EXT2 -related nephropathy with severe podocyte injury and modifiable proteinuria

Abstract Autosomal-recessive EXT2 -related disease is a rare multisystem disorder with poorly characterized kidney involvement. We describe a 2-year-old girl homozygous for the founder complex allele EXT2 :c.[260T > G;283C > T], p.[Met87Arg;Arg95Cys], who developed severe albumin-predominant proteinuria with preserved kidney function. Kidney biopsy showed diffuse podocyte foot-process effacement (> 80%) with minimal chronic injury, focal glomerular basement membrane irregularity, and mild mesangial remodeling. Daily prednisone reduced the urine protein-to-creatinine ratio from 903 to 342 mg/mmol and increased serum albumin from 32 to 36 g/L, but the response was not sustained after tapering. Following corticosteroid withdrawal, enalapril reduced the urine protein-to-creatinine ratio from 666 to 385 mg/mmol while serum albumin remained 36 g/L. Impaired heparan-sulfate assembly may therefore contribute to severe podocyte injury while leaving the downstream proteinuric phenotype modifiable. The responses to corticosteroids and enalapril support sequential, quantitatively monitored treatment rather than assuming that monogenic disease is therapeutically irreversible.