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Two Cases of Γ-Heavy Chain Disease and a Review of the Literature

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Two Cases of Γ-Heavy Chain Disease and a Review of the Literature Hindawi Case Reports in Hematology Volume 2018, Article ID 4832619, 8 pages https://doi.org/10.1155/2018/4832619 Case Report Two Cases of γ-Heavy Chain Disease and a Review of the Literature I. Ramasamy 1 and Z. Rudzki2 1Department of Biochemistry, Worcester Royal Hospital, Worcester, UK 2Heart of England NHS Trust, Birmingham, UK Correspondence should be addressed to I. Ramasamy; [email protected] Received 5 May 2018; Revised 4 July 2018; Accepted 12 July 2018; Published 12 August 2018 Academic Editor: Marie-Christine Kyrtsonis Copyright © 2018 I. Ramasamy and Z. Rudzki. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gamma heavy chain disease (c-HCD) is a rare lymphoproliferative disorder characterised by the production of a truncated immunoglobulin heavy chain. Fewer than 200 cases have been reported in the literature. In some cases, c-HCD occurs with other lymphoid neoplasms. +is study reports clinical, biochemical, haematological, and histological findings in two cases of c-HCD. We describe newer biochemical diagnostic tools (HevyLite measurement, capillary electrophoresis, and immunotyping) that can aid in the characterisation of c-HCD. +e first case is an 88-year-old woman with c-HCD. +e second case is an 81-year-old woman who developed c-HCD during treatment for Waldenstrom’s macroglobulinemia. In the second patient, histopathology identified a separate clone responsible for the secretion of the gamma heavy chain. Studies on the clonal evolution of the disease may provide insight into therapeutic implications and the genomic complexity of the disease. 1. Introduction addition harbor somatic point mutations. One possibility is that several types of oncogene translocations happen as Gamma heavy chain disease (c-HCD) is also called a by-product of somatic hypermutation [1]. It has been Franklin’s disease, named after the author of the first report established the c-HCD immunoglobulins are the products of in 1964. +e disease is defined as a neoplasm of lymphocytes, aberrant biosynthesis, for example, deletions, splice site plasmacytoid lymphocytes, and plasma cells characterised correction, and amino-terminal proteolysis [2]. Structural by the production of an abnormally truncated gamma heavy analysis of the defective gamma heavy chain in 23 patients chain protein that lacks associated light chains. Since showed some common features. In most cases, the variable Franklin first reported the case, fewer than 200 cases have region sequence was short and interrupted by large deletions, been described in the literature. A wide variety of disorders usually including the CH1 domain. Normal sequence began at have been associated with c-HCD. In some cases, c-HCD the hinge region or at the CH2 domain [3]. occurs with other lymphoid neoplasms or with a history of Genetic subtypes of multiple myeloma (MM) have been autoimmune disorder. c-HCD shows a wide clinical spec- identified which have different biological features and het- trum ranging from completely asymptomatic to pro- erogeneity in clinical outcomes [4]. New gene sequencing gressively malignant forms. techniques have yielded new insights into the pathogenesis Normal heavy chains not associated with light chains and evolution of the disease and potential individualised have not been detected in serum of healthy individuals. In treatment by novel targeted approaches [5]. c-HCD abnormally short truncated heavy chains can be We report two cases of c-HCD: one case in a patient with isolated from patient’s serum without associated light lymphadenopathy and a second case in a patient with a his- chains. In several instances where the gene encoding the tory of Waldenstrom’s macroglobulinemia (WM). Further, shortened heavy chain gene has been characterised, the we review previous case series on c-HCD. +ese two cases truncation originated from deletions and/or insertions were diagnosed using the techniques of capillary zone elec- within the rearranged variable region genes (V) that in trophoresis, immunofixation, and “HevyLite” measurement. 2 Case Reports in Hematology Use of newer commercially available techniques simplified the 2.2. Case 2. Patient 2 is an 81-year-old lady under treatment diagnosis of c-HCD. In one patient, there was no evidence of for WM (IgMkappa paraprotein). Details of her treatment previous chemotherapy. +e second patient developed are given in Figure 5. Capillary zone electrophoresis prior to c-HCD during treatment for WM. the development of c-HCD is shown in Figure 6(a). Gamma heavy chain developed during treatment and an unusually 2. Case Report diffuse c-heavy chain band was identified by gel electro- phoresis (Figure 1(b)) and capillary zone electrophoresis 2.1. Case 1. An 88-year-old woman presented with a change (Figures 6(b) and 6(c)) (Sebia, UK) and confirmed by in the bowel habit. A colonoscopy showed some diverticular a second gel electrophoresis method (Helena, UK). Urine disease. +e CT scan showed splenomegaly and some immunofixation identified the c-heavy chain and kappa light lymphadenopathy particularly in the region of the splenic chain (Figure 3(b)). hilum. +e liver, kidney, pancreas, and adrenals were nor- Her biochemistry and hematology prior to the develop- mal. She had a past history of osteopenia, type II diabetes, ment of c-HCD and during follow-up are given in Tables 1 and fragility fracture. She was taking vitamin B12, vitamin D, and 2. HevyLite measurements confirmed an IgMkappa and bisphosphonates. +ere was no history of sweating, paraprotein, and ratios of IgGkappa/IgGlambda were within weight loss, bruising, or recent infections. Her biochemistry the reference range, confirming increased IgG measurements and hematology at diagnosis and 3 months after diagnosis were due to the IgG heavy chain (Table 5). +e ratio of are summarised in Tables 1 and 2. ((IgGkappa + IgGlambda)/total IgG) was 0.096. Gel protein electrophoresis and immunofixation +e serum-free light chain ratio was elevated secondary (Figure 1(a)) and capillary zone electrophoresis and to the presence of IgMkappa paraprotein (Table 4). Her total immunotyping (Figures 2(a) and 2(b)) (Sebia, UK) identified IgG levels were increased at 35.1 g/L, at diagnosis of c-HCD, 2 c-heavy chains. Both methods were negative for kappa and with suppressed IgA and an IgMkappa paraprotein of lambda light chains. Differing sensitivities of heavy and light 10.7 g/L (Tables 1 and 2). IgG1 subtype was elevated, and chain reagents can cause false-negative results for light chain other IgG subtypes were either decreased or at the lower immunofixation, and the results were confirmed by a second reference range (Table 3). She is currently under observation gel electrophoresis (Helena, UK) method. Urine immuno- for ibrutinib treatment. fixation identified a c-heavy chain (Figure 3(a)). Her bone marrow results are shown in Figures 7(a) and Total IgG (determined by immunoturbidimetry on the 7(b) and in the Supplementary Material (available here). Binding Site SPA-plus analyser) was elevated at 38.7 g/L (RR Lymphoma cells were CD5−, CD20+, and partially CD79a 7–16), with decreased levels of IgA and IgM (Table 1). IgG1 +, CD10+, CD23+, CD56+, and CD138+. A second CD56+ subclass levels were elevated, and other subclass levels were plasma cell clone most likely to be the c-heavy chain lower than the reference range (Table 3). Serum-free light producer was identified. Bone marrow histology identified chain ratios (determined by the Binding Site method, UK) lymphoplasmacytic lymphoma/WM, which appeared as were within the reference range (Table 4). HevyLite (Binding IgM/kappa plus another population of scattered plasma Site, UK) measurements are specific for individual heavy cells, occasionally expressing IgG and/or lambda. chains with either kappa or lambda light chains and can provide more specific information than individual immu- 3. Discussion noglobulin quantitation. Observed increased heavy chain pair ratios (e.g., IgMkappa/IgMlambda) can be indicative of clonal Heavy chain diseases are rare B-cell lymphoproliferative dis- expansion. IgGkappa/IgGlambda ratios were within the ref- orders that are characterised by the production of immuno- erence range confirming the absence of clonal expansion of globulin heavy chains without associated light chains. c-HCD IgGkappa/IgGlambda intact immunoglobulins (Table 5). has a variety of clinical presentations. +e Mayo Clinic re- In a previous study, HevyLite reagents which did not ported a series of 23 patients of whom 70% had an underlying recognise intact IgG immunoglobulin ratios ((IgGkappa lymphoplasma cell proliferative disorder, 13% an autoimmune + IgGlambda)/total IgG) were used as indirect measures of disorder, and 4% no underlying disease. Pathological diagnosis heavy chain fragmentation [6]. +e ratio of 0.04 in this of underlying disease reported in the 23 patients was lym- patient was less than the average value of 0.18 found in the phoplasma cell proliferative disorder, lymphoma, chronic previous study [6]. lymphocytic leukemia, plasmacytoma, and plasma cell pro- Bone marrow biopsy showed subtle infiltrates by low- liferative disorder. +e disease was associated with lymph- grade B-NHL, associated with groups of clonal plasma cells, adenopathy (34%), hepatomegaly (4%), splenomegaly (30%), which expressed neither kappa nor lambda chain but stained or bone marrow involvement (30%). +e median survival of with IgG heavy chain (Figures 4(a)–4(g)). Lymphatic in- the 23 patients was 7.4 years (range 1 month to more than filtrate was surrounded by a rim of CD138+ plasma cells. 21 years) [7]. In a further series of 13 patients, 8 patients +ough there was equal expression of kappa and lambda showed a lymphoplasmacytic neoplasm that was difficult to light chains, the sum of kappa- and lambda-positive cells classify. In the remaining 5 patients, biopsy identified well- appeared to be much less than the number of CD138+ cells defined neoplasms: splenic diffuse red pulp and small B-cell which indicated that most plasma cells do not express light lymphoma, splenic marginal zone lymphoma, MALT lym- chains.
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