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 kappa light chain (kappa LC) crystals. Although CSH is usually associated with systemic manifestations, renal involvement is uncommon.


METHODS
To investigate the molecular mechanisms implicated in kappa LC crystallization, we performed immunopathological and molecular studies in three patients with CSH and renal Fanconi syndrome (CSH/FS). The V kappa sequences were determined, and resulting molecular models were compared with previously reported myeloma-associated FS kappa LC sequences.


RESULTS
All patients presented with chronic tubulo-interstitial nephritis and renal FS with accumulation of monoclonal kappa LC crystals within proximal tubular cells. They showed peri-renal and interstitial infiltration by histiocytes containing eosinophilic crystalline inclusions (pseudo-pseudo-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 V kappa domain 3D structures with the germline-encoded structures and those from patients with myeloma-associated FS underlined distinct hydrophobic residues exposed to the solvent in two patients, likely favouring the formation of a variant form of crystals that may further resist degradation after phagocytosis.


CONCLUSIONS
Although CSH/FS and myeloma-associated FS are closely related disorders, peculiar mutations in the V domains of CSH/FS monoclonal kappa LCs, different from those in myeloma-associated FS, may account for crystal morphology, predominant accumulation within histiocytes and multiple organ involvement in CSH.
El Hamel
Chahrazed
C
Université de Limoges, Centre National de la Recherche Scientifique (CNRS) UMR 6101, CHU Limoges, France.
Thierry
Antoine
A
Trouillas
Patrick
P
Bridoux
Frank
F
Carrion
Claire
C
Quellard
Nathalie
N
Goujon
Jean-Michel
JM
Aldigier
Jean-Claude
JC
Gombert
Jean-Marc
JM
Cogné
Michel
M
Touchard
Guy
G
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D003460:Crystallization; D005198:Fanconi Syndrome / Q000145:classification / Q000209:etiology / Q000473:pathology*; D005260:Female; D015614:Histiocytosis / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry* / Q000235:genetics; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D017386:Sequence Homology, Amino Acid
D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains