Search

Heavy chain deposition disease (HCDD) is characterized by the deposition of truncated monoclonal immunoglobulin heavy chains along glomerular basement membranes. Truncated heavy chains are thought to be associated with plasma cell disease (PCD), but previous bone marrow cytology tests showed that only 30% of HCDD cases are related to PCDs. We report the first known use of immunoglobulin heavy chain (IGH) gene rearrangement to diagnose a patient with γ3-HCDD, although bone marrow morphology test identified no abnormalities. Our findings provide strong evidence for a correlation between PCDs and HCDD, which could help understand the genetic background underlying abnormal heavy chains and assess disease prognosis. Further, concordant with previous findings, bortezomib-based chemotherapy had a good therapeutic effect in our patient. We summarize the experience of diagnosing and treating a case of HCDD, and combine this with a literature review to further explore the correlation between PCDs and HCDD, which has important clinical value.

Background: Gamma heavy chain disease (γ-HCD) is a monoclonal gammopathy defined by an abnormal clonal and isolated production of incomplete heavy chain gamma (γ), unable to bind with light chains kappa or lambda. This disease is rare and remains poorly described. Its association to lymphoid neoplasm is well established, but exceptional forms of γ-HCD may also accompany auto-immune diseases. We report here a new case of γ-HCD characterized by an indolent course with a 4-year follow-up, and its association with quiescent rheumatoid arthritis (RA)., Case Presentation: We report the case of a 85-year old French white man followed for quiescent anti-CCP+ rheumatoid arthritis treated by prednisolone 4 mg/day and hydroxychloroquine 200 mg/day since 10 years, and a monoclonal gammopathy of undetermined significance for 6 years, who was hospitalized for costal fractures after a fall. Serum protein electrophoresis showed a stable small monoclonal peak, and capillary electrophoresis/immunosubtraction technique identified an isolated clonal γ-heavy chain (HC). Bone marrow aspiration was normal and he had no other lymphoproliferation. The monoclonal peak remained stable after 4 years of follow-up., Conclusions: In case of monoclonal peak without complete monoclonal Ig on serum protein electrophoresis, the diagnosis of γ-HCD should be discussed and capillary electrophoresis/immune-subtraction is a mean to detect isolated monoclonal heavy chain (HC). Gamma-HC disease is rare, may be associated to RA, and may have an indolent course.

Heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. Gamma HCD is a subgroup of HCD. A 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema. Based on the results of heart catheterisation, he was diagnosed with pulmonary hypertension. Laboratory tests revealed an elevated level of IgG, and serum immunoelectrophoresis showed that IgG was a monoclonal gamma heavy chain without light chains. Finally, he was diagnosed with gamma HCD complicated by pulmonary hypertension. Bortezomib and dexamethasone therapy was initiated, but became refractory within 8 months. Therefore, the treatment was switched to lenalidomide and dexamethasone therapy, and the disease has been stably controlled for more than 2 years. To the best of our knowledge, this is the first case of gamma HCD being successfully treated by lenalidomide and dexamethasone therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Heavy chain disorders are rare B-cell disorders and include heavy chain disease, heavy chain deposition disease, and heavy chain amyloidosis. These disorders share the pathognomonic finding of a truncated immunoglobulin heavy chain without an associated light chain in the serum or urine in the case of heavy chain disease or in the tissues in the case of heavy chain deposition disease and heavy chain amyloidosis but are clinically distinct entities. The clinical recognition and systematic approaches to these disorders are challenging because of the rarity of the diseases, lack of consensus on treatment approaches, and minimal data with novel therapy. Herein we present a review of the literature and 5 consecutive cases at a single institution of gamma heavy chain disease and heavy chain deposition disease treated with novel agents including regimens of CRd (cyclophosphamide, lenalidomide, and dexamethasone), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), R-CVP (rituximab, cyclophosphamide, vincristine, and dexamethasone), BR (bendamustine and rituximab), V-EPOCH (bortezomib, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), and autologous hematopoietic stem cell transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale & Objective: Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China., Study Design: Case series., Setting & Participants: 25 patients with biopsy-proven HCDD were studied retrospectively., Results: 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3 was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (γ1, 13; γ2, 2; γ3, 6; γ4, 2; γ1 and γ4, 1; and γ2 and γ4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy., Limitations: Retrospective study, single-center experience., Conclusions: In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Heavy-chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy-chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1-HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage., (© 2018 Japanese Dermatological Association.)

Background: Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the non-amyloid deposition of monoclonal immunoglobulin fragments in the basement membranes. Heavy chain deposition disease (HCDD) is a type of MIDD. HCDD is an extremely rare disease, and only three cases have been reported in Japan up to the present. The prognosis of HCDD is very poor, and optimal treatment has not been established. Only a few cases of HCDD with favorable long-term renal prognosis have been reported to date., Case Presentation: The authors describe a 61-year-old woman who presented with massive proteinuria, progressive kidney impairment, and hypocomplementemia. Kidney biopsy was performed for a precise diagnosis. On light microscopy, glomerules were lobulated and presented with nodular sclerosing glomerulopathy with membranoproliferative glomerulonephritis-like features. Immunofluorescence studies were positive for IgG, C3, and C1q within the mesangial nodules and in a linear distribution along the capillary walls without associated deposition of light chains. Staining for IgG showed the presence of linear deposits along tubular basement membranes. The analysis of the IgG subclass stain demonstrated intense positivity for IgG3 only. Electron microscopy revealed non-organized electron-dense deposits in the expanded mesangial area and inner aspect of the glomerular basement membranes. In accordance with the histological findings, we diagnosed γ3-HCDD. There was no evidence of plasma cell dyscrasia as a result of bone marrow aspiration. Serum and urine monoclonal proteins were not detected by immunoelectrophoresis and immunofixation electrophoresis. The serum free light chain ratio was within normal range. At first, prednisolone was administrated at a dose of 40 mg/day. However, a therapeutic effect was not observed. Urinary protein was not decreased and renal function further deteriorated. Therefore, melphalan plus prednisolone (MP) therapy was initiated. After 4 courses of MP therapy, the clinical parameters, including proteinuria, serum creatinine, albumin, and complement level (C3 and C4) were ameliorated. To date, the patient has been followed for 28 months, and long-term renal survival has been observed., Conclusions: In this case, hematologic disease such as multiple myeloma was not detected; however, MP therapy was effective. Recently, the novel concept of monoclonal gammopathy of renal significance (MGRS) has been reported. MIDD, which includes HCDD, is one category of MGRS. In MGRS, aggressive chemotherapy may induce favorable renal outcomes.

Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of γ-heavy chain in 12 patients or α-heavy chain in 3 patients, without concurrent light chain staining. Only 2 patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15 patients. Serum-free kappa to lambda light chain ratio was abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11 patients. All patients received chemotherapy, including bortezomib in 10 cases. Renal parameters improved in 11 patients who achieved a hematological response, as assessed by normalization of the free light chain ratio in 8 cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective and Importance: Gamma heavy chain diseases (γHCD) and large granular lymphocyte (LGL) leukemia are two rare lymphoproliferative diseases, respectively with B and T phenotype. Both γHCD and LGL leukemia share some similar clinical features, such as cytopenias, splenomegaly, and recurrent infections. Association of these two diseases is exceptional and suggest pathogenic link. We report two cases of γHCD associated with T-LGL leukemia., Clinical Presentation: Patient 1 was a 70-year-old woman, with lymphoplasmacytic lymphoma, refractory to chlorambucil-rituximab treatment. She developed during the follow up a γHCD with T-LGL leukemia, unresponsive to melphalan, thalidomide, and steroids, requiring supportive care. Patient 2 was a 40-year-old man with chronic severe asymptomatic neutropenia, revealing both γHCD and T-LGL leukemia. He is still well without any treatment nor complications, with 7 years follow up., Conclusion: Several types of B lymphoproliferative disease are associated with LGL leukemia. Although exceptional, this association of two rare lymphoproliferative disorders, with a different phenotype, does not seem fortuitous.

Monoclonal immunoglobulin deposition disease is rare in medical practice. The light and heavy chain deposition disease is characterized by deposition of monoclonal antibodies in the basement of membrane. Kidney is the most frequently involved organ. There was a male patient diagnosed as light and heavy chain deposition disease in department of Nephrology of the Second Xiangya Hospital, Central South University by renal biopsy. After treatment by oral prednisone, melphalan and thalidomide, the patient's proteinuria and serum creatinine decreased. The retrospective analysis of this case provides a guide for doctors to understand the light and heavy chain deposition disease. Early diagnosis and treatment could improve the prognosis.

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin κ locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomib-based treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology., (© 2015 by The American Society of Hematology.)

Extranodal Marginal zone lymphoma (EMZL) is a rare, usually localized disease in children. Advanced stage EMZL in adults is considered incurable, with prolonged remissions after chemotherapy. Gamma heavy chain disease (γHCD) is a rare disease of adults associated with lympho-proliferative processes with no comparable reports in children. A case of stage-IV EMZL with γHCD in an adolescent is discussed including treatment with Bendamustine plus Rituximab. The patient remains disease free 18 months from diagnosis. This case highlights necessity for careful diagnostic work-up to identify indolent lymphomas in children which may respond to less toxic chemotherapy than used for common pediatric lymphomas., (© 2015 Wiley Periodicals, Inc.)

Heavy-chain deposition disease (HCDD) is a rare complication of plasma cell dyscrasia in which monoclonal heavy chains deposit in glomerular and tubular basement membranes of the kidney. Clinical and pathologic features of HCDD have been well described in case reports and series, but evidence supporting specific therapies is sparse. Historically, the disease has had a poor prognosis, intensifying the need to clarify optimal treatments. We describe 3 cases of HCDD with biopsy-proven glomerular involvement, severe nephrotic syndrome, and decline in kidney function that were treated successfully with bortezomib, a proteasome inhibitor. None of these patients had multiple myeloma. In all cases, bortezomib-based therapy resulted in sustained resolution of nephrotic syndrome and improvement in kidney function. All 3 patients developed peripheral neuropathy; otherwise, treatment was well tolerated. To our knowledge, this is the first description of the clinical effectiveness of bortezomib against HCDD., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Heavy chain deposition disease (HCDD) is characterized by glomerular and tubular deposition of non-amyloidotic monoclonal heavy chains without associated light chains. We describe a case of gamma1-HCDD who presented with nephrotic syndrome, microhematuria, and hypocomplementemia. Renal biopsy showed lobular and nodular glomerulosclerosis along with IgG and C3 deposition. Electron microscopy revealed electron-dense deposits on the glomerular and tubular basement membranes and mesangium. Congo red staining was negative. Staining was positive for IgG1 on glomerular and tubular basement membranes but negative for IgG2-4, kappa and lambda light chains. Staining for the constant heavy chain domains showed the deletion of the first constant heavy chain domain. Thus, we diagnosed gamma1-HCDD. She was considered to be early-stage HCDD because proteinuria and hematuria were not observed before the nephrotic syndrome onset. Melphalan and prednisolone (MP) therapy reduced proteinuria as well as improved renal function and complement levels. Although renal prognosis of HCDD is poor, aggressive chemotherapy with MP may be effective in early-stage HCDD patients.

Heavy-chain deposition disease (HCDD) is a rare entity accompanying to nonamyloidotic monoclonal immunoglobulin deposition disease. We report a case of gamma3-HCDD in which follow-up biopsy could be done after complete remission was achieved by chemotherapy. Follow-up biopsy 2 years after initial biopsy showed remarkable diminution of both nodular glomerular lesions and IgG heavy-chain deposits. This is the first case report to indicate that the original structure of glomeruli in patients with HCDD could be restored within a few years by an appropriate treatment at an early stage of the disease.

A 53-year-old man with nephrotic syndrome and severe renal failure was diagnosed with light- and heavy-chain deposition disease (LHCDD) by renal biopsy. The patient had no monoclonal protein and mild marrow plasmacytosis (6%), but marrow plasma cells expressed CD19(-)CD56+ and predominant monoclonal kappa-chain, indicating plasma cell dyscrasia. Conventional chemotherapy was ineffective and did not improve renal failure. High dose chemotherapy/peripheral blood stem cell transplantation (HDC/PBSCT) was introduced even after hemodialysis to eliminate aberrant clone and normalization of bone marrow cell surface markers. Immunophenotypic analysis of marrow cells facilitates clinical decision making regarding the use of HDC/PBSCT for LHCDD patients without monoclonal protein.

We report a case of light and heavy chain deposition disease (LHCDD), a rather rare monoclonal immunoglobulin deposition disease (MIDD) with successful therapeutic effect. A 58-year-old woman suffered from proteinuria and renal insufficiency (serum creatinine 1.0 mg/dl, creatinine clearance 49.2 ml/min) in February 2003. In serum and urine samples, monoclonal IgG-kappa was detected. A bone marrow aspiration showed a slightly hypocellular marrow and plasma cell population was increased to 7.0%. Renal histological findings revealed lobulated glomeruli with nodular lesions on light microscopy, characteristic findings of MIDD. Intense deposition of IgG heavy chains in the linear pattern in the glomerular and tubular basement membranes was observed. Immunohistochemistry revealed both kappa and lambda light chain depositions in glomeruli. Electron-microscopic examination revealed fine granular electron-dense deposits accompanied by microfibrils. Based on these findings, this patient was diagnosed as LHCDD. She received three courses of melphalan and prednisone chemotherapy, resulting in disappearance of proteinuria, prevention of renal functional deterioration and the decrease of monoclonal immunoglobulin. This case clearly demonstrates that the earlier and accurate diagnosis and initiation of chemotherapy at the early stage with serum creatinine level below 4.0 mg/dl are necessary to improve renal and patient outcome.

Heavy chain diseases (HCDs) are rare B-cell lymphoplasma-cell proliferative disorders characterized by production of truncated monoclonal immunoglobulin heavy chains without associated light chains. HCDs involving the three main immunoglobulin classes have been described; alpha-HCD is the most common and has the most uniform presentation, gamma- and mu-HCDs have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma: alpha-HCD presents as an extranodal marginal-zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD as lymphoplasmacytoid non-Hodgkin lymphoma, and mu-HCD as small lymphocytic non-Hodgkin lymphoma or chronic lymphocytic leukemia. Diagnosis of HCD requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine. Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.

Heavy chain diseases (HCD) are monoclonal lymphoproliferative disorders of B-cells characterized by the synthesis of truncated heavy chains without associated light chains. In patients with mu-HCD, which is a very rare form of HCD, neoplastic cells produce immunoglobulin M heavy chain. The prognosis for patients with mu-HCD is poor, and there is no specific treatment for mu-HCD. In this report, we present a patient with mu-HCD accompanied by splenomegaly and thrombocytopenia. We treated this patient with the fludarabine monophosphate therapy we use for patients with B-cell chronic lymphocytic leukemia. After 5 courses of fludarabine monophosphate treatment, the splenomegaly and thrombocytopenia improved. Fludarabine monophosphate therapy may be a new strategy to improve the prognosis of patients with mu-HCD.

The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomeruli with the deposition of immunoglobulin gamma3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of gamma-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of gamma-heavy-chain deposition disease (gamma-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring gamma3-heavy-chain deposition who showed severe hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with hypocomplementemia. The authors also discuss here the relationship of HCDD to hypocomplementemia.

In 1990 and 1992, in previous reviews of the literature and in reports of their experience with both amyloid and non-amyloid monoclonal immunoglobulin deposition diseases, the authors proposed a classification scheme encompassing all the forms of non-antibody-mediated monoclonal immunoglobulin deposition. The premise underlying the proposal was that the mode of pathogenesis of each of the various disorders is similar. Monoclonal expansion of a B-cell and plasma-cell population producing an excess immunoglobulin polypeptide with structural characteristics predisposing to tissue deposition in either the fibrillar or nonfibrillar state would be associated with organ-compromising deposits in tissue. At that time it appeared that LCDD and LHCDD were more likely to occur in the course of myeloma in which the other features of the neoplastic cells (i.e., marrow suppression, lytic lesions, recurrent infections) were also clearly evident. At this time, the authors' additional experience suggests that this judgment may have been premature, based in part on too small an initial sample and in part on the use of diagnostic criteria for multiple myeloma that may have not been sufficiently precise. The authors now believe that the nodular glomerulopathic form of NAMIDD is similar in both course and prognosis to AL amyloidosis occurring in the absence of multiple myeloma (primary amyloidosis). The primarily tubular basement-membrane form of the disease usually seen with concurrent myeloma kidney with BJCN, is associated with more aggressively proliferative plasma-cell neoplasms. The authors believe that these associations relate to the size of the malignant clone which, in turn, determines the amount of depositionogenic protein available and the rate of its presentation to the target organ (primarily the kidney). The distinction is not trivial, for if the authors are correct, their data suggest that not all forms of renal disease occurring in the course of plasma-cell dyscrasias have the same bleak prognosis. The outlook for nodular glomerular disease, as an indirect marker of clone size, may be intrinsically better than that of a renal biopsy showing cast nephropathy and tubular basement membrane LCDD deposits and clinical renal failure. Since 1992, it has also become less certain that there are general structural differences between light chains forming amyloid and those producing non-Congophilic tissue deposits. The current data suggest that light-chain proteins with the capacity to form pathogenic tissue deposits may exist in a spectrum, with one end represented by those only capable of forming amylord, the other by those depositing in a more amorphous, nonfibrillar manner, and a group in the center capable of either or both, depending on circumstances that are presently not understood. An alternative view suggests that all or most proteins depositing as fibrils pass through a non-Congophilic, nonfibrillar phase, of a length varying according to their primary structure, which is not detected in vivo because of the vagaries imposed by clinical sampling. More structural analyses of material extracted from deposits in tissue may resolve this issue.

We report here for the first time a patient with mu heavy-chain disease (HCD), hyperimmunoglobulinemia, and a positive direct antiglobulin test (DAT, Coombs test). The heavy-chain diseases involve the proliferation of lymphoplasma cells of B cell origin and are characterized by the production of incomplete heavy chains devoid of light chains. The association of mu heavy-chain disease with either hyperglobulinemia or a positive DAT has not been reported in the literature to date. In this patient, immunofixation of serum proteins with monospecific antisera to alpha-, gamma-, mu,- or delta-chains and to kappa- and lambda-chains revealed a precipitation band with antibody to IgM, but not with kappa and lambda light-chain antibodies, indicating mu heavy-chain disease. Hyperglobulinemia was present, which is very uncommon for HCD. A DAT of the patient's red blood cells (RBC) was found to be strongly positive for anti-IgG but negative for anti-IgM, -IgA, -C3c, and -C3d. However, when the eluate from the patient's red blood cells was investigated with nephelometry, it was found to contain antigens reactive with anti-y as well with anti-mu-antiserum. When a DAT was performed with a randomly chosen test cell incubated with the eluate, the antibody-containing eluate was shown to react with anti-IgG as well as with anti-IgM-antiserum. In summary, the eluate from the patient's RBCs contained IgG and an immunoglobulin structure reactive with anti-IgM in an RBC agglutination assay as well as with anti-mu antiserum in a nephelometric investigation. Whether this IgM on the patient's erythrocytes is penta- or oligomeric, complete IgM, or the heavy chain cannot be concluded from these observations.

A 79-year-old man with marked hepatosplenomegaly and lymphadenopathy was admitted to the hospital. Analysis of serum protein resulted in the diagnosis of gamma-chain disease (total protein 6.2 g/dl, M-protein positive, IgG 4150 mg/dl, IgG-Fc fragment positive). Specimens obtained by lymph node biopsies showed infiltration of plasmacytoid cells, which were stained with anti-IgG but not with anti-kappa or anti-lambda antibodies. The patient was given combination chemotherapy, but without effect. Then a regimen of long-term administration of low-dose etoposide was begun, and resulted in remission of the lymphadenopathy, hepatosplenomegaly, and abnormal IgG.

We describe a case of gamma-heavy chain disease presenting with lymphadenopathy, splenomegaly, lytic lesions and bone marrow infiltration. Chemotherapy with epirubicin, chlorambucil and prednisolone produced a partial remission which lasted 5 months. The patient was then treated with fludarabine. After six courses of fludarabine a good partial remission was achieved which converted to complete remission with disappearance of the monoclonal IgG3 in the ensuing 12 months without further therapy. This response has, so far, been sustained for 2 1/2 years after stopping treatment.

Intestinal flora was explored in twelve patients affected with alpha-chain disease at different stages (stage A: 2 cases; stage B: 6 cases; stage C: 4 cases). Bacterial overgrowth in the jejunum was observed in 11 cases, but intestinal flora was diverse and no one species was always present; although a 3-month oral antibiotic treatment induced complete remission in one patient (stage A) it was not possible to demonstrate any pathogenic bacterial species. Intestinal lambliasis was present in 40 p. 100 of cases. Virologic studies were negative. At stages A and B of the disease, antibiotic treatment was able to improve malabsorption and/or plasma protein digestive losses in 62 p. 100 of cases; this effect seemed related to the reduction of the bacterial flora and to giardiasis eradication.

Two patients with alpha heavy chain disease are described. In the first patient, treatment with cyclophosphamide, prednisone and doxycycline was associated with a 28 month-long remission and the disappearance of the paraprotein and lymphoplasmocytic infiltration of the intestine. Shortly afterwards, a retroperitoneal immunoblastic lymphoma was found associated with an immunoglobulin G-kappa-paraproteinemia, and gamma heavy and kappa-light chains in the urine; the intestinal biopsy specimen was normal. In the other patient, the alpha chain only appeared two years after the malabsorption syndrome. The fact that in the first, apparently cured patient, a tumor of different anatomic site and secretory capacity appeared, suggests the existence of a B-cell neoplasia of different clone from that which gave rise tothe original disease. In the second patient, it is probable that only the increase in the mass of neoplastic cells led to the detection of the protein abnormality, or alternatively the antigenic-oncogenic stimulus led to the abnormal secretion only after two years.

A case of alpha-chain disease is presented. Diagnosis was clinched by the discovery of typical heavy alpha-chains on analysis of serum proteins. The clinical picture included non-gluten-dependent semi-coeliac malabsorption, Hippocratic fingers, flattened villi, plasma cell infiltration of the jejunal mucosa, alpha- and beta-globulin dysprotidaemia, and abdominal masses; these signs are indicative of, but not conclusive evidence of alpha-chain disease. The presence of Coccidioides organules in the mucosa and glandular tuberculosis rises aetiopathogenetic questions that suggest that due attention be given to microbiological examination. Rapid progression to neoplasia following immunodepressive management underscores the risks associated with the administration of immunodepressors in patients with immunitary deficiencies. It is still not clear whether alpha-chain disease should be regarded as a self-perpetuating immunoproliferative disease, or as a form neoplasia ab initio, with a protracted, though of inevitably fatal, course.

Description of a case presenting as an inflammatory polyarthritis. A uterine sarcoma was detected one year later and led to the death of the patient. The abnormal protein belonged to the gammal subclass. Biosynthesis experiments, performed on the marrow plasma cells, showed that light chains were not produced and that the molecular weight of the monomeric unit of the serum protein was slightly smaller than that of the protein secreted in vitro, suggesting the occurrence of a secondary and limited extracellular proteolysis.

A patient, CAL, with gamma heavy chain disease is presented who has had a complete remission lasting over 2 yr with combination chemotherapy consisting of pulsatile cyclophosphamide and prednisone. The patient exhibited many features of an atuoimmune process including a vasculitis, low serum complement levels, a positive antiglobulin (Coombs) test, Raynaud's phenomenon, and keratoconjunctivitis sicca. The CAL paraprotein was found to have several previously undescribed characteristics. It reacted with antisera to Fd, Fab, and Fab', suggesting that most of the Fd portion of the molecule was intace. CAL protein consists of two polypeptide chains of molecular weight 49,000 covalently linked to form a dimer of 95,000 molecular weight. The covalent linkage suggests that the hinge region of this gamma heavy chain is intact.

A 40-year-old man born in Bangladesh developed alpha heavy chain disease whilst a resident in the United Kingdom. An incomplete, low molecular weight alpha heavy chain protein, devoid of light chains was demonstrated in his serum. Clinical remission of his disease was achieved by antibiotics alone.

About one hundred cases of alpha-chain disease have been reported to date from various Mediterranean and Middle-Eastern countries. We report eleven Iranian patients with primary lymphoma of the duodenum and upper small intestine and positive alpha-chain protein in their sera. The clinical, laboratory and pathological findings in these patients are discussed. The initial favourable response of some of these patients to antibiotic treatment is noted. It is concluded that the optimal treatment of alpha-chain disease is not yet well established, and the clinical improvement might not coincide with histological and immunological remission.

Clinical, immunological, and histological recovery in a patient with alpha-chain disease is described. The patient, a 27-year-old Greek man, presented with severe steatorrhoea, abdominal pain, oedema, and hypogammaglobulinaemia. Treatment with tetracycline produced only temporary remission. Intermittent therapy with prednisone and cyclophosphamide together with antibiotics was followed by clinical recovery, return of histological appearances of the small intestine to normal, and disappearance of free alpha-chain protein from the serum. The patient remained well one year later without treatment.