Molecular and clinical characteristics of 5-alpha reductase type 2 deficiency: A systematic review

The 46, XY differences of sex development (46, XY DSD) due to 5-alpha reductase type 2 deficiency (5ARD2) are characterized by extensive phenotypic variability. Molecular analysis of the specific mutated SRD5A2 gene is employed in diagnosing enzymatic defects in the androgen biosynthesis cascade. This review systematically elaborates on the current literature regarding 46, XY DSD caused by 5-alpha reductase type 2 deficiency. Three international databases were searched for literature published from 2014 to 2024. The articles were summarized and reviewed, focusing on molecular causes and clinical presentation. A total of 412 articles were retrieved from the search. Of these, 31 articles met the inclusion criteria and had sufficient power for review. We identified 2,235 patients with 5ARD2 deficiencies from 17 countries, with most cases originating from China (29%), Iran (13%), and India (10%). Sixty-nine percent of patients were assigned female at birth. Regarding genetic variants, 70% were homozygous allelic variants, and 30% were compound heterozygous. Most mutations were missense variants, with homozygous mutations and compound heterozygous mutations being predominant. Additionally, small insertions and deletions (indels), splicing mutations, and large deletions were reported. These mutations were distributed across all exons, with exon 1 accounting for 33% and exon 4 for 25%. Although research remains limited, molecular technology is essential for rapid gene localization in patients, providing valuable clinical information.