eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

5-Alpha-Reductase Deficiency

Author: Bruce E Wilson, MD, Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine at East Lansing
Contributor Information and Disclosures

Updated: Jun 23, 2009

Introduction

Background

The condition 5-alpha-reductase type 2 deficiency (5-ARD) is an autosomal recessive sex-limited condition resulting in the inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT). Because DHT is required for the normal masculinization of the external genitalia in utero, genetic males with 5-alpha-reductase type 2 deficiency are born with ambiguous genitalia (ie, male pseudohermaphroditism).

The described clinical abnormalities range from infertility with normal male genital anatomy to underdeveloped male with hypospadias to predominantly female external genitalia, most often with mild clitoromegaly. The uterus and fallopian tubes are absent because of the normal secretion of the müllerian-inhibiting factor. Testes are intact, as are wolffian structures (epididymis, vas deferens, seminal vesicles). Male internal ducts are present but terminate either in a blind pseudovaginal pouch or on the perineum. A hypoplastic prostate may be present, regardless of degree of undervirilization of the external genitalia.

Pathophysiology

A deficiency of the type 2 isozyme 5-alpha-reductase, which transforms testosterone to DHT, is the root cause of this disorder. The conversion involves hydroxylation at the 5 carbon position of the A ring of the steroid molecule. This steric change flattens the configuration of DHT, allowing it to fit into the androgen receptor in a way testosterone cannot. Thus, DHT, the most potent androgen, is bound selectively to the androgen receptors in genital skin and fibroblasts, making its action necessary for the development of normal male genital anatomy in the fetus. As with most single enzyme disorders, 5-alpha-reductase type 2 deficiency is autosomal recessive and sex limited because it only affects genetic males.

Biochemical effects of 5-alpha-reductase type 2 d...

Biochemical effects of 5-alpha-reductase type 2 deficiency in testosterone biosynthesis. Typically levels of testosterone are elevated, whereas levels of dihydrotestosterone (DHT) are significantly decreased, leading to male undervirilization.

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Biochemical effects of 5-alpha-reductase type 2 d...

Biochemical effects of 5-alpha-reductase type 2 deficiency in testosterone biosynthesis. Typically levels of testosterone are elevated, whereas levels of dihydrotestosterone (DHT) are significantly decreased, leading to male undervirilization.



Two genes coding for 5-alpha-reductase have been identified, each for a slightly different isoenzyme. The gene for 5-alpha-reductase type 1 has been determined to be on chromosome 5. Its product is expressed only in nongenital skin and liver at low levels from the time the individual is aged 3 years to puberty, at which time enzyme expression is measurable in sebaceous glands and scalp. Linkage analysis has demonstrated that the type 1 enzyme is unrelated to the clinical syndrome of 5-alpha-reductase type 2 deficiency. The other isoenzyme, 5-alpha reductase type 2, determined on chromosome 2, correlates with clinical symptoms. It is expressed in high levels in the prostate and other androgen-sensitive tissues. Interestingly, partial virilization of males with 5-alpha-reductase type 2 deficiency occurs at puberty and may be attributable to the rise in type 1 enzyme activity at that time.1

More than 20 different mutations of this gene have been reported in people with clinical and biochemical evidence of the enzyme deficiency. The clinical picture caused by most mutations widely varies, even within the same family.

Frequency

United States

The carrier frequency and number of individuals with this disorder are not established.

International

Although overall frequencies for various countries are not established, increased frequency is reported in the Dominican Republic,2 some highland tribes in New Guinea,3 and in Turkey.4 The high frequency in these areas represents the effect of consanguinity in specific kindreds. For a study in Hong Kong, see Chan et al.5

Mortality/Morbidity

This enzyme deficiency is not life threatening; however, if intra-abdominal testes are retained, an increased risk of gonadoblastoma is noted. Secondary issues include a risk of osteoporosis if hormone replacement therapy is not initiated in the patient with a gonadectomy and psychological morbidity due to gender or sexual identity issues (see Treatment).

Sex

Clinical 5-alpha-reductase type 2 deficiency is limited to genetic males. Although the enzyme deficiency can be documented in heterozygous females, no clinical or developmental need for DHT is documented in women.

Age

Most individuals with 5-alpha-reductase type 2 deficiency are identified in the neonatal period because of ambiguous genitalia.6 However, some of these children are misdiagnosed as having partial or complete androgen insensitivity syndrome (AIS), which can produce almost identical phenotypes. As noted above, some patients with 5-alpha-reductase type 2 deficiency virilize partially at puberty. Adult males presenting for infertility with anatomically normal genitalia have been diagnosed with 5-alpha-reductase type 2 deficiency. These incidents represent mutations with very mild effects on residual enzyme activity.

Clinical

History

  • Diagnosis of 5-alpha-reductase type 2 deficiency (5-ARD) is usually made in the newborn period when the infant presents with ambiguous genitalia.6,5 No risk factors or clinical markers in pregnancy are known. Genital ambiguity is rarely diagnosed prenatally when an infant who is demonstrated by amniocentesis or chorionic villus sampling to be karyotypically XY fails to have a demonstrable penis on ultrasonography.
  • Some infants are misdiagnosed as having partial or complete androgen insensitivity syndrome (AIS). Diagnosis is then suggested when the child begins to virilize rather than feminize in early puberty.

Physical

  • Neonatal presentation
    • Phenotypic findings in a newborn are limited to the genitalia.6,7  The spectrum of findings ranges from minimal undervirilization presenting with normal male anatomy, except for isolated micropenis or hypospadias, to severe undervirilization presenting as normal female external genitalia with mild clitoral enlargement as the only physical finding.
    • Most commonly, the external genitalia exhibit labial appearance to the labioscrotal folds with some mild rugation or pigmentation present in some patients.
    • The phallus is indeterminate in size. Its length falls between 1 cm (ie, usual maximum for a clitoris) and 2 cm (ie, lower limit of normal for a penis).
    • The urethra may empty anywhere from the tip of the phallus to the perineum, with the latter observed more often.
    • The testes are usually in the inguinal canals bilaterally; however, in some individuals with 5-alpha-reductase type 2 deficiency, the testes can be found in the labioscrotal folds or retained in the abdomen.
    • A pseudovaginal blind-ending introitus is usually present with a normal hymen.
    • Because the uterus is absent, a rectal examination results are negative for a cervical mass.
    • The rest of the examination findings are within normal limits.
  • Presentation of males at puberty
    • Clear signs of virilization predominate at this age.
    • The escutcheon is male in distribution.
    • The phallus exhibits definite enlargement.
    • The shoulders are relatively broad and the hips are narrow.
    • Muscularity and body hair may increase.
    • No breast development is generally present.
    • A prominent Adam's apple may start to develop.
    • Facial hair develops.
    • The child's voice may begin to deepen.
    • The mucosa of the vaginal introitus remains atrophic in appearance (remaining red) rather than the thickened pink of estrogen-stimulated mucosa.
  • Presentation of females
    • Females homozygous for 5-alpha-reductase type 2 deficiency have very subtle manifestations, such as delayed menarche and minimal body hair.
    • Fertility is normal in females.

Causes

  • The cause of 5-alpha-reductase type 2 deficiency is the deficiency of the type 2 isozyme of 5-alpha-reductase.
  • As with most single enzyme disorders, 5-alpha-reductase type 2 deficiency is an autosomal recessive trait and sex limited because the clinical syndrome only affects genetic males.8

More on 5-Alpha-Reductase Deficiency

Overview: 5-Alpha-Reductase Deficiency
Differential Diagnoses & Workup: 5-Alpha-Reductase Deficiency
Treatment & Medication: 5-Alpha-Reductase Deficiency
Follow-up: 5-Alpha-Reductase Deficiency
Multimedia: 5-Alpha-Reductase Deficiency
References
Further Reading
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References

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Keywords

5-alpha-reductase deficiency, familial incomplete male pseudohermaphroditism type 2, pseudovaginal perineoscrotal hypospadias, 5-ARD, 5-alpha-reductase type 2 deficiency, ambiguous genitalia, male pseudohermaphroditism, dihydrotestosterone, DHT, gonadoblastoma, sexual identity issues, androgen insensitivity syndrome, AIS, treatment, diagnosis

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Contributor Information and Disclosures

Author

Bruce E Wilson, MD, Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine at East Lansing
Bruce E Wilson, MD is a member of the following medical societies: American Diabetes Association, Association of Clinical Scientists, Lawson-Wilkins Pediatric Endocrine Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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