usually detected at birth or at the beginning of puberty 
  • First, check hormone levels:
    • Elevated testosterone/dihydrotestosterone (DHT) ratio (↑ or normal testosterone levels with ↓ DHT levels)
  • Definitive diagnosis is made by a karyotype/genetic testing
    • Visualize sex chromosomes → confirm chromosomal gender
    • Genetic analysis of abnormalities in the SRD5A2 gene

Management

  • Initial gender assignment: 
    • Most affected newborns are now assigned the male gender at birth since most individuals assigned the female gender tended to change to male social gender at or beyond puberty. 
    • It is strongly recommended to refer patient to specialized centers which treat disorders of sex development.
  • Hormonal therapy:
    • Female gender identity → estrogen substitution therapy (upon completion of longitudinal growth)
    • Male gender identity → testosterone substitution therapy
  • Surgical procedures: restoration of external genitalia (in cases of a female gender identity → gonadectomy )

Differential Diagnosis

The following conditions are differential diagnoses for 5-alpha-reductase deficiency:

  • 17-beta-hydroxysteroid dehydrogenase deficiency: an autosomal recessive disorder that affects male sexual development. Individuals with this condition have a 46,XY karyotype and decreased production of 17-beta-hydroxysteroid dehydrogenase 3, which converts androstenedione to testosterone. Thus, it presents with external genitalia that appear female or are ambiguous at birth. During puberty, these individuals usually develop male secondary sex characteristics.
  • Congenital adrenal hyperplasia: a group of rare autosomal recessive diseases characterized by defects in enzymes of the adrenal glands involved in cortisol, androgen, and aldosterone synthesis. Patients may present with a wide range of symptoms, including virilization in females, salt wasting leading to hypotension and other electrolyte abnormalities, and premature completion of growth resulting in short stature.
  • Pure gonadal dysgenesis: a condition in which premature ovarian failure occurs in an otherwise healthy female with 46,XX karyotype. The patient presents a normal female phenotype at birth, but streak ovaries that are unable to produce estrogen leading to primary amenorrhea and impaired maturation of secondary sexual characteristics during puberty.
  • Hypopituitarism (panhypopituitarism): a disorder characterized by a deficiency in pituitary hormone production, which results from a disease of the hypothalamus or the pituitary gland itself. Most cases affect the adenohypophysis hormones, such as the growth hormone, prolactin, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Rarely, this condition can also affect the hormones of the neurohypophysis (antidiuretic hormone [ADH] and oxytocin), leading to panhypopituitarism.
  • Androgen insensitivity syndrome: an X-linked recessive condition in which a genetic mutation causes a partial or complete resistance to testosterone. As a result, individuals with this disorder are genotypically a male with 46,XY karyotype, but without masculinization of external genitalia or virilization.

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