Denys-Drash syndrome

Denys-Drash syndrome (DDS) is a rare genetic disorder characterized by a classic triad of diffuse mesangial sclerosis (a severe kidney disease), disorders of sexual development (particularly 46,XY male pseudohermaphroditism), and an increased risk of Wilms tumor (nephroblastoma). The condition is caused by heterozygous missense mutations in the WT1 gene located on chromosome 11p13, which encodes a transcription factor critical for normal kidney and gonadal development. Most cases arise from de novo (new) mutations rather than being inherited from a parent. The kidney disease in Denys-Drash syndrome typically presents in infancy or early childhood with nephrotic syndrome — characterized by heavy proteinuria, edema, low serum albumin, and elevated cholesterol. The underlying pathology is diffuse mesangial sclerosis, which progresses rapidly to end-stage renal disease (ESRD), often before the age of three years. Genotypic males (46,XY) frequently exhibit ambiguous genitalia or female-appearing external genitalia due to impaired testicular development, while genotypic females (46,XX) typically have normal external genitalia. The risk of developing Wilms tumor is very high, estimated at over 90% in affected individuals, and bilateral tumors are common. Management of Denys-Drash syndrome requires a multidisciplinary approach. Treatment of the nephropathy is largely supportive, including management of nephrotic syndrome and eventual renal replacement therapy (dialysis or kidney transplantation) when ESRD develops. Bilateral nephrectomy is often recommended early to prevent Wilms tumor development and to manage refractory nephrotic syndrome. Wilms tumor, when it occurs, is treated with surgery, chemotherapy, and sometimes radiation according to standard oncologic protocols. Disorders of sexual development require careful evaluation and individualized management, including hormonal therapy and potentially surgical intervention. Gonadectomy may be recommended for individuals with dysgenetic gonads due to the risk of gonadoblastoma. Genetic counseling is important for affected families.

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