Del mimetismo clínico al diagnóstico certero: nefropatía asociada a COL4A4 oculta tras poliquistosis renal

Abstract

Type IV collagen related nephropathy caused by heterozygous variants in the COL4A3 or COL4A4 genes shows a wide phenotypic variability, with asymptomatic individuals being relatively common. A cystic phenotype in these cases is uncommon and rarely presents with nephromegaly mimicking autosomal dominant polycystic kidney disease (ADPKD).

We report a family with hereditary kidney disease showing an autosomal dominant inheritance pattern and marked phenotypic variability. Some family members were diagnosed with urate nephropathy, others met the Ravine-Pei criteria for ADPKD, and others were labeled as having chronic kidney disease of unknown etiology; five progressed to renal replacement therapy.

The proband, who presented with bilateral renal cysts fulfilling ADPKD criteria, along with microhematuria and non-nephrotic proteinuria, tested negative for PKD1 and PKD2 variants after sequential genetic analysis. Meanwhile, another family member studied for persistent microhematuria and non-nephrotic proteinuria underwent a renal biopsy that revealed thinning of the glomerular basement membrane on electron microscopy, suggesting Alport syndrome. Genetic testing in both individuals identified the c.735 + 2T >C (p?) variant in the COL4A4 gene, classified as likely pathogenic due to its disruption of a splicing site.

This case illustrates the phenotypic heterogeneity of heterozygous COL4A4-related Alport syndrome and highlights the importance of implementing genetic testing in the differential diagnosis of hereditary kidney disorders to prevent diagnostic delays with potential clinical consequences.