Guevedoces, or “penis at twelve,” is the name used in the Dominican Republic for girls who turn into boys at puberty (BBC, 2015). This extraordinary phenomenon is the result of a condition called 5-alpha reductase deficiency, which is also found in other communities around the world. Babies born with 5-a-reductase deficiency are genetically male (they possess an X and a Y chromosome) but appear female, because their external male genitalia do not develop until puberty (Okeigwe & Kuohung, 2014).

5-a-reductase deficiency is a genetic disease. It is the result of mutations in the steroid 5-alpha reductase type 2 (SRD5A2) gene located on chromosome 2. So far, fifty separate mutations of SRD5A2 have been discovered, with certain ones being more common in particular communities. In the Guevedoces, the mutation responsible is in exon (coding region) 5 of the SRD5A2 gene, and leads to production of an incorrect amino acid (thymidine instead of cytosine) (Okeigwe & Kuohung, 2014). The disease is recessive, meaning two disease alleles (versions of the gene leading to the disease) must be inherited (one from each parent) for symptoms to appear. Even though females may possess two mutated copies of SRD5A2, only males show any effect. The SRD5A2 gene is responsible for producing the enzyme 5-a-reductase. Mutations may lead to reduced, altered, or complete loss of function of the enzyme (NLM, 2008).

The function of 5-a-reductase is to transform testosterone to dihydrotestosterone (DHT) by facilitating the breaking of the carbon-carbon double bond in testosterone and the addition of two hydrogen atoms. DHT is more potent than testosterone because it binds better to the cell’s androgen receptors (AR). The binding of DHT to the ARs causes them to be phosphorylated and form dimers (pairs). When paired in this way, the ARs bind to the promoter region of genes, inducing growth and development of the male genitalia (Feldman & Feldman, 2001). Guevedoces and others with 5-a-reductase deficiency do not produce enough DHT to activate the androgen receptors required for normal development. However, at puberty, the body produces greater amounts of testosterone. Even though testosterone is not as effective as DHT at activating the AR complex, the large amounts present are enough to stimulate genitalia growth, causing the Guevedoces to change appearance from female to male (Okeigwe & Kuohung, 2014).

Researchers studying the Guevedoces had to work backwards, theorizing that the effect was a result of low DHT production. Testing the affected individuals showed that they did have lower DHT to testosterone ratios than unaffected individuals. Urine tests also showed irregular results for 5-a-reductase metabolites. Genetic testing of the affected families allowed the researchers to discover the gene responsible for 5-a-reductase production. Eventually the entire pathway from SRD5A2 gene to 5-a-reductase enzyme to DHT hormone to observable physical effects was uncovered. The results of the research are used to produce treatments for enlarged prostates and male pattern baldness, as the Guevedoces do not experience either condition (Okeigwe & Kuohung, 2014).

 

BBC. (2015, September 20). The extraordinary case of the Guevedoces. Magazine.  Retrieved from http://www.bbc.com/news/magazine-34290981

Feldman, B. J., & Feldman, D. (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer, 1(1), 34-45.

NLM. (2008, April 2008). 5-alpha reductase deficiency. Genetics Home Reference.  Retrieved from https://ghr.nlm.nih.gov/condition/5-alpha-reductase-deficiency

Okeigwe, I., & Kuohung, W. (2014). 5-Alpha reductase deficiency: a 40-year retrospective review. Current Opinion in Endocrinology, Diabetes and Obesity, 21(6), 483-487. doi:10.1097/med.0000000000000116