Characteristics and clinical outcomes of Denys-Drash syndrome: a systematic review of case reports and case series.

backgroundDenys-Drash syndrome (DDS) is a rare genetic disorder caused by pathogenic variants in the WT1 gene, presenting with the classical triad of progressive nephropathy, steroid-resistant nephrotic syndrome (SRNS), disorders of sex development (DSD) encompassing a spectrum of genital presentations, and increased predisposition to Wilms tumor. The condition is associated with early-onset nephrotic syndrome, rapid progression to kidney failure, and significant morbidity. Despite numerous case reports, a comprehensive synthesis of clinical characteristics and outcomes remains limited.

objectivesThis systematic review aimed to evaluate and synthesize the clinical, genetic, and therapeutic characteristics of DDS, while highlighting management strategies and long-term outcomes.

methodsA systematic search of PubMed and Google Scholar was performed up to May 2025, following PRISMA 2020 guidelines. Case reports and case series providing individual-level data on patients with genetically or clinically confirmed DDS were included. Data extraction covered demographic, phenotypic, genotypic, clinical, therapeutic, and outcome-related variables. Risk of bias was assessed using the JBI Checklist for Case Reports.

resultsSeventy-five studies comprising 107 patients were included. Pathogenic WT1 mutations were identified in 83.2% (89/107) of patients, with missense variants accounting for 55.1% (59/107) of pathogenic variants and most frequently involving exons 7-9 (63.6%, 68/107). The hotspot variant c.1180C>T (p.Arg394Trp) was identified in 17 patients. DSD was observed in 59.8% (64/107) of patients. Wilms tumor developed in 49.5% (53/107) of patients, and nephrectomy was performed in 61.6% (66/107) of the overall cohort. Kidney failure occurred during the disease course in 46.7% (50/107) of patients; among these, 50.0% (25/50) underwent kidney transplantation. Gonadectomy was performed in 18.7% (20/107) of patients, either for treatment of gonadal tumors or prophylactically in high-risk patients.

conclusionDDS remains a clinically and genetically heterogeneous condition requiring multidisciplinary management. Early genetic diagnosis, vigilant tumor surveillance, and timely kidney transplantation are crucial to improving outcomes in severe cases. Further research is warranted to refine genotype-phenotype correlations and management guidelines.