Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature

Abstract

Crystal-storing histiocytosis (CSH) is a rare event in disorders associated with monoclonal gammopathy. The intracellular crystal formation is almost always accompanied by the expression of κ light chains. However, the exact mechanism for the storage has not been clarified until now. We report a case of generalized CSH in a 73-year-old man who presented with IgA κ paraproteinemia and paraproteinuria. The initially observed CSH in the bone marrow biopsy was associated with the clinical and pathomorphologic features of a monoclonal gammopathy of undetermined significance. The progression of disease could not be affected by steroid therapy and the patient died of septic shock 7 months after detection of CSH. At the time of autopsy there was evidence for multiple myeloma and generalized CSH. Two-dimensional gel electrophoresis of liver tissue combined with immunoblotting revealed the massive storage of heavy chains of α type and light chains of κ type, each in a monoclonal pattern. Analysis of the stored κ light chain by nanoelectrospray-ionization mass spectrometry indicated that it belongs to the variable κI variability subgroup. We identified some unusual amino acid substitutions including Leu59, usually important for hydrophobic interactions within a protein, at a position where it has never been previously described in plasma cell disorders. In conclusion, we present the first case of CSH with molecular identification of the stored κ subgroup and detection of unusual amino acid substitutions. Our results suggest that conformational alterations induced by amino acid exchanges represent a crucial pathogenic factor in CSH.