Introduction: Congenital nephrotic syndrome (CNS) is a rare disorder marked by early-onset massive proteinuria. In its hereditary form, CNS results from mutations in genes that affect podocyte function and glomerular slit diaphragm integrity. One such gene is CRB2 (Crumbs Cell Polarity Complex Component 2), which encodes a protein involved in cellular processes during embryonic development. Mutations in CRB2 have been linked to focal segmental glomerulosclerosis type 9 (FSGS9) and ventriculomegaly with cystic kidney disease. Despite its clinical relevance, the full spectrum of CRB2-related disorders is poorly understood, with few case reports. We describe two monozygotic female twins with a rare CRB2 homozygous mutation, presenting a complex phenotype with severe post-transplant complications.
Methods: The twins were referred to our pediatric nephrology clinic during the neonatal period for cystic kidney disease suspected prenatally and were later diagnosed with full-blown congenital nephrotic syndrome. Initial genetic testing using the TruSite One clinical exome sequencing panel yielded negative results, but a subsequent re-analysis with whole exome sequencing identified a homozygous likely pathogenic variant in CRB2, which was confirmed through familial segregation analysis. Both twins received comprehensive care in our pediatric nephrology institute, with all complications systematically assessed and addressed.
Results: Both twins developed early-onset nephrotic syndrome, requiring frequent albumin infusions and supportive care. Associated findings included ventriculomegaly, cerebral grey matter heterotopia, cardiac involvement, and developmental delay. They both progressed to end-stage kidney disease (ESKD), with hemodialysis starting at 2.8 and 3.5 years. Post-transplant complications were challenging, with the first twin unfortunately succumbing to extensive fungal infection during the peri-transplant period. The second twin had an initially uneventful peri-transplant course but later developed multiple immune dysregulation-related, including post-transplant lymphoproliferative disorder (PTLD), immune thrombocytopenic purpura (ITP), pseudo tumor cerebri, multiple viremias, proximal tubulopathy, and de novo donor-specific antibodies (DSA).
Conclusions: This report highlights the phenotype of two monozygotic twins with a CRB2 homozygous mutation, characterized by early-onset nephrotic syndrome, multi-system involvement, and a challenging post-transplant course. Our findings expand the phenotypic spectrum of CRB2-related disease and underscore the complexity of managing such cases. Additionally, this report demonstrates the evolving nature of genetic testing and the potential for novel findings through timely re-analysis. The underlying mechanism linking CRB2 disruption to the phenotype remains to be determined.