Pathophysiologic classification of the main monoclonal gammopathy of clinical significance-related disorders

	Monoclonal immunoglobulin deposits	Main characteristics of monoclonal gammopathy	Main involved organ(s)
Immunoglobulin deposition in tissue*
AL amyloidosis	Fibrillar	Lambda LC (75%), kappa LC (25%), IgM (<10%)	Systemic Heart (80%), kidney (70%)
Type I cryoglobulinemia	Microtubular/crystalline	IgG or IgM	Systemic Skin +++, kidney, peripheral nerve, systemic symptoms (crystal-cryoglobulin)
Immunotactoid glomerulopathy/GOMMID	Microtubular	CLL-like clonal B cell proliferation (50%)	Kidney
Acquired Fanconi syndrome	Crystalline	Kappa LC (>90%, mostly Vk1)	Kidney (proximal tubulopathy)
Crystal storing histiocytosis	Crystalline	Kappa LC	Systemic (kidney, cornea, joints, lymphoid tissue)
Crystalline keratopathy	Crystalline	IgG	Cornea
Monoclonal immunoglobulin deposition disease (MIDD)	Non-organized	LCDD: LC only Usually kappa LC (80%, Vk1 and Vk4) HCDD: truncated HC only Mostly gamma (gamma-1 and gamma-3), alpha, delta LHCDD: LC plus truncated HC	Systemic Kidney (approximately 100%, glomerular and tubular basement membrane), liver (30%), heart (30%)
Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)	Non-organized	Usually IgG3	Kidney
Macroglobulinosis	Non-organized	IgM	Skin (dermis)
Autoantibody activity
Type II mixed cryoglobulinemia^¶	Rheumatoid	IgM	Immune complex-mediated vasculitis Skin +++, kidney, peripheral nerve May be systemic
C1 inhibitor deficiency	C1 inhibitor		Angioedema
Von Willebrand (vW) disease	vW factor		Bleeding
Bullous skin diseases	Dermo-epidermal junction (collagen VII)		Skin
Xanthomatosis	Various lipoproteins	Usually IgG	Cholesterol accumulation in macrophages Skin and tendons Other localizations (necrobiotic xanthogranumathosis)
Cold agglutinin disease	Red blood cell (Ii)	IgM	Cold-induced skin manifestations plus intravascular hemolysis
IgM associated peripheral neuropathy	Myelin associated glycoprotein (MAG) +++ Gangliosides	IgM	Peripheral nerve Ataxic polyneuropathy (anti-MAG) CANOMAD
CAP^¶ activation
C3 glomerulonephritis	Mechanism to be determined Autoantibody activity against CAP regulator protein (factor H) in some cases	IgG	Kidney only
Atypical hemolytic-uremic syndrome (HUS)	Mechanism to be determined Autoantibody activity against CAP regulator protein (factor H) in some cases	IgG	Systemic
Cytokine-mediated
POEMS syndrome	Vascular endothelial growth factor	Lambda LC (approximately 100%) IgA (50%) V-gamma-1 (100%) Osteosclerotic bone lesions	Peripheral nerve (100%) Various other manifestations
Unknown mechanism
Systemic capillary leak syndrome		IgG, IgA (rare)	Systemic
TEMPI syndrome		IgG	Systemic
Neutrophilic dermatosis^Δ		IgA (>80%; except Sweet's syndrome)	Skin +++ Different types and different associated manifestations
Acquired cutis laxa		Usually IgG Association with gamma HCDD	Skin +++ Other manifestations (lung, digestive tract)
Scleromyxedema		IgG with slow electrophoretic mobility	Skin +++ Other localizations
Scleredema		IgG	Skin only
Schnitzler's syndrome	Acquired auto-inflammatory syndrome by IL-1 deregulation?	IgM	Skin +++ Systemic symptoms Osteosclerotic bone lesions
Sporadic late onset nemaline myopathy (SLONM)			Exclusively muscles (skeletal and possibly cardiac)

MGCS: monoclonal gammopathy of clinical significance; AL amyloidosis: immunoglobulin light chain amyloidosis; LC: light chain; IgM: immunoglobulin M; IgG: immunoglobulin G; GOMMID: glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits; CLL: chronic lymphocytic leukemia; LCDD: light chain deposition disease; HCDD: heavy chain deposition disease; HC: heavy chain; LHCDD: light and heavy chain deposition disease; CANOMAD: Chronic Ataxic Neuropathy, Ophthalmoplegia, Monoclonal IgM protein, cold Agglutinins, and Disialosyl antibodies; CAP: complement alternative pathway; POEMS: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes; IgA: immunoglobulin A; TEMPI: Telangiectasias, Erythrocytosis with elevated erythropoietin level, Monoclonal gammopathy, Perinephric fluid collection, and Intrapulmonary shunting; IL-1: interleukin 1.
* AL amyloidosis is the most frequent type with an incidence of about 10/million inhabitants/per year in Western countries. MIDD incidence is estimated to be 10-fold lower. Other types of MGCS due to deposition of monoclonal Ig are rare (type I cryoglobulinemia, PGNMID), even scarcer (Fanconi syndrome) or exceptional (macroglobulinosis, crystalline keratopathy).
¶ A type II mixed cryoglobulinemia was observed in about 10% of patients with chronic virus C infection.
Δ Including pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, and erythema elevatum diutinum.

Republished with permission of the American Society of Hematology, from: Fermand JP, Bridoux F, Dispenzieri A, et al. Monoclonal gammopathy of clinical significance: A novel concept with therapeutic implications. Blood 2018; permission conveyed through Copyright Clearance Center, Inc. Copyright © 2018.

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Pathophysiologic classification of the main monoclonal gammopathy of clinical significance-related disorders