A Novel NPHS1-Associated Phenotype Characterized by Recurrent Transient Proteinuria

We herein report the case of a 2-year-old girl with novel compound heterozygous NPHS1 variants, p.R460Q (a known loss-of-function mutation) and p.V822M (a rare variant with reported pathogenicity and relatively mild functional effects). She initially presented with typical features of idiopathic nephrotic syndrome and achieved complete remission on Day 10 of corticosteroid therapy. After tapering, the patient developed recurrent episodes of infection-associated heavy proteinuria, which often remitted spontaneously but sometimes left residual low-grade proteinuria. Despite the introduction of cyclosporine, these episodes continued, and the effect of immunosuppression remained unclear. Over a 4-year follow-up, recurrent transient proteinuria persisted, but no relapse of nephrotic syndrome or renal dysfunction was observed. This atypical clinical pattern, characterized by incomplete remissions and limited response to immunosuppressive therapy, prompted genetic testing, which revealed compound heterozygous NPHS1 variants. This case expands the phenotypic spectrum of NPHS1-associated disease, thus highlighting that nephrin variants may manifest as steroid responsiveness, preserved renal function, and repeated transient proteinuria. Our findings emphasize the role of genetic testing in clarifying diagnosis and guiding management in steroid-sensitive nephrotic syndrome with atypical features.