What is 5-Alpha-Reductase Deficiency?
Ambiguous genitalia is an unusual condition found in newborns, affecting about 1 in 4500 live births. Despite advancements like genetic tests, hormone assays, and karyotyping, a diagnosis can only be made 20% to 40% of the time in these children. One significant cause of ambiguous genitalia in children is a deficiency in 5-alpha-reductase type 2 (5α-RD2). The physical appearance of children with this deficiency can range from underdeveloped male genitalia to fully developed female genitalia.
What Causes 5-Alpha-Reductase Deficiency?
Testosterone, often associated with men, is a hormone that doesn’t affect all tissues in the body. There is an enzyme called 5alpha-RD2 which converts testosterone into a stronger form called dihydrotestosterone (DHT). This hormone transformation is very important during the development of a male fetus. Testosterone is mainly responsible for forming the male internal sexual organs, including a structure known as the Wolffian duct. On the other hand, DHT plays a part in shaping male external sexual organs.
When boys reach puberty, testosterone leads to more forceful sexual behavior, a deeper voice, increased muscle mass, and the initiation of sperm production. DHT, however, contributes to the development of the prostate and typical male hair growth patterns during puberty.
There is a rare condition called 5α-RD2 deficiency, frequently caused by a mutation in a gene known as SRD5A2 located on a certain part of chromosome 2. Children who have this deficiency produce less DHT during fetal development, which can lead to improper formation of the external genitalia and uncertainty about the child’s gender at birth.
Risk Factors and Frequency for 5-Alpha-Reductase Deficiency
The disease is extremely rare in people with white skin. However, it’s much more common in the Dominican Republic due to a history of marriages between blood relatives. In fact, the first reported case of this deficiency was found there. Beyond the Dominican Republic, this condition also shows up in southern Lebanon and Papua New Guinea. It was officially identified in patients in 1993. There are two forms of the deficiency that were discovered, and researchers have identified 2 different genes related to the condition.
Signs and Symptoms of 5-Alpha-Reductase Deficiency
5α-RD2 deficiency is a genetic disorder linked to mutations in the SRD5A2 gene, affecting sexual development. The symptoms can differ greatly between two individuals, even if they have the same gene mutation, suggesting the involvement of other genes. The exact relationship between the gene mutation and symptoms is not well understood.
Newborns with this condition may have genital features that resemble female structures. For example, they may have unfused labioscrotal folds that look like the female labia and a phallus more resembling a clitoris than a penis. However, internally, these children will have male reproductive organs like the seminal vesicles, epididymis, vas deferens, and ejaculatory duct. These children’s testes may be located in the inguinal sac, though in rare cases, they can be found within the abdomen. Often, such children are assumed to be and raised as females until puberty, at which point they may begin to show male traits.
- The phallus may grow into a penis
- The testes may descend into the labioscrotal folds
- Development of a deeper voice
- Growth of facial hair
It’s important to note that these changes arise from testosterone and are not influenced by DHT, a type of male sex hormone.
There can be gender identity challenges for kids with a 5α-RD2 deficiency. Although some of these children are raised as girls, they often change their gender identity to male during puberty following such physical changes. A range of factors can influence these gender changes, including cultural and environmental pressures. However, the most significant factor seems to be exposure to male sex hormones like testosterone, which develop more masculine behaviour. As a result, the child may identify more as a male than a female.
Testing for 5-Alpha-Reductase Deficiency
The process of evaluating the deficiency of 5α-RD2 enzyme includes two main steps – biochemical tests and gene analysis.
Biochemical testing typically involves estimating the balance between testosterone and another hormone called DHT after the administration of Human Chorionic Gonadotropin (hCG). Children with this disorder generally show an increase in the balance of testosterone to DHT after hCG is given. But it’s important to remember that even if the balance does not increase with hCG administration, this does not definitely rule out the disorder, making it harder to diagnose.
This test isn’t always dependable, as the balance of testosterone to DHT can vary due to things like the severity of the enzyme deficiency and the age of the child. The test also doesn’t work well in cases of partial enzyme deficiencies.
On the other hand, a gene analysis looks at the changes in the SRD5A2 gene, which provides the blueprint for the protein that becomes the 5α-RD2 enzyme, containing 254 amino acids. This enzyme tends to attract more testosterone than another version of the enzyme, 5α-RD1.
At least 54 changes in the gene have been discovered. These changes are primarily missense mutations, which often change the protein product of a gene. The severity or impact of the condition depends on how much the enzymatic activity is reduced by these gene changes. In about half the cases, these gene changes result in an enzyme that doesn’t have any measurable biological activity. The other half of the time, the mutated gene might still produce an enzyme, but with very little measurable activity.
Treatment Options for 5-Alpha-Reductase Deficiency
The treatment for a child with 5α-RD2 deficiency, a condition that impacts sex development, depends on a variety of factors, including the child’s physical characteristics and their identified gender at the time of diagnosis.
If the child has significant abnormalities in the development of male genitalia, it might be more appropriate for the child to be raised as a girl. If the child feels comfortable with this and wishes to be brought up as a girl, their testicles would need to be removed before they hit puberty, and they would need surgery to reshape the external genitals. This surgery could include creating a vaginal opening and ensuring the urethra and vagina are separated. As the child grows into a teenager, creating a vagina (a procedure known as vaginoplasty) could become a possible treatment option.
On the other hand, if the child is raised as a boy, the type of corrective surgery needed would depend on their physical traits. The size of the penis when the condition is diagnosed and its potential to grow into a functional one is a major factor to consider before deciding to raise the child as a boy. Corrective surgeries for boys could include fixing hypospadias (a condition where the urethral opening is not at the tip of the penis), correcting any bending of the penis, and rebuilding the urethra. These procedures are usually performed during the first two years of life.
Parents of a child with ambiguous genitalia have the legal right to get assistance, support, and information on their child’s condition. They are also given ample time to make decisions about treatment options and their child’s gender.
What else can 5-Alpha-Reductase Deficiency be?
For patients with unusual physical genital features, other conditions that might resemble 5-alpha-reductase-2 deficiency should be considered. These include Androgen Insensitivity Syndrome (AIS) and 17 beta-hydroxysteroid dehydrogenase type 3 insufficiency. Proper medical examinations and hormone tests are crucial to distinguish between these conditions.
In particular, it’s important to correctly diagnose between 5-alpha-reductase-2 deficiency and AIS, because individuals with these conditions are often raised as different genders – males for the former and females for the latter.
Even more confusingly, the characteristics of 5-alpha-reductase-2 deficiency can sometimes appear similar to another condition called Leydig cell hypoplasia, which is related to a mutation of LH receptor on the Leydig cells. Hence, precise diagnosis becomes crucial to ensure accurate treatment and care.
What to expect with 5-Alpha-Reductase Deficiency
People with a 5α-RD2 deficiency typically have a good prognosis. There have been no cases of prostate cancer or benign prostate enlargement reported in these patients. Despite having less facial and body hair, these individuals still produce a normal amount of sebum, the body’s natural oil. However, most males with this deficiency struggle with infertility.
Infertility in these individuals can be caused by several issues, including undescended testes, low sperm count, narrow urethra, and urethroscrotal fistulas, which are abnormal connections between the urethra and scrotum. But there’s positive news, some individuals with 5α-RD2 deficiency have been able to have children through techniques such as intrauterine insemination and in vitro fertilization.
Possible Complications When Diagnosed with 5-Alpha-Reductase Deficiency
The biggest issue related to a lack of the 5α-RD2 enzyme is a change in the appearance of the genitals. There’s no reported data on how frequently individuals with this deficiency develop testicular tumors. Some research has been conducted on bone growth and development in patients with this deficiency, but the findings suggest that they have normal bone mineral density. Women with a specific genetic makeup (known as genotype 46 XX) who also have a specific mutation in the SRD5A2 gene might experience a delayed first menstruation, but their ability to reproduce is usually unaffected.
