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Monoclonal immunoglobulin deposition diseases (MIDDs), including light and heavy chain deposition disease (LHCDD), are rare and heterogeneous disorders associated with underlying B-cell clonal disorders. Adrenal involvement is a potential extrarenal manifestation of MIDDs; however, limited data are available regarding its prevalence and clinical presentation. Herein, the present report describes, for the first time, a case of primary adrenal insufficiency that developed twenty-two years after a diagnosis of LHCDD had been made. A 69 year-old woman with a 10 year history of hemodialysis suddenly became bedridden after falling down stairs in the absence of focal neurological deficits. Subsequently, she experienced appetite loss, nausea, vomiting, a fever of unknown origin, and unexplained hypotension. Several months later, primary adrenal insufficiency and normal pressure hydrocephalus were diagnosed and successfully managed. The long-term clinical prognosis of MIDDs has not been fully elucidated despite recent advances in the management of the disorders. This report may contribute to improving our understanding of the disease course., Competing Interests: Declarations. Conflict of interest: The author has declared that no Conflict of interest exists. Informed consent: Informed consent was obtained from the patient included in the study., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the deposition of nonamyloid monoclonal immunoglobulin and its free fragment light chain and/or heavy chain in systemic tissues and organs, and the kidney is most vulnerable organs. MIDD can be divided into three types: light-chain deposition disease (LCDD), light and heavy chain deposition disease (LHCDD), and heavy-chain deposition disease (HCDD), of which LHCDD and HCDD are rarer (Bridoux et al. in Kidney Int 2015;87:698-711; Preud'homme et al. in Kidney Int 1994;46:965-72). Poor outcome in most HCDD, but in this paper, we will report a case of HCDD with good long-term renal survival and review the literature for reference., Case Presentation: A 32-year-old man presented to our department with skin laxity and nephritic syndrome, accompanied by an significant increase of serum creatinine and received short-term hemodialysis treatment. Both the blood and urine free light chain ratio increased significantly. Renal biopsy showed mesangial nodular glomerulosclerosis on light microscopy, and immunofluorescence staining showed positivity for γ-heavy chain (HC), with negative light chain (LC) staining; the diagnosis was considered HCDD. After six courses of bortezomib combined with dexamethasone chemotherapy and thalidomide 100 mg/day, the renal function gradually recovered, while also with proteinuria and hematuria significantly improved. The blood and urine free light chain ratio decreased to normal. Until now, the patient has been followed for four years, and long-term renal survival has been observed., Conclusion: Herein, we report a case presenting with proteinuria, hematuria, renal impairment, and skin laxity, and a renal biopsy showed linear IgG deposition in the glomerular basement membranes and tubular basement membrane. However, they ultimately proved to have HCDD. Bortezomib combined with dexamethasone, and oral thalidomide led to a good long-term renal survival. We also provide a review of currently available literature, and this is the first large-scale review summarizing the characteristics of HCDD up to date., (© 2024. The Author(s).)

Gamma heavy chain disease (gHCD) is a rare B-cell lymphoproliferative disorder that mostly occurs after childbearing age. Here we report the first case of gHCD in a pregnant patient that was diagnosed in the second trimester, and another pregnancy in the same patient after initial treatment for gHCD. The former pregnancy ended in intrauterine fetal death, believed to be caused by insufficient maternal blood flow due to multiple placental infarcts. The latter pregnancy course was uneventful. Although we cannot rule out the possibility that the poor outcome of the former pregnancy was due to an unfortunate complication independent of gHCD, the courses of these pregnancies suggest that non-lymphomatous gamma heavy chain may have a significant impact on pregnancy and that its removal by treatment may improve outcomes., (© 2024. Japanese Society of Hematology.)

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 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.)

Heavy chain diseases (HCD) are B-cell lymphoprolipherative disorders characterized by the production of monoclonal heavy chains without associated light chains. Some cases of gamma-HCD (γ-HCD) are concurrent with other lymphoid neoplasm. The monoclonal component is not always detectable by serum electrophoresis, and often an immunofixation procedure is necessary to detect this component. Prognosis is variable, and no established guidelines for follow-up are available. We describe a case of a challenging diagnosis of γ-HCD due to the absence of clinical signs frequently reported in the disease (anaemia and palatal oedema among others). Haematological malignancy was the first suspicion but bone marrow examination was negative. In addition, the presence of an autoimmune bicytopenia and a Klinefelter syndrome complicated the clinical context of the patient. A thoracoabdominal computed tomography reported many small adenopathies whose pathological and immunohystochemical study revealed a follicular lymphoma. Shortly after, serum inmunofixation secondary to an abnormal electrophoretic pattern revealed a gamma paraprotein without light chains. Eventually, γ-HCD in association with follicular lymphoma was the final diagnosis. This is the first case reporting this association., Competing Interests: Potential conflict of interest: None declared.

Gamma-heavy chains disease is a rare disease, with very few cases described in the literature. It is characterized by the presence of a monoclonal gamma-heavy chain without associated light chain. Its prevalence and prognosis are unknown. We report here the accidental discovery of a case of gamma-heavy chain disease during a pancytopenia exploration, performed in the hospital, in a patient known since 2002 for a lymphoplasmacytic type lymphoma first localized in bone marrow.

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.

Gamma heavy chain disease (gHCD) is a rare lymphoproliferative disorder characterized by the production of a truncated immunoglobulin heavy chain. Although some cases of gHCD are concurrent with other lymphoid neoplasms, few have been reported. We herein present the case of a 73-year-old woman with gHCD and T-cell large granular lymphocytic leukemia. A multiparameter flow cytometry analysis revealed neoplastic cells that were positive for CD28, a marker of T-cell activation, the anti-apoptotic antigen of neoplastic plasma cells, CD38 and CD45. The results of this multiparameter flow cytometry analysis may contribute to furthering the understanding of the clinicopathological features of gHCD.

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.)

Monoclonal immunoglobulin heavy chain (HC) diseases are rare proliferative disorders of B lymphocytes or plasma cells characterized by the presence of monoclonal α-, µ-, or γ-HC without associated light chains in the blood, urine, or both. We report a 59-year-old woman with a history of Hodgkin disease who developed hypercalcemia, proteinuria, and impaired kidney function. Protein electrophoresis and immunofixation displayed γ-HC without associated light chains in the serum and urine. Pathologic examination demonstrated severe tubulointerstitial nephritis associated with diffuse and strong linear staining of the glomerular and tubular basement membranes as well as Bowman capsules for γ-HC, but not for κ- or λ-light chains. Immunohistochemical examination of the kidney and bone marrow demonstrated numerous CD138+ plasma cells immunoreactive for γ-HC, but not for κ- or λ-light chains. This is the first report of tubulointerstitial nephritis associated with γ-HC deposition and γ-HC restricted plasma cells in the kidney. This report heightens awareness about tubulointerstitial nephritis as a possible manifestation of γ-HC deposition in the kidney.

Background: The recently described heavy-chain deposition disease (HCDD) is a comparatively rare monoclonal immunoglobulin disorder characterized histopathologically by glomerular and tubular basement membrane deposition of nonamyloidotic monoclonal heavy chains without associated light chains., Method: We have described a case of γ2-HCDD presenting with proteinuria, microhematuria, severe hypertension, and rapidly progressive renal failure, which serum creatinine level was only 1.52 mg/dL in early stage HCDD, and the clinicopathologic features of this case have been compared with other reported cases of γ2-HCDD., Results: Renal biopsy disclosed nodular sclerosing glomerulopathy. Immunofluorescence analysis revealed IgG2 (2+) heavy chain and C3 (+) in the mesangium and along the capillary walls and tubular basement membranes without IgA, IgM, κ and λ light chains. Electron microscopy revealed electron-dense deposits along the glomerular and tubular basement membranes as well as in the mesangium. Moreover, regardless of therapy, the condition of the patient progressively deteriorated, with less than 3 months of renal survival., Conclusion: Rapid progressive renal failure was a common feature in both cases of γ2-HCDD. We propose that a possible link exists between prognosis of renal HCDD and the subclass of heavy chain deposited in the kidney.

Background: Lichen myxedematosus (LM) is a rare idiopathic disorder characterized by papules, plaques, and/or nodules in the skin secondary to mucin deposition and variable dermal fibrosis in the absence of thyroid disease. Case reports are the predominant literature on LM due to its rarity, and the data are limited regarding the disease. No standard treatment regimen exists, and the response to treatment varies., Objective: This report adds to the limited literature on atypical LM associated with thyroid dysfunction and contributes to the growing body of evidence supporting intravenous immunoglobulin (IVIg) as effective therapy for extensive cases., Methods and Results: We report an unusual case of atypical LM associated with hypothyroidism, central nervous system (CNS) disturbances, and atrial fibrillation in a 64-year-old male. The patient experienced remarkable improvement within 3 months of beginning IVIg treatment; however, he required repeat therapy due to the recurrence of CNS symptoms 3 months after treatment., Conclusion: We agree with previous authors that thyroid dysfunction alone should not preclude a diagnosis of LM. Additionally, we contribute to the increasing evidence of IVIg being an effective treatment, particularly in the setting of systemic complications or acute worsening of LM.

Background: Gamma heavy chain disease with underlying thyroid pathology is rare. There are 5 reported cases in the English literature, including the present case of an elderly female with γ heavy chain disease with underlying lymphoplasmacytic lymphoma of the thyroid who initially presented with long-standing goiter and chronic thyroiditis., Methods: The protein studies and histopathologic findings in her thyroid are described. Her case is compared with reported cases of γ heavy chain disease with thyroid involvement., Results: Initial impression on most cases was chronic thyroiditis; however pathology showed 3 cases with plasmacytoma and 2 with lymphoplasmacytic infiltrate. All were diagnosed and followed up using serum and urine electrophoresis., Conclusion: Gamma heavy chain disease has a protean manifestation; however there appears to be a more uniform pattern of the disease when it is associated with the thyroid. The inclusion of protein studies in cases diagnosed with chronic thyroiditis by FNA may aid in establishing γ heavy chain disease with underlying thyroid involvement. In this case serum and urine electrophoresis, and immunofixation studies which are simple and affordable tests facilitated the hematologic workup and follow up., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We report an association between histologically confirmed progressive multifocal leukoencephalopathy (PML) and an extremely rare humoral immunodeficiency disease, Franklin disease. In our patient, clinical presentation has been typical and prompted us, together with radiological findings, to perform a brain biopsy to confirm the diagnosis even if there was no evidence of any other risk factor except hypogammaglobulinemia. We suggest that PML should be suspected in patients in whom immunosuppression is not obvious (i.e. not only in the setting of HIV infection or disseminated end-stage lymphomas) and involves defects in humoral immunity.

Acquired cutis laxa (generalized acquired elastolysis) is a condition of unknown etiology characterized by a degeneration of elastic fibers in the skin, resulting in laxity with reduced elastic recoil. We describe a patient with acquired cutis laxa associated with an underlying heavy chain deposition disease. Direct immunofluorescence testing of lesional skin demonstrated immunoglobulin G deposition on elastic fibers, suggesting that in some cases, cutis laxa may have an immune-mediated etiopathogenesis.

Heavy chain diseases are rare B-cell disorders that are characterized by an overproduction of abnormal and structurally incomplete monoclonal immunoglobulin (Ig) heavy chains and are devoid of light chains. We describe a case of a 62 year-old African-American woman with a long history of poorly controlled type 2 diabetes and subsequent probable diabetic nephropathy, hypertension, and recent onset of peripheral neuropathy involving all extremities. Routine laboratory testing revealed a distinct beta spike by urine protein electrophoresis (UPEP). No serum abnormality was noted on serum protein electrophoresis (SPEP). Serum and urine immunofixation demonstrated an IgG heavy chain protein devoid of any corresponding light chains. IgG subclasses identified IgG1 as the predominant IgG component but when we added all the subclasses, the sum, 683.4 mg/dL, failed to come close to our total IgG of 1,770 mg/dL. Therefore, a urine IgG subclass determination was performed in-house and we identified a subclass 3 gamma chain. In conclusion, we portray a patient with an underlying monoclonal gamma heavy chain disease (HCD) who presented with a complex medical history. The evaluation of IgG subclasses in the context of a HCD may be limited by the capability of the test to recognize the particular IgG fragment., ((Copyright ) 2008 Wiley-Liss, Inc.)

The authors present a case of concurrent hypertrophic spinal pachymeningitis (HSP) and heavy-chain disease (HCD). The patient was a 71-year-old woman presenting with leg paralysis and fever. Laminectomy was performed for thoracic HSP, and chemotherapy was administered for HCD. Because the dura mater was not surgically opened, marked hypertrophy remained postoperatively. Once the HCD was controlled by chemotherapy, the fever subsided and the hypertrophy was resolved. No previous reports have supported a link between the two diseases. Idiopathic HSP may be secondary to rare conditions such as HCD, and systemic examinations should be performed to the fullest extent possible to investigate the possibility of some underlying disease.

Immunotactoid glomerulopathy is one of several renal disorders characterized by the extracellular deposition of nonamyloid fibrillary deposits. There is considerable debate as to whether immunotactoid glomerulopathy should be distinguished from fibrillary glomerulonephritis, a closely related entity. Currently, the distinction is based on fibril size and arrangement. We report the case of a 59-year-old woman in whom a diagnosis of immunotactoid glomerulopathy was made after a 2-year history of proteinuria. Electron microscopy of her renal biopsy showed randomly arranged microtubular subepithelial and mesangial deposits, which measured 34 nm in average diameter. She was later discovered to have circulating immunoglobulin G heavy chains without associated light chains (gamma-heavy-chain disease) and, subsequently, non-Hodgkin lymphoma, follicular lymphoma, grade I (World Health Organization classification). Approximately 100 cases of gamma-heavy-chain disease have been reported in the literature since it was originally described by Franklin in 1964. However, while there are 10 reports in the literature of heavy-chain disease with fibrillary deposits in the kidney, none fit the criteria for immunotactoid glomerulopathy.

The authors report a patient with progressive renal dysfunction caused by severe renal amyloidosis associated with a gamma-heavy chain variable region (V(H)) fragment. The patient was a 71-year-old woman who had renal insufficiency without nephrotic syndrome. Laboratory data showed a monoclonal IgG lambda component in her serum and urine. Renal biopsy results showed massive amyloid deposition in the mesangial region, but the glomerular basement membranes and epithelial cells were preserved. Because immunohistochemical studies using antibodies against a number of known amyloid fibril proteins failed to detect the amyloid protein, the amyloid protein extracted from a small piece of the biopsied renal tissue was subjected to biochemical analysis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the extracted amyloid protein showed a prominent band at 11-kDa, and this protein was identified by amino acid sequence analysis as a gamma-heavy chain variable region fragment (V(H)3 subgroup) without the first N-terminal residue. Our results indicate that the patient's renal amyloidosis was associated with a gamma-heavy chain variable region fragment. Microextraction and biochemical characterization of amyloid fibrils was of great use for reaching a definitive diagnosis.

mu-heavy chain disease (HCD) is very rare, with only 30 cases reported in the literature. We report a patient with mu-HCD associated with systemic amyloidosis. The diagnosis of mu-HCD was based on findings of mu-heavy chain fragments in the serum, Bence Jones proteinuria and vacuolated plasma cells in the bone marrow. To our knowledge, this is the third case in which systemic amyloidosis led to the patient's death., (Copyright 2004 Taylor and Francis Ltd.)

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.

We report a highly unusual case of monoclonal immunoglobulin deposition disease-associated nephrotic syndrome in which a patient developed both lambda light chain deposition disease and 6 years afterward IgG-heavy chain amyloidosis. The patient initially underwent autologous peripheral blood stem cell transplantation as treatment of the underlying plasma cell dyscrasia causing the light chain deposition disease-related nephrotic syndrome. After 6 years of clinical remission, recurrence of the nephrotic syndrome led to a renal biopsy demonstrating IgG-heavy chain amyloidosis. Interestingly, much of the characteristic nodular glomerular sclerosis seen in light chain deposition disease regressed between the time of the first biopsy and the second. Given the length of time between the development of the two diseases and the apparent success of stem cell transplantation in treating the first, we think that the patient produced two distinctly different abnormal plasma cell clones. To our knowledge, this is the first report of two different monoclonal immunoglobulin deposition diseases occurring in the same patient.

Background: Cutis laxa is a heterogeneous group of inherited and acquired disorders characterized clinically by loose skin and histologically by altered elastic tissue. Heavy chain deposition disease is a very rare monoclonal immunoglobulin disorder, distinct from multiple myeloma, in which there is production and deposition of defective immunoglobulin heavy chains without light chain deposition., Objective: We describe a case of acquired cutis laxa associated with heavy chain deposition disease., Results: A 50-year-old male presented with acute renal failure, IgG4 heavy chain deposition in the kidneys, and no evidence of multiple myeloma. Four years later, he developed generalized acquired cutis laxa, emphysema, and a peripheral polyneuropathy. On pathology, there was destruction of elastic fibers within the dermis., Conclusion: This case describes a previously unreported association between acquired cutis laxa and heavy chain deposition disease.

We report the cases of 23 patients with gamma-heavy chain disease seen at our institution (8 patients previously reported, 15 new patients). There were 15 women and 8 men; the median age at diagnosis was 68 years (range, 42-87 yr). Sixteen patients had an associated lymphoplasma cell proliferative disorder, 3 had a lymphoplasma cell proliferative disorder and an autoimmune disorder, another 3 had an autoimmune disorder only, and 1 had no underlying disease. The lymphoplasma cell proliferative disorder was disseminated in 10 patients and localized in 6. Patients with localized lymphoplasma cell proliferative disorder included 3 with plasmacytoma (1 tongue, 1 submandibular area, and 1 thyroid), 2 with lymphoplasma cell proliferative disorder involving the bone marrow only, and 1 with amyloid of the skin. At the time of diagnosis, lymphadenopathy was present in 8 patients, splenomegaly in 7, and hepatomegaly in 1. A monoclonal spike on serum protein electrophoresis was documented in 19 patients. gamma-Heavy chain was documented by immunofixation in the serum of all patients; 2 had an additional immunoglobulin M-lambda. gamma-Heavy chain was present in the urine in 19 of 22 patients. Sixteen patients were treated for lymphoplasma cell proliferative disorder or autoimmune disorder (14 with chemotherapy, 1 splenectomy, and 1 thyroidectomy followed by radiation therapy). For 5 patients, treatment was not felt to be necessary; 2 patients were thought to be too sick for treatment. Of the 16 patients treated, 6 had a complete clinical response (in 2, gamma-heavy chain disappeared; in 2, gamma-heavy chain persisted; and for 2, no serologic follow-up was available); in 10 patients, clinical disease persisted (in 3, gamma-heavy chain disappeared; in 6, it persisted; and for 1, no serologic follow-up was available). Of 7 patients not treated, 2 died within 5 months; 1 died after 15 months; 2 had no clinical disease at latest follow-up, although gamma-heavy chain persisted; and 2 had no change in clinical and serologic status. The median duration of follow-up was 33 months (range, 1-261 mo). Median survival was 7.4 years.

A 35-year old woman was admitted to our hospital because of systemic edema. Laboratory examination revealed that she had Bence Jones protein(lambda), hypocomplementemia, and proteinuria(0.5 g/day). Renal biopsy showed nodular glomerular lesions with IgG heavy chain and C3 deposition, but not other immunoglobulin and light chains. An extensive study about the character of circulating and deposited IgG demonstrated that the complexes of CH2-CH3 lacking CH1 domain was an important factor in the glomerular heavy chain deposition.

The association of Hodgkin disease with monoclonal gammopathy has rarely been reported. We present a case of a 48-year-old woman with a history of autoimmune hemolytic anemia and Graves disease who presented with hepatosplenomegaly and a gamma-heavy-chain paraprotein. Histopathology of lymph node and bone marrow revealed nodular lymphocyte-predominance Hodgkin disease, while examination of the spleen revealed plasmacytosis consistent with gamma-heavy-chain disease. Following splenectomy, the patient has remained in complete remission for both conditions with no further treatment. To our knowledge, this is the first report of a patient with both gamma-heavy-chain disease and nodular lymphocyte-predominance Hodgkin disease. Given recent data indicating the B-cell nature of this form of Hodgkin disease, the authors propose that in this unique case there may be a clonal relationship between these 2 concurrent B-cell lymphoproliferative processes.

mu heavy chain deposition disease is very rare. We report the first case of glomerulonephritis in a woman without evidence of hematopoietic malignancy. Nodular glomerulosclerosis and monotypic mu heavy chain mesangial deposits were identified by immunofluorescence without kappa or lambda deposits. Electron microscopy showed fibrillar mesangial deposits of 16-18 nm in diameter. Serum immunoglobulins, cryoglobulins, serum immunoelectrophoresis, and immunofixation, bone marrow biopsy, and Bence Jones proteins in urine were negative. The patient has stable renal disease and is free of malignancy 6 years after the initial occurrence of proteinuria.

In 1991, gamma heavy chain disease was diagnosed in a 43-year-old female, who 3 years earlier had contracted an erosive seronegative chronic arthropathy. In 1996, her lymphoproliferative disorder required treatment with melphalan and prednisolone. Laboratory studies revealed a gamma3 heavy chain monoclonal component in serum and urine. Massive localization of plasma cells and blasts with cytoplasmic or cell membrane staining for gamma3 chains, but no staining for light chains, was observed by immunohistochemical studies of bone marrow as well as affected synovial tissue. Large amounts of extracellular gamma3-chains were also deposited in the synovial membrane. This is the first documentation of gamma heavy chain deposition disease directly affecting articular structures. Whether it represents the primary pathogenic event followed by reactive inflammatory changes in the joints, or another example of gamma heavy chain disease preceded by chronic arthritis, remains elusive. Regardless, several common cellular and molecular mechanisms discussed here suggest a pathogenic link between the two disease processes.

A 45-year-old white woman was found to have microscopic hematuria during her annual physical examination. After a negative urologic workup, she returned 5 months later with nephrotic syndrome, renal insufficiency, and hypocomplementemia. Renal biopsy showed a nodular sclerosing glomerulopathy that could not be further characterized because of inadequate tissue for immunofluorescence. The patient returned 8 months later with chronic renal failure. A repeat renal biopsy showed deposits composed of immunoglobulin G (IgG) heavy chain and complement components C3 and C1 along glomerular, tubular, and vascular basement membranes, with negativity for kappa and lambda light chains, findings consistent with heavy chain deposition disease (HCDD). The heavy chain subclass was exclusively IgG3. Staining with monoclonal antibodies to epitopes of the constant domains of IgG heavy chain showed a CH1 deletion, indicating a truncated heavy chain. On review of the previously reported cases of HCDD, common clinical presentations include nephrotic syndrome, renal insufficiency, hematuria, and, in some cases, hypocomplementemia. In most patients, the hematologic disorder is mild, without overt myeloma. Light microscopy shows a nodular sclerosing glomerulopathy, and heavy chain deposits are detectable within basement membranes throughout the kidney by immunofluorescence and electron microscopy. There is no effective treatment for this condition, and virtually all patients progress to chronic renal failure.

The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of gamma1 heavy chains lacking CH1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGlambda containing a short gamma1 heavy chain lacking CH1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete CH1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1lambda with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal gamma1 chain lacking CH1 epitopes. These data strongly suggest that renal deposition of a CH1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The CH1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.

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.

In 1991, gamma heavy chain disease was diagnosed in a 43-year-old female, who 3 years earlier had contracted an erosive seronegative chronic arthropathy. Her gamma heavy chain disease had a benign course, requiring no specific therapy for 5 years. In 1996, however, her lymphoproliferative disorder underwent a more malignant course, with renal and cardiac failure and increasing articular problems, requiring treatment with melphalan and prednisolone, following the protocol for myelomatosis. Laboratory studies revealed a monoclonal component in serum and urine. consistent with dimers of gamma-chains of the gamma3 subclass, but with a smaller molecular mass than normal gamma3-chains, suggesting molecular aberrations as consistently observed in this disorder. Massive localization of plasma cells and blasts with cytoplasmic or cell membrane staining for gamma3-chains, but no staining for kappa or lambda light chains, was observed by immunohistochemical studies of tissue specimens from bone marrow as well as affected synovial tissue. Large amounts of extracellular gamma3-chains were deposited in the synovial membrane. In addition, marked inflammatory changes with synovial cell hyperplasia were seen. Whether the present case represents primarily a gamma heavy chain deposition disease with reactive inflammatory changes in the joints, or another example of gamma heavy chain disease preceded by seronegative rheumatoid arthritis, remains elusive. Regardless, a possible pathogenic link between the two disease processes is an intriguing possibility.

The occurrence of kidney diseases was very rarely reported in heavy chain diseases (HCD). At variance with gamma and alpha HCD in which there is no free light chain secretion, about two-thirds of mu HCD patients have urinary Bence Jones (BJ) proteins. We report on a 66 year-old man affected with typical mu HCD who developed renal failure after a 3-year follow-up. He had presented with chronic lymphocytic leukemia with bone marrow vacuolated plasma cells, serum mu HCD protein and serum and urine BJ protein. After an apparent hematological remission following fludarabine therapy, anemia and blood hyperlymphocytosis recurred together with microscopic hematuria, proteinuria and increased creatininemia. Kidney biopsy showed numerous tubular eosinophilic casts which stained for kappa chain determinants by immunofluorescence and an interstitial infiltration by lymphocytes and plasma cells. The hematological and renal condition improved after reinitiation of chemotherapy. This appears to be the first documented report of a light chain-dependent visceral complication in HCD.

Introduction: Monoclonal light and heavy chain deposition disease is a rare syndrome distinct from light chain amyloid, which is defined by the presence of monoclonal deposits of immunoglobulins in various tissues., Case-Report: A 65-year-old man presented with renal symptoms due to membranoproliferative glomerulonephritis, associated with urticarial papules located on the arms and back. Histological examination of a skin biopsy specimen showed lymphocytic vasculitis. Direct immunofluorescence examination of kidney and skin lesions using anti-gamma 2 and anti-Kappa monoclonal antibodies, showed a similar staining on the basement membrane zone and vessel walls., Comments: As far as we know, this is the first documentation of monoclonal light and heavy chain deposition disease associated with a lymphocytic skin vasculitis and renal involvement caused by similar monoclonal deposits of immunoglobulins in the kidney and skin.

We describe a 35-year-old woman who had nodular glomerulosclerosis associated with deposition of fragmented gamma (gamma 1)-heavy chains. She presented with edema of lower legs, mild proteinuria, and hematuria. Laboratory examination revealed hypocomplementemia, and a small amount of monoclonal IgG-lambda (lambda) in the blood. Renal biopsy disclosed prominent nodular expansion of the mesangium. Ultrastructurally, the nodules were composed of electron dense deposits and fibrillar structures. An immunofluorescent study showed depositions of gamma-heavy chains and C3 in the central portion of nodules and capillary walls, whereas kappa (kappa)-, lambda-light chains, and Fab fragments of the heavy chain were negative. The accumulation of collagen I, IV, V, and VI was demonstrated in the mesangium. Western blot analysis of serum protein disclosed fragmented gamma-heavy chains that did not combine with light chains. Glomerular nodular lesions, thus, can occur in heavy chain deposition disease, as in light chain deposition disease. Fragmented gamma-heavy chains may also induce hypocomplementemia by the activation of the complement pathway.