Background: 5-alpha-reductase 2 (5α-RD2) deficiency is an autosomal recessive 46 XY disorder of sexual development (DSD), characterized by undervirilized prepubertal males with inguinal testes, and ambiguous genitalia. At Puberty, the physiological rise in testosterone and elevated activity of 5α-RD1 isoenzyme result in virilization , and often in gender identity change from female to male.
Precise diagnosis in DSD is critical for treatment and gender assignment and to anticipate function.
Objective: To elucidate the genetic cause and the pathophysiology of a unique 46 XY DSD patient.
Methods and results: Consanguineous Palestinian parents requested a change to male gender assignment in their 2.5 years old girl.The girl had labial embedded testis, aphallia, XY karyotype, normal bazal and ACTH stimulated glucocorticoids levels, high basal and HCG stimulated testosterone and a testosterone/androstenedione ratio of 2.4.
Considaring 5α-RD2 deficiency, we sequence the SRD5A2 gene and found a new 271 T to C, Y91H mutation,in an exon encoding a transmembranal segment of 5α-RD2 enzyme. Patient`s Urine metabolome analysis showed a dramatically decreased ratio between 5alpha/5beta metabolites of corticosterone and cortisol indicating a decreased function of the mutated 5α-RD2 in this case.
The rare phenotype of absence of clitoromegaly and complete aphallia indicated severe dysfunction and complicated so far the decision of gender assignment.
Conclusion
The new Y91H mutation in the SRD5A2 gene causes a severe and rare XY DSD phenotype with complete aphalia. Further studies on the SRD5A2 enzymatic activity relating to genotype-phenotype correlation may help in predicting the clinical outcome and determining gender assignment.
