Background: 5-alpha-reductase-2 (5α-RD2) deficiency is an autosomal recessive 46,XY disorder of sexual development, characterized by undervirilized prepubertal males with ambiguous genitalia. The pubertal rise in testosterone and 5α-RD1 isoenzyme activity causes virilization, often resulting in gender assignment change. Early precise diagnosis which anticipate adult function is critical for treatment and gender assignment.
Objective and hypotheses: To elucidate the genetic cause and the optimal treatment for a unique 46,XY DSD patient.
Method and results: Consanguineous Palestinian parents requested a change to male gender assignment in their 2.5 year old girl. The girl had labial embedded testis, aphallia, high anogenital ratio (0.78) indicating testosterone responsive genitalia. Laboratory examinations revealed XY karyotype, normal basal and ACTH stimulated glucocorticoids levels, high HCG stimulated testosterone and a testosterone/androstenedione ratio of 2.4. Given the high testosterone and the high anogenital ratio, we sequenced the SRD5A2 gene and found a new 271T>C, Y91H mutation, in an exon encoding 5α-RD2 transmembranal domain. Urinary steroid metabolites profile showed a dramatically decreased ratio between 5alpha/5beta metabolites of corticosteroids indicating a decreased function of the mutated 5α-RD2 in this case. The rare phenotype of absence of clitoromegaly and complete aphallia with seemingly impossible surgical penile reconstruction, complicated the adherence to the parents request for male gender assignment. A 3 months trial of daily local dihydrotestosterone administration resulted in dramatic enlargement of the rudimentary clitoris to a phallus of >2 cm length enabling reconstruction urological surgery.
Conclusion: The new Y91H mutation in SRD5A2 gene, causing a severe reduction in 5α-RD2 activity as reflected in urine metabolites, results in a rare XY-DSD phenotype with complete aphallia. The prepubertal use of local dihydrotestosterone may alleviate the conflict between male gender assignment and a complete female phenotype. Further studies correlating quantitative SRD5A2 enzymatic activity to genotype and phenotype may contribute to early comprehensive decisions regarding gender assignment.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology