5-alpha reductase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

5-alpha reductase deficiency is a condition that affects sexual development before birth and during puberty. People with this condition are genetically male, with one X and one Y chromosome in each cell, and they have male gonads (testes). Their bodies, however, do not produce enough of a hormone called dihydrotestosterone (DHT). DHT has a critical role in male sexual development, and a shortage of this hormone disrupts the formation of the external sex organs before birth.

Many people with 5-alpha reductase deficiency have external genitalia that appears female. In other cases, affected infants have male-typical external genitalia, often an unusually small penis (micropenis) and the urethra opening on the underside of the penis (hypospadias). Still other affected infants have external genitalia do not look clearly male or clearly female.

During puberty, an increase in the levels of male sex hormones leads to the development of some secondary sex characteristics, such as increased muscle mass, deepening of the voice, development of pubic hair, and a growth spurt. The penis and scrotum (the sac of skin that holds the testes) may grow larger. People with 5-alpha reductase deficiency do not develop much facial or body hair. Most affected individuals are unable to have biological children (infertile) without assisted reproduction.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the SRD5A2 gene cause 5-alpha reductase deficiency. The SRD5A2 gene provides instructions for making an enzyme called steroid 5-alpha reductase 2. This enzyme is involved in processing androgens, which are hormones that direct male sexual development. Specifically, the steroid 5-alpha reductase 2 enzyme is responsible for a chemical reaction that converts the hormone testosterone to DHT. DHT is essential for the normal development of male sex characteristics before birth, particularly the formation of the external genitalia.

Variants in the SRD5A2 gene prevent steroid 5-alpha reductase 2 from effectively converting testosterone to DHT in the developing reproductive tissues. These hormonal factors underlie the changes in sexual development seen in infants with 5-alpha reductase deficiency.

During puberty, the testes produce more testosterone. Researchers believe that people with 5-alpha reductase deficiency develop secondary male sex characteristics in response to higher levels of this hormone. Some affected people also retain a small amount of 5-alpha reductase 2 activity, which may produce DHT and contribute to the development of secondary sex characteristics during puberty.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the SRD5A2 gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Although people who are genetically female (with two X chromosomes in each cell) may inherit variants in both copies of the SRD5A2 gene, their sexual development is not affected. The development of female sex characteristics does not require DHT, so a lack of steroid 5-alpha reductase 2 activity does not cause physical changes in these individuals. Only people who have variants in both copies of the SRD5A2 gene and are genetically male (with one X and one Y chromosome in each cell) will have the characteristic signs of 5-alpha reductase deficiency.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

5-alpha reductase deficiency is a rare condition; the exact incidence is unknown. Large families with affected members have been found in several countries, including the Dominican Republic, Papua New Guinea, Turkey, and Egypt.

Which doctor should you see?

The suggested department for discussing 5-alpha reductase deficiency is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for 5-alpha reductase deficiency. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.