SRD5A2 – 5-alpha-reductase 2 deficiency

Steroid 5-alpha-reductase type 2 deficiency is an autosomal recessive disorder characterized by 46,XY individuals presenting with undervirilization, ambiguous genitalia (HP:0000062), penoscrotal hypospadias (HP:0000808), and occasionally primary amenorrhea (HP:0000786). Affected patients harbor biallelic pathogenic variants in the SRD5A2 gene with reduced conversion of testosterone to dihydrotestosterone, leading to impaired masculinization. This phenotype ranges from mild hypospadias to complete female-appearing external genitalia with Wolffian structures.

Genetic studies have identified biallelic SRD5A2 variants in over 150 probands from more than 30 unrelated families, supporting autosomal recessive inheritance. Initial case reports described two Turkish siblings with a homozygous missense variant c.368G>A (p.Gly123Glu) (PMID:16098368) and two Indonesian siblings with three compound heterozygous variants including p.Gly34fs and c.699-1G>T (PMID:21714467). A Brazilian cohort of 20 patients from 18 families revealed recurrent and novel mutations such as G183S and R246W in homozygous or compound heterozygous states (PMID:15770495).

Segregation analyses demonstrate parental and sibling carrier status consistent with autosomal recessive transmission in multiple pedigrees, including Turkish and Indonesian families. In total, at least 19 additional affected relatives have been documented to segregate pathogenic alleles in trans with clinical phenotypes.

The SRD5A2 variant spectrum includes over 50 missense changes, multiple frameshift and splice variants, and founder alleles such as p.Arg246Gln in Indian patients and p.Pro212Arg in Mexican populations. A prototypical variant c.368G>A (p.Gly123Glu) exemplifies the missense class with complete loss of enzyme function in cell-based assays.

Functional evidence from genital skin fibroblast assays and recombinant enzyme studies consistently shows markedly reduced or absent 5α-reductase activity for pathogenic SRD5A2 variants. Biochemical assays (e.g., intact monolayer conversion of 3H-testosterone) and in vitro splicing analyses confirm loss-of-function as the mechanism of pathogenicity (PMID:7554313; PMID:8784107).

Taken together, genetic and functional data conclusively establish SRD5A2 deficiency as the cause of 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency. Early molecular diagnosis enables accurate gender assignment, family counseling, and targeted management including androgen supplementation and surgical correction. Key take-home: Biallelic SRD5A2 loss-of-function variants underlie autosomal recessive 5α-reductase 2 deficiency with a consistent clinical and biochemical phenotype.

References

• Urology • 2005 • A novel missense mutation of 5-alpha reductase type 2 gene (SRD5A2) leads to severe male pseudohermaphroditism in a Turkish family. PMID:16098368
• Journal of pediatric endocrinology & metabolism • 2010 • Two novel mutations of SRD5A2 gene in Indonesian siblings with clinical 5-alpha-reductase deficiency. PMID:21714467
• Journal of molecular medicine (Berlin, Germany) • 2005 • New mutations, hotspots, and founder effects in Brazilian patients with steroid 5alpha-reductase deficiency type 2. PMID:15770495
• Clinical Endocrinology • 1995 • A new deletion of the 5 alpha-reductase type 2 gene in a Turkish family with 5 alpha-reductase deficiency. PMID:7554313
• The Journal of Clinical Endocrinology and Metabolism • 1996 • Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency. PMID:8784107

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