5-alpha-reductase Deficiency

5-alpha-reductase deficiency is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceintersex or “disorder of sex development” (DSD) condition caused by a loss-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism, bifid scrotum, and a rudimentary prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands. No Müllerian structures are present.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the SRD5A2 gene on the short arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. 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 Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
  • Hypospadia (congenital malformation in which the opening of the penile urethra is abnormally located on the ventral side of the penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis, scrotum, or perineum)
  • Puberty → ↑ testosterone levels leads to virilization
    • Testicular descent
    • Phallic growth
    • Male secondary sexual characteristics
    • Development of male gender identity
Cognition/intelligence Normal
Behavioral phenotype Normal
Associations Normal internal male urogenital organs

Diagnosis and Management

Diagnosis

  • Clinical diagnosis by physical examination usually detected at birth or at the beginning of puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. 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 Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. 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 Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder 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 Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty, these individuals usually develop male secondary sex characteristics.
  • Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia: a group of rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancediseases characterized by defects in enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. 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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. 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 Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries that are unable to produce estrogen leading to primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and impaired maturation of secondary sexual characteristics during puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty.
  • Hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism (panhypopituitarism): a disorder characterized by a deficiency in pituitary hormone production, which results from a disease of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus or the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland itself. Most cases affect the adenohypophysis hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview, 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 Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview of the neurohypophysis (antidiuretic hormone [ADH] and oxytocin), leading to panhypopituitarism.
  • Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome: an X-linked recessive condition in which a genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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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