Gross hematuria as a manifestation of LAMA5-Related Nephropathy

Laminin α5, encoded by LAMA5, is a crucial component of the glomerular basement membrane (GBM). Pathogenic variants in LAMA5 have been predominantly associated with steroid-resistant nephrotic syndrome. However, recurrent episodes of gross hematuria have not previously been documented as a clinical manifestation of LAMA5-related nephropathy.

We describe a 2-year-old boy with no significant family or past medical history. Following an upper respiratory infection, he developed gross hematuria, hypoalbuminemia, and heavy proteinuria, while kidney function remained within the normal range. Although the nephrotic-range proteinuria spontaneously improved, heavy proteinuria and microscopic hematuria continued. Because episodes of gross hematuria were repeatedly triggered by febrile illnesses, a kidney biopsy was performed. Light microscopy revealed focal mesangial proliferative glomerulonephritis, and immunofluorescence studies were negative. Electron microscopy demonstrated segmental thinning of the GBM, and immunostaining for type IV collagen α5 was preserved.

Given the atypical clinical course, genetic analysis was undertaken to evaluate for hereditary nephropathy. Next-generation sequencing using a comprehensive kidney disease gene panel identified compound heterozygous LAMA5 variants, c.7681C>T (p.Arg2561*) and c.3434G>A (p.Cys1145Tyr), confirming the diagnosis of LAMA5-related nephropathy. Following initiation of a renin–angiotensin system inhibitor, proteinuria markedly decreased, and kidney function has remained stable during follow-up.

To date, 21 affected individuals from 14 unrelated families with LAMA5 variants have been reported. Among these, no individuals has presented hematuria or gross hematuria with LAMA5-related nephropathy caused by LAMA5 variants alone, except for those harbored pathogenic variants in both LAMA5 and COL4A. In our case, no pathogenic variants were detected in other GBM components, COL4A or LAMB2, which are well known to cause hematuria and immunostaining for type IV collagen α5 was preserved. Furthermore, hypomorphic Lama5 mutant mise exhibit disrupted GBM architecture and develop both hematuria and proteinuria. Together with kidney biopsy in our case showing segmental thinning of the GBM, these findings also suggest that hematuria resulted from GBM fragility caused by LAMA5 variants. This case thus represents a novel hematuria-dominant phenotype within the LAMA5-associated disease spectrum. Recognition of this phenotype is clinically important, as it facilitates accurate genetic diagnosis and prevents unnecessary corticosteroid or immunosuppressive therapy in patients who might otherwise be misdiagnosed with glomerulonephritis.

We report a unique case of LAMA5-related nephropathy manifesting as recurrent gross hematuria rather than nephrotic syndrome. To our knowledge, this is the first report of LAMA5-related nephropathy presenting predominantly with hematuria in the absence of other GBM gene variants. The findings expand the phenotypic and molecular spectrum of GBM-associated nephropathies and underscore the diagnostic and therapeutic significance of early genetic evaluation in children with atypical glomerular disease