Table 2.

Nonmalignant diseases associated with monoclonal gammopathy of undetermined significance and may respond to lymphoplasmacytic cell-directed therapy

Primary organ involvedClinical presentationRole of monoclonal protein/pathophysiologyReference
Dermatologic    
 Acquired C1 inhibitor deficiency Recurrent angioedema without urticaria or pruritus Antibody to C1 esterase inhibitor 69  
 Cryoglobulinemia Acrocyanosis, purpura, cutaneous ulcer, peripheral neuropathy, arthralgia, glomerulonephritis Immunoglobulin precipitation or antibody binding to antigens causing hyperviscosity or vasculitis 70  
 Necrobiotic xanthogranuloma Yellow-orange papules/plaques with frequent ulcerations; may have proptosis and cardiopulmonary involvement Unclear 71  
 Schnitzler syndrome Chronic urticaria, fever, bone pain, IgM-MGUS Unclear 72  
Endocrinologic    
 Insulin autoimmune syndrome Episodic confusion, diaphoresis, dizziness, lethargy, palpitation, seizure Antibody to insulin causing its inactivation 73  
Hematologic    
 Acquired von Willebrand syndrome Easy bruising, mucosal bleeding; may have soft tissue bleeding due to decreased factor 8 level Antibody to von Willebrand factor causing its clearance or interference with platelet or collagen binding 74  
 Cold agglutinin disease Acrocyanosis, C3+ autoimmune hemolytic anemia, red cell agglutination, mostly IgMκ-MGUS Antibody to red cell I antigen-causing agglutination and hemolysis 75  
 TEMPI Telangiectasias, erythrocytosis, elevated erythropoietin level, MGUS, perinephric fluid collections, and intrapulmonary shunting Unclear 76  
Rheumatologic    
 Scleromyxedema Waxy papules or plaques, arthralgia, restrictive lung disease, seizure Unclear 77  
Nephrologic    
 Antiglomerular basement membrane disease Hematuria, proteinuria Antibody to glomerular basement membrane 78  
 C3 glomerulonephritis Hematuria, proteinuria Antibody to C3 convertase or complement factors B, H, or I causing C3 deposition in glomeruli 79  
 Dense deposit disease Hematuria, proteinuria Antibody to C3 convertase or complement factors B, H, or I causing C3 deposition in glomeruli 80  
 Fibrillary glomerulonephritis Hematuria, proteinuria, renal impairment, mostly IgG-MGUS Fibrillary deposition of immunoglobulin in glomeruli 81  
 Immunotactoid glomerulonephritis Hematuria, hypertension, proteinuria, renal impairment, IgG-MGUS Microtubular deposition of immunoglobulin in glomeruli 82  
 Light-chain proximal tubulopathy Aminoaciduria, hyperphosphaturia, normoglycemic glycosuria, proximal renal tubular acidosis, uricosuria, mostly κ-MGUS Direct light-chain toxicity to proximal renal tubules 83  
 Membranous nephropathy IgG3κ-MGUS Antibody to phospholipase A2 receptor 84  
 Monoclonal immunoglobulin deposition disease Hematuria, hypertension, proteinuria, renal impairment, mostly κ-MGUS Granular deposition of immunoglobulin in glomeruli 85  
 Progressive glomerulonephritis with monoclonal immunoglobulin deposits Hematuria, hypertension, proteinuria, renal impairment, mostly IgG3κ-MGUS Granular deposition of immunoglobulin in glomeruli 86  
Neurologic    
 CANOMAD Chronic ataxic neuropathy, ophthalmoplegia, IgM-MGUS, cold agglutinin, and disialosyl antibodies Antibody to disialosyl ganglioside 87  
 POEMS Polyneuropathy, organomegaly, endocrinopathy, mostly λ-MGUS, skin changes Unclear 88  
 Sensorimotor neuropathy Distal, acquired, demyelinating, symmetric neuropathy (sensory ataxia, motor involvement typically mild), IgM-MGUS Antibody to myelin-associated glycoprotein, ganglioside, or asialo-GM1 25  
 Sporadic late-onset nemaline myopathy Muscular weakness and atrophy frequently resulting in “head drop,” respiratory insufficiency, congestive heart failure Unclear 89  
Ophthalmologic    
 Corneal copper deposition Decreased visual acuity, diffuse brownish discoloration of cornea, hypercupremia, IgG-MGUS Corneal deposition of antibody with strong affinity to copper 90  
 Crystalline keratopathy Decreased visual acuity, corneal opacity, IgGκ-MGUS Corneal deposition of antibody forming a crystalline structure 91  
Other    
 Capillary leak syndrome Recurrent hypovolemic shock with generalized edema Unclear 92  
 Crystal-storing histiocytosis Mass or tissue infiltration, which may involve the bone marrow, breast, gastrointestinal tract, kidneys, lymph node, skin, or spleen Accumulation of light-chain crystals in histiocytes 93  
Primary organ involvedClinical presentationRole of monoclonal protein/pathophysiologyReference
Dermatologic    
 Acquired C1 inhibitor deficiency Recurrent angioedema without urticaria or pruritus Antibody to C1 esterase inhibitor 69  
 Cryoglobulinemia Acrocyanosis, purpura, cutaneous ulcer, peripheral neuropathy, arthralgia, glomerulonephritis Immunoglobulin precipitation or antibody binding to antigens causing hyperviscosity or vasculitis 70  
 Necrobiotic xanthogranuloma Yellow-orange papules/plaques with frequent ulcerations; may have proptosis and cardiopulmonary involvement Unclear 71  
 Schnitzler syndrome Chronic urticaria, fever, bone pain, IgM-MGUS Unclear 72  
Endocrinologic    
 Insulin autoimmune syndrome Episodic confusion, diaphoresis, dizziness, lethargy, palpitation, seizure Antibody to insulin causing its inactivation 73  
Hematologic    
 Acquired von Willebrand syndrome Easy bruising, mucosal bleeding; may have soft tissue bleeding due to decreased factor 8 level Antibody to von Willebrand factor causing its clearance or interference with platelet or collagen binding 74  
 Cold agglutinin disease Acrocyanosis, C3+ autoimmune hemolytic anemia, red cell agglutination, mostly IgMκ-MGUS Antibody to red cell I antigen-causing agglutination and hemolysis 75  
 TEMPI Telangiectasias, erythrocytosis, elevated erythropoietin level, MGUS, perinephric fluid collections, and intrapulmonary shunting Unclear 76  
Rheumatologic    
 Scleromyxedema Waxy papules or plaques, arthralgia, restrictive lung disease, seizure Unclear 77  
Nephrologic    
 Antiglomerular basement membrane disease Hematuria, proteinuria Antibody to glomerular basement membrane 78  
 C3 glomerulonephritis Hematuria, proteinuria Antibody to C3 convertase or complement factors B, H, or I causing C3 deposition in glomeruli 79  
 Dense deposit disease Hematuria, proteinuria Antibody to C3 convertase or complement factors B, H, or I causing C3 deposition in glomeruli 80  
 Fibrillary glomerulonephritis Hematuria, proteinuria, renal impairment, mostly IgG-MGUS Fibrillary deposition of immunoglobulin in glomeruli 81  
 Immunotactoid glomerulonephritis Hematuria, hypertension, proteinuria, renal impairment, IgG-MGUS Microtubular deposition of immunoglobulin in glomeruli 82  
 Light-chain proximal tubulopathy Aminoaciduria, hyperphosphaturia, normoglycemic glycosuria, proximal renal tubular acidosis, uricosuria, mostly κ-MGUS Direct light-chain toxicity to proximal renal tubules 83  
 Membranous nephropathy IgG3κ-MGUS Antibody to phospholipase A2 receptor 84  
 Monoclonal immunoglobulin deposition disease Hematuria, hypertension, proteinuria, renal impairment, mostly κ-MGUS Granular deposition of immunoglobulin in glomeruli 85  
 Progressive glomerulonephritis with monoclonal immunoglobulin deposits Hematuria, hypertension, proteinuria, renal impairment, mostly IgG3κ-MGUS Granular deposition of immunoglobulin in glomeruli 86  
Neurologic    
 CANOMAD Chronic ataxic neuropathy, ophthalmoplegia, IgM-MGUS, cold agglutinin, and disialosyl antibodies Antibody to disialosyl ganglioside 87  
 POEMS Polyneuropathy, organomegaly, endocrinopathy, mostly λ-MGUS, skin changes Unclear 88  
 Sensorimotor neuropathy Distal, acquired, demyelinating, symmetric neuropathy (sensory ataxia, motor involvement typically mild), IgM-MGUS Antibody to myelin-associated glycoprotein, ganglioside, or asialo-GM1 25  
 Sporadic late-onset nemaline myopathy Muscular weakness and atrophy frequently resulting in “head drop,” respiratory insufficiency, congestive heart failure Unclear 89  
Ophthalmologic    
 Corneal copper deposition Decreased visual acuity, diffuse brownish discoloration of cornea, hypercupremia, IgG-MGUS Corneal deposition of antibody with strong affinity to copper 90  
 Crystalline keratopathy Decreased visual acuity, corneal opacity, IgGκ-MGUS Corneal deposition of antibody forming a crystalline structure 91  
Other    
 Capillary leak syndrome Recurrent hypovolemic shock with generalized edema Unclear 92  
 Crystal-storing histiocytosis Mass or tissue infiltration, which may involve the bone marrow, breast, gastrointestinal tract, kidneys, lymph node, skin, or spleen Accumulation of light-chain crystals in histiocytes 93  
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