Background <p>Post-infectious glomerulonephritis (PIGN) is one of the leading causes of acute nephritis in children worldwide. C3 glomerulopathy (C3G) is a rare form of membranoproliferative glomerulonephritis (MPGN) characterised by either genetic or acquired dysregulation of the alternative complement pathway resulting in predominant C3 deposition within the glomeruli. The overlap between atypical post-streptococcal glomerulonephritis (PSGN), a subset of PIGN primarily induced by streptococcal species, and C3G has attracted considerable attention in recent clinical trials. Here, we describe an extremely rare case of a child with atypical signs of PSGN and concomitant genetically confirmed susceptibility in the thrombomodulin gene (THBD).</p> Case presentation <p>A 2.5-year-old girl with a positive maternal history for systematic lupus erythematosus presented with macroscopic haematuria, fatigue and reduced appetite. Her results revealed acute kidney injury, nephrotic range proteinuria, macroscopic glomerular haematuria, positive Anti-streptolysin-O titre and reduced C3 levels, findings highly suggestive of PSGN. However, during her admission she experienced severe autoimmune haemolytic anaemia with positive direct Coombs test, whereas her immunological screen was positive for lupus anticoagulant, anticardiolipin antibodies and anti-phosphatidylserine antibodies. Due to the aforementioned findings, persistent nephrotic range proteinuria, macroscopic haematuria and low C3 titres she underwent kidney biopsy, which revealed strong C3 deposition and trace IgM staining, with the differential diagnosis including both PSGN and C3G. Subsequently she was commenced on corticosteroids, while C3G complete investigation was pending, for a total course of 3 months with favorable outcome. Her C3 levels normalised at ~ 8 weeks after her initial presentation, while genetics identified an extremely rare polymorphism in the THBD gene [c.1418&#xa0;C (p. Ala473)], known to be associated with the pathogenesis of C3G and atypical haemolytic uremic syndrome.</p> Conclusions <p>This case illustrates the difficulty of classifying MPGN at onset. Her polymorphism in the THBD gene could have possibly contributed to her atypical presentation. Corticosteroids showed a beneficial effect towards the remission of proteinuria and gross haematuria. Whether our patient has a higher tendency to progress to C3G in the future and subsequently to chronic kidney disease remains to be determined. Further studies are deemed necessary to provide insight into the prognosis and benefits of immunosuppression in this rare population.</p> Clinical trial number <p>Not applicable.</p>