Expanded CRB2-related disease phenotype: multisystem involvement and post-transplant complications in monozygotic twins.

backgroundCongenital nephrotic syndrome (CNS) is a rare disorder caused by mutations in genes essential for podocyte function and glomerular slit diaphragm integrity, including CRB2 (Crumbs Cell Polarity Complex Component 2). CRB2 mutations are linked to focal segmental glomerulosclerosis and ventriculomegaly with cystic kidney disease, but their full phenotypic spectrum remains unclear. We describe the clinical course of monozygotic twins with a homozygous CRB2 mutation, highlighting severe complications following kidney transplantation.

methodsThe twins, who were followed and managed throughout their clinical course, were diagnosed with CNS after prenatal suspicion of polycystic kidney disease. Initial exome sequencing was negative, but subsequent whole exome sequencing revealed a homozygous CRB2 variant.

resultsBoth twins presented with CNS, requiring intensive supportive care. Additional findings included cerebral heterotopia, cardiac involvement, and developmental delay. They both progressed to kidney failure, necessitating hemodialysis in early childhood. Post-transplant, the first twin succumbed to a systemic fungal infection, while the second developed complications linked to immune dysregulation, including post-transplant lymphoproliferative disease (PTLD), immune thrombocytopenic purpura (ITP), multiple viremias, and de novo donor-specific antibodies (DSA).

conclusionsThis case expands the phenotypic spectrum of CRB2-related disease, highlights management challenges, and underscores the need for genetic re-analysis in rare diseases. Further research is required to understand CRB2-related mechanisms.