Diffuse mesangial sclerosis is the second most common cause of infantile nephrotic syndrome associated with glomerular injury and rapid progression to end stage-renal failure. The same glomerular lesions are observed in the Denys-Drash syndrome, which is characterized, by the combination of nephropathy, male pseudohermaphroditism and Wilms’ tumor. The nephrotic syndrome, which may be present at birth, but more often, develops at age 1 or 2 years is resistant to corticosteroids and immunosuppressive drugs. All children progress to end-stage renal failure, frequently in association with hypertension, usually before the age of 3 years and, within a few months of the discovery of renal symptoms. The glomerular lesions are characterized during the early stages by more fibrils in the mesangial matrix with out mesangial cell proliferation. The capillary walls are lined by hypertrophied podocytes. The mesangial sclerosis eventually contracts the glomerular tuft in to a scleotic mass. Mutations of WT1 gene, which is also involved in some patients with Wilms’ tumor, have been found in most patients with Denys-Drash syndrome as well as in some patients with isolated diffuse mesangial sclerosis. Treatment is supportive and consists of maintaining electrolyte and water balances and adequate nutrition, prevention and treatment of infectious complications, and management of renal failure including dialysis and transplantation.