Crystal-storing histiocytosis with renal Fanconi syndrome: pathological and molecular characteristics compared with classical myeloma-associated Fanconi syndrome

Background. Crystal-storing histiocytosis (CSH) is a poorly described complication of monoclonal gammopathy featuring histiocyte lysosomal storage of κ light chain (κLC) crystals. Although CSH is usually associated with systemic manifestations, renal involvement is uncommon. Methods. To investigate the molecular mechanisms implicated in κLC crystallization, we performed immunopathological and molecular studies in three patients with CSH and renal Fanconi syndrome (CSH/FS). The Vκ sequences were determined, and resulting molecular models were compared with previously reported myeloma-associated FS κLC sequences. Results. All patients presented with chronic tubulo-interstitial nephritis and renal FS with accumulation of monoclonal κLC crystals within proximal tubular cells. They showed peri-renal and interstitial infiltration by histiocytes containing eosinophilic crystalline inclusions (pseudopseudo-Gaucher cells). LC sequences were determined and assigned to their germline counterparts, in strong homology with previously reported myeloma-associated FS sequences. Comparison of CSH/FS Vκ domain 3D structures with the germline-encoded structures and those from patients with myeloma-associated FS underlined distinct hydrophobic residuesexposedtothesolventintwopatients, likely favouring the formation of a variant form of crystals that may further resist degradation after phagocytosis. Conclusion. Although CSH/FS and myeloma-associated FS are closely related disorders, peculiar mutations in the V domains of CSH/FS monoclonal κLCs, different from those in myeloma-associated FS, may account for crystal morphology, predominant accumulation within histiocytes and multiple organ involvement in CSH.