CFHR5-ASSOCIATED C3 glomerulopathy masquerading as steroid-resistant focal segmental glomerulosclerosis: A rare case report

C3 glomerulopathy (C3G) is a rare, complement-mediated glomerular disease that can be difficult to distinguish from other proteinuric glomerulopathies, particularly when the classical ultrastructural and immunofluorescence hallmarks of complement-dominant deposition are absent. We report the case of a 35-year-old woman with adult-onset nephrotic syndrome who presented with facial puffiness, pedal oedema, and heavy proteinuria (24-hour urine protein 7 g). An initial renal biopsy showed focal segmental glomerulosclerosis (FSGS), not otherwise specified, with no immune deposits on immunofluorescence, and she was treated as steroid-dependent FSGS with corticosteroids, later escalated to tacrolimus after a relapse complicated by prolonged loss to follow-up following bereavement. A repeat ultrastructural study performed after relapse showed diffuse podocyte foot-process effacement without electron-dense deposits, again favouring a primary podocytopathy. However, clinical exome sequencing performed during the same period identified a heterozygous missense variant in CFHR5, c.1702T>A (p.Cys568Ser), classified as a variant of uncertain significance and associated with C3 glomerulopathy-3 (OMIM #614809), an autosomal dominant complement-regulatory disorder. This case highlights the diagnostic overlap between complement-mediated glomerulopathies and FSGS on conventional light microscopy and electron microscopy when dedicated complement-component immunostaining and functional complement studies are not performed, and underscores the value of genetic testing in atypical, relapsing, or steroid-resistant nephrotic syndrome. It further illustrates how psychosocial disruption and treatment non-adherence can shape the course of a complex glomerular disease.