Genotype-phenotype Correlation, Gonadal Malignancy Risk, Gender Preference, and testosterone/dihydrotestosterone Ratio in Steroid 5-alpha-reductase Type 2 Deficiency: A Multicenter Study From Turkey

J Endocrinol Invest. 2019 Apr;42(4):453-470. doi: 10.1007/s40618-018-0940-y. Epub 2018 Aug 21.


Background: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients.

Objective: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2.

Materials and methods: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated.

Results: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty.

Conclusion: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

Keywords: Gender preference; Malignancy; Phenotype; SRD5A2 gene; Testosterone/dihydrotestosterone ratio.

Publication types

  • Multicenter Study

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / deficiency*
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics*
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Dihydrotestosterone / blood*
  • Disorders of Sex Development / complications*
  • Disorders of Sex Development / metabolism
  • Disorders of Sex Development / pathology
  • Female
  • Genetic Association Studies
  • Genital Neoplasms, Female / etiology*
  • Genital Neoplasms, Female / metabolism
  • Genital Neoplasms, Female / pathology
  • Genital Neoplasms, Male / etiology*
  • Genital Neoplasms, Male / metabolism
  • Genital Neoplasms, Male / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Retrospective Studies
  • Risk Factors
  • Sex Factors
  • Sexual Maturation
  • Testosterone / blood*
  • Turkey
  • Young Adult


  • Dihydrotestosterone
  • Testosterone
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • steroid-5alpha-reductase type 2