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.