A 30-year-old man with nephrotic syndrome has a renal biopsy. Light microscopy shows no significant changes, electron microscopy shows diffuse effacement of podocyte foot processes, and immunofluorescence is negative. A targeted genetic panel reveals a heterozygous missense mutation in NPHS2 (podocin). The diagnosis and expected response to steroids are:

• A Minimal change disease — excellent response to steroids (90%)
• B C1q nephropathy — variable response to steroids
• C Diffuse mesangial sclerosis — steroid-responsive in adults
• D Genetic FSGS due to podocin mutation — typically steroid-resistant ✓

Explanation

NPHS2 mutations cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). Podocin is a lipid raft protein that recruits nephrin to the slit diaphragm; mutations disrupt the nephrin-podocin interaction. Histologically it may appear as minimal change disease early or progress to FSGS. Crucially, NPHS2-related disease does not respond to steroids or calcineurin inhibitors, making genetic testing essential before prolonged immunosuppression. Adult-onset NPHS2 mutations are an underrecognized cause of FSGS and SRNS.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.