Mild clinical course in siblings with NPHS1-associated familial nephrotic syndrome: two case reports

NPHS1-associated nephrotic syndrome (NS) has traditionally been considered a severe hereditary podocytopathy that presents in infancy with heavy proteinuria, poor response to immunosuppressive therapy, and early progression to kidney failure. However, accumulating evidence suggests that the clinical course varies by genotype, with some variants associated with partial preservation of nephrin function and a relatively milder phenotype. We report two brothers with NS onset beyond the congenital period who were later found to have identical compound heterozygous NPHS1 variants. Despite sharing the same genotype, the siblings differed in age at presentation; however, both followed a relatively indolent course, with preserved kidney function for more than 10 years and partial proteinuria response to immunosuppressive therapy. These cases expand the phenotypic spectrum of NPHS1-associated disease by showing that it can present beyond infancy and follow a milder clinical course than expected. This report underscores the importance of genetic testing in children with steroid-resistant or atypical NS regardless of age at onset, because early molecular diagnosis may aid prognostic assessment, prevent diagnostic delay, and support individualized management.