Fanconi's syndrome induced by a monoclonal Vκ3 light chain in Waldenström's macroglobulinemia

Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal κ LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal κ LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vκ1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenström's macroglobulinemia and full-blown FS with accumulation of a monoclonal κ LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vκ3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS κI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of κ LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.