Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is 
catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 
gene. The potent androgen DHT is required for full masculinization of the 
external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, 
diminish DHT formation, and hence cause masculinization defects of varying 
degree. The classical syndrome, formerly described as pseudovaginal 
perineoscrotal hypospadias, is characterized by a predominantly female phenotype 
at birth and significant virilization without gynecomastia at puberty. We 
investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). 
Phenotypes, which were classified according to the severity of the 
masculinization defect, varied between completely female (SRD type 5), 
predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male 
with micropenis and hypospadias (SRD type 2), and completely male without overt 
signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( 
> 50) in the classical syndrome (SRD type 5), but variable in the less severe 
affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been 
characterized using PCR-SSCP analysis and direct DNA sequencing. A small 
deletion was encountered in two patients, while all other patients had single 
base mutations which result in amino acid substitutions. We conclude that 
phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the 
whole range from completely female to normal male without distinctive clinical 
signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be 
considered not only in sex reversed patients with female or ambiguous 
phenotypes, but also in those with mild symptoms of undermasculinization as 
encountered in patients with hypospadias and/or micropenis. A classification 
based on the severity of the masculinization defect may be used for correlation 
of phenotypes with enzyme activities and genotypes, and for comparisons of 
phenotypes between different patients as the basis for clinical decisions to be 
made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 
deficiency.