Mediterranean Journal of Hematology and Infectious Diseases

. The heavy chain diseases (HCDs) are rare B-cell malignancies characterized by the production of a monoclonal immunoglobulin heavy chain without an associated light chain. There are three types of HCD, defined by the class of immunoglobulin heavy chain produced: IgA (α-HCD), IgG (γ-HCD), and IgM (μ-HCD). Alpha-HCD is the most common and usually occurs as intestinal malabsorption in a young adult from a country of the Mediterranean area. Gamma-and μ-HCDs are rarer and associated with a B-cell non-Hodgkin lymphoma that produces an abnormal Ig heavy chain. These patients may occasionally be diagnosed with a monoclonal gammopathy of undetermined significance (MGUS). Fanconi syndrome, on the other hand, can be primary (inherited) or secondary (acquired). The only exception to this rule is the idiopathic form. Adult acquired Fanconi syndrome can be a rare complication of a monoclonal gammopathy. At diagnosis, most patients have an MGUS or smoldering multiple myeloma, with renal failure and evidence of osteomalacia. During follow-up, patients can develop an end-stage renal disease. Chemotherapy provides little benefit on renal function.

Introduction.Heavy chain diseases (HCDs) are a group of three rare B-cell neoplasms that are clinically and morphologically distinct from one another, but have in common the production of an abnormal immunoglobulin (Ig) heavy chain incapable of binding light chains (LCs).The altered heavy chains contain deletions, insertions, and point mutations that are acquired during somatic hypermutation.[3] In the absence of an associated LC, the CH1 domain of the regular heavy chain binds to heatshock protein 78 (HSP78) and undergoes degradation in the cell proteasome compartment.Regular heavy chains unassociated with LCs are therefore never detected in serum or urine.In the HCDs, the altered structure of the CH1 domain prevents the heavy chain from binding both the LC and HSP78, thereby allowing it to bypass degradation by the proteasome and be secreted into the serum or urine. 4In addition, recent work suggests that the altered heavy chain, which forms part of the transmembrane B-cell receptor, may facilitate antigen-independent aggregation and down-stream signaling by the receptor, thereby conferring a growth advantage to neoplastic cells. 5his characteristic feature gives rise to three different HCDs, depending on the heavy chain class that is produced-each with a unique clinical presentation and characteristic findings on immunologic evaluation and in biopsy specimens of involved tissues.Each HCD appears to represent an unusual variant of a type of lymphoma, and none of them can be defined a true plasma cell neoplasms. 6uido Fanconi, a Swiss pediatrician, described a child with a symptomatology characterized by glycosuria, albuminuria, rickets, and dwarfism. 7his syndrome bears his name. 8Environmental agents that cause Fanconi syndrome (FS) include exposure to heavy metals (like cadmium, lead, mercury, platinum, uranium), other substances (lysol, paraquat, toluene, the amino acid lysine taken as a nutritional supplement).Moreover, it may be caused by various drugs, including certain chemotherapeutic drugs (e.g., ifosfamide, streptozotocin), antiretrovirals (e.g., didanosine, cidofovir, tenofovir), and tetracycline.Acquired FS can also occur after renal transplantation and in patients with multiple myeloma, amyloidosis, intoxication with heavy metals or other chemicals, or vitamin D deficiency. 9,10FS may complicate plasma cell dyscrasias when free LCs (FLCs) undergo homotypic polymerization within the endo-lysosomal system of the proximal tubular epithelium to form intracellular crystals.In this case, it is defined adult acquired FS, 11,12 a rare complication of plasma cell dyscrasias, usually associated with a monoclonal gammopathy of undetermined significance (MGUS).Overt hematologic malignancies may occur, such as multiple myeloma, Waldenström's macroglobulinemia, or other lymphoproliferative disorders. 11,12avy-Chains Diseases.

Epidemiology and clinical features (Table 1).
α-HCD -It is the most common of the three HCDs, with more than 400 cases described in the literature since its initial description in 1968. 13It has a striking epidemiology, affecting primarily subjects of Mediterranean, Northern African, and Middle Eastern descent, particularly those of low socio-economic background, suggesting an environmental, possibly infectious, pathogenetic mechanism. 14HCD is most prevalent during the second and third decades of life, with a slight male predominance, typically affects the gastrointestinal system and rarely the respiratory tract.Lymphoma-like pictures have also been described (Figure 1).Malabsorption syndrome with weight loss that can cause growth retardation, amenorrhea, alopecia, diarrhea, and abdominal discomfort are the typical symptoms of gastrointestinal α-HCD.Nausea and emesis can also be present.In advanced gastrointestinal α-HCD, ascites and anasarca can be detected at the physical examination.Finger clubbing and tetany can also be seen. 15Generalized lymphadenopathy and hepato-splenomegaly are hallmarks of the lymphomatous forms that have been recognized as a distinct entity. 16Patients with respiratory tract involvement show a restrictive pattern on pulmonary function tests.They present dyspnea, mild hypoxemia, and diffuse pulmonary infiltrates and, in some cases, eosinophilia, skin rash, hilar lymphadenopathy, and lymphomatous involvement of the pharyngeal mucosa. 17-HCD -It is also called Franklin's disease, after the physician who first described it in 1964. 180][21] An autoimmune disease such as rheumatoid arthritis (the most common), Sjögren syndrome, systemic lupus erythematosus, vasculitis, myasthenia gravis and autoimmune cytopenias (particularly idiopathic thrombocytopenic purpura) can be found in about 25% of patients. 22The manifestations of the associated autoimmune disease often herald the diagnosis of γ-HCD by many years.A lymphoplasmacytic neoplasm is present in 83% to 91% of these patients.
Three different clinical patterns of γ-HCD have been described, based on the presence or absence of an associated lymphoma.In 57% to 66% of patients, a disseminated lymphoma associated with constitutional symptoms (i.e., fever, malaise, and weight loss) is present.Generalized lymphadenopathy, splenomegaly, and hepatomegaly are present in 50% of cases, 14,20 whereas roughly 25% of patients present a lymphomatous bone marrow involvement (localized medullary disease) or a localized extranodal disease (localized extramedullary disease).This last form commonly involves the skin, less  frequently the thyroid or parotid gland, the oropharyngeal cavity, and the gastrointestinal tract. 20,22Finally, 10-17% of patients have a preexisting autoimmune disease with a clinical presentation characterized by rheumatoid nodules, rashes, synovitis, and joint deformities.µ-HCD.-It is the rarest of the HCDs, with only 30 to 40 cases reported in the literature.The first two patients were described in 1970 by Forte et al. 23 and Ballard et al.. 24 The disease occurs predominantly in Caucasian males, with a median age of 58 years at diagnosis. 14Most patients with µ-HCD have a lymphoid neoplasm resembling chronic lymphocytic leukemia/small lymphocytic lymphoma. 1,25alpable, superficial lymphadenopathy can be identified in 40% of the patients.Splenomegaly is frequent, and hepatomegaly can be found in about 25%. 14[28][29] Diagnostic Approach.The diagnosis of HCDs remains challenging due to their rarity, their variable clinical presentation, and the skill required in interpreting immunologic laboratory tests and tissue biopsies from affected patients.A close collaboration between clinicians and pathologists is usually needed.Two-dimensional immunoelectrophoresis has been shown to be a useful diagnostic tool for all three types of HCD. 30 α-HCD.-Common laboratory abnormalities include mild-to-moderate hypochromic anemia, deficiency of vitamins and minerals, high levels of alkaline phosphatase (the gastrointestinal isoform of the enzyme), electrolytic disorders (i.e., hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia). 15erum protein electrophoresis may appear normal or show hypogammaglobulinemia, but sometimes a broad monoclonal band migrating to the α2 or β region of the electrophoretic pattern can be seen.Positivity for the anti-IgA antiserum by immunofixation is mandatory to confirm the diagnosis (Figure 1 panel A, B). 31 The abnormal α-heavy chains can be detected in jejunal or gastric fluids as well as in urine in only small amounts, but Bence Jones proteinuria has never been detected. 31adiologic studies of the gastrointestinal apparatus can show diameter alterations (dilations and strictures) (Figure 1 panel D), hypertrophic or pseudo-polypoid mucosa, or coarse mucosal folds.
Since α-HCD typically affects the proximal small bowel at the level of the duodenum or jejunum, endoscopy is mandatory and can reveal five different patterns: i) infiltrative, ii) nodular, iii) ulcerations, iv) mosaic, v) isolated mucosal fold thickening.The first two patterns are most sensitive and characteristic for the diagnosis of α-HCD. 32he histological features of α-HCD are those of an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (Figure 1 panel E, F, G), also named immunoproliferative small intestinal disease (IPSID).4][35] A lymphoplasmacytic infiltrate rich in plasma cells can be detected in the lamina propria of the bowel, and lymphoepithelial lesions may also be present.7][38] All the α-heavy chain cells (plasma cells and marginal zone cells) typically express monoclonal cytoplasmic α-chain without light chains (Figure 1 panel C).The immunophenotype of α-heavy chain cells is shown in Table 2. Finally, the presence of intestinal bacteria and parasites should be looked for on biopsy specimens.
γ-HCD.-Laboratory evidence of autoimmune diseases or bone marrow infiltration can be detected during diagnostic procedures in patients with γ-HCD.These comprise cytopenias, in particular, normochromic normocytic anemia, Coombs-positive autoimmune hemolytic anemia, and thrombocytopenia.In some cases, monoclonal plasmacytoid lymphocytes or plasma cells are present in the circulation, as well as features of chronic lymphocytic leukemia or plasma cell leukemia. 14Serum protein electrophoresis may appear normal or show a monoclonal band migrating to the β-region of the electrophoretic pattern, where it is often concealed by other proteins.Rarely, biclonal gammopathy with an additional intact monoclonal Ig may be present. 20ositivity for the anti-IgG antiserum, without associated light chains, by immunofixation is mandatory to confirm the diagnosis.
Due to their low molecular weight and existence as dimers, the abnormal γ-heavy chains often can be detected in the urine. 2 Small amounts of FLCs may be excreted in urine as Bence Jones protein. 39Other laboratory findings include high serum levels of IgG, with normal serum FLCs.
The pathologic heterogeneity of γ-HCD makes the histological diagnosis rather difficult.Histological findings of γ-HCD are typically associated with a lymphomatous infiltration of affected tissues such as bone marrow, spleen, lymph nodes, as well as extra-nodal sites involved in MALT lymphomas, such as skin, thyroid, salivary glands, gastrointestinal tract, and conjunctiva. 21,22The infiltrate is formed by a mixed population of lymphocytes, plasmacytoid lymphocytes, and plasma cells, similarly to a lymphoplasmacytic lymphoma or, in some cases, it is more polymorphous showing immunoblasts, eosinophils, and histiocytes in a variable number.Atypical Reed-Sternberg-like cells have been described, thus inducing Hodgkin lymphoma or certain types of peripheral T-cell lymphoma to be considered in a morphologic differential diagnosis. 22Less frequently, γ-HCD can be similar to B-cell neoplasms, such as MALT lymphoma, splenic marginal zone lymphoma, or other splenic small B-cell lymphomas. 21The association of γ-HCD with T-cell large granular lymphocytic leukemia and extranodal marginal zone lymphoma have also been reported. 40,41he immunophenotype of γ-heavy chain cells is shown in Table 2.
µ-HCD.-Hypoproliferative anemia related to bone marrow infiltration by neoplastic cells is the most common laboratory abnormality of µ-HCD; thrombocytopenia and lymphocytosis are less common. 27,28Serum protein electrophoresis is generally normal or shows a rather broad monoclonal band.In a few cases, biclonal gammopathy with an additional intact monoclonal Ig may be present. 1Immunofixation that is positive with anti-µ but not with anti-kappa or anti-lambda LCs confirms the diagnosis. 42Bence Jones proteinuria is frequently detected because the neoplastic cells also produce monoclonal LCs, usually of kappa type, that fail to assemble with the truncated heavy chain; 1,24,42   Bone marrow smears and touch preparations show characteristic plasma cells with prominent cytoplasmic vacuoles admixed with small, round lymphocytes. 1,24,44,45The immunophenotype of µheavy chain cells is shown in Table 2.

Treatment and Prognosis.
No standardized therapies are available for the HCDs, because of their rarity and their clinicopathologic features characterized by association with various conditions such as infectious, autoimmune and lymphoproliferative diseases.
α-HCD.-Since it has a higher incidence in subjects of lower socio-economic status, sanitation improvement would be expected to reduce its occurrence.If untreated, α-HCD may initially progress locally, and then spread systemically.Small bowel obstruction, perforation, and intussusception that can be fatal are the dreadful local complications of enlargement of the lymphomatous tissue.Other potential causes of death are severe malnutrition and subsequent cachexia, as well as infectious complications. 46f a bacterial or parasitic gastro-intestinal infection is documented, it should be eradicated with appropriate antimicrobial therapy.An empirically administered antibiotic treatment is often recommended even in the absence of a demonstrated infection.Metronidazole, ampicillin, or tetracycline are the antibiotics of choice for this empiric therapy.Antimicrobial treatment should be administered for a 6-months course, although an early regression or a rapid improvement of symptoms is typically observed in antibiotic-sensitive patients.A shorter duration has been shown to cause a relapse of the disease.
Although 33-71% of patients with early-stage show clinical, laboratory, and histological remission in response to antimicrobial treatment, disease recurrences are frequent. 47Refractory disease is treated with either total abdominal radiation or, more commonly, with doxorubicincontaining combination chemotherapy.9][50] The complete remission rate after treatment with multi-drug chemotherapy is 64%, and 5-year overall survival is 67%. 51urgical debulking of the tumor mass can be pursued, followed by systemic chemotherapy, but it should be limited to the management of complications. 52For patients with a refractory or relapsing disease, high-dose therapy with autologous hematopoietic stem cell transplantation should be considered.
γ-HCD.-Treatment of γ-HCD is typically tailored to the symptomatology of the patient and to the presence of an accompanying autoimmune disease or overt lymphoma.Chemotherapy is recommended in patients with lymphomatous dissemination or with a localized medullary disease.Chlorambucil, or melphalan and prednisone, or bortezomib and prednisone, and rituximab in CD20-positive disease are the treatment of choice for plasma cell-predominant disease.CHOP regimen (with rituximab in CD20positive cases) shows the best results in aggressive/refractory patients.Inoue et al. 53 reported that the combination of fludarabine and rituximab was effective in patients with γ-HCD associated with pancytopenia.
While surgical resection or radiation therapy have been successfully employed in patients with localized extra-nodal disease, 22 a 'watch and wait' strategy can be adopted in asymptomatic patients without lymphoma.When co-existing autoimmune disorders are diagnosed, they should be treated with immunosuppressive treatments according to usual guidelines.Adequate prophylaxis and surveillance for infectious complications are critical points.Prognosis is highly variable because of the heterogeneity of γ-HCD and the lack of a standardized treatment.
Occasional spontaneous remissions have been reported in patients with no overt lymphoma, who are nonetheless expected to undergo a prolonged survival without treatment. 22A sustained, complete clinical and immunologic remission is usually achieved in patients with treated, localized lymphoma.The natural history of γ-HCD associated with systemic lymphoma may be either aggressive and rapidly progressive, and hence associated with poor prognosis, or exhibit an indolent course.In the Mayo Clinic series, median survival was 7.4 years (range, one month to more than two decades). 20-HCD.-Only a few data have been reported about the treatment and prognosis of this disease because of its rarity.A 'watch and wait' approach is recommended in patients with detectable monoclonal µ heavy chains who are otherwise asymptomatic. 54If and when an underlying malignancy develops, useful treatment regimens are CHOP, CVP (cyclophosphamide, vincristine, and prednisone), single-agent fludarabine or cyclophosphamide. 14,45Reported median overall survival is approximately two years, ranging from less than a month to over a decade.However, these data are likely underestimated, since the presence of monoclonal µ heavy chains is frequently missed on serum protein electrophoresis, especially in the absence of an associated overt lymphoma.A spontaneous remission of µ-HCD can rarely be observed. 14

Myeloma-Associated Fanconi Syndrome (MAFS).
Pathophysiology.The precise pathophysiology of MAFS is still unknown.The biological and clinical features result from the impaired function of the proximal renal tubule, consequent to reabsorption of some filtered substances. 55,56In particular, FLCs, generally of kappa isotype, secreted by plasma cells are a major cause of MAFS or other plasma cell dyscrasias.In virtually all cases, the diagnosis of FS precedes that of the underlying hematological disorder, generally a 'smoldering' multiple myeloma. 11,12LCs slowly accumulate in the epithelial cells of the proximal tubule, forming crystals that can be demonstrated in all cases. 11,57,58Accumulation and crystallization take place in the lysosomes of tubular cells and endoplasmic reticulum of plasma cells.7][58] This peculiar sequence is responsible for the crystallization because of the resistance of the LC variable domain to proteolysis by several enzymes such as cathepsin B 54,55 and of the subsequent damage of the proximal tubule.The functional impairment of the proximal kidney tubule can cause aminoaciduria, glycosuria with normal glycemia, metabolic acidosis and increased clearances of uric acid and phosphate.Phosphate loss is responsible for osteomalacia, with bone pain and pseudofractures. 59,60] In contrast, when the LC variable domain derives from another germline variable segment such as LCO8/O18, MAFS occurs without evidence of intracellular crystallization, even when searched for by electron microscopy. 63,64In this case, defects of tubular reabsorption and urine acidification are usually a consequence of the direct toxicity of FLCs on epithelial cells of the proximal tubule, in the absence of crystalline deposits. 65Myeloma FLCs can interfere with the uptake of alanine, phosphate, and glucose. 66,67here has also been one report of LC-FS and nephrogenic diabetes insipidus, suggesting that resistance to antidiuretic hormone can also occur. 68Interestingly, this patient had distal (type I), not proximal, renal tubular acidosis.

Clinical features and diagnostic approach.
Clinical manifestations of MAFS include defects in sodium-coupled co-transport processes producing type II renal tubular acidosis, aminoaciduria, phosphaturia, and glycosuria.The associated multiple myeloma is often low-grade. 11he offending monoclonal FLCs are usually of the kappa type and possess uncommon non-polar or hydrophobic residues in the complementaritydetermining region-1 (CDR1). 61] Involvement of the proximal tubule occurs specifically when the monoclonal FLCs are overproduced, because intact Igs are not filtered through the glomerulus.
The typical histological finding is intralysosomal crystalline deposits of FLCs within epithelial cells of the proximal tubule.There may be extra-renal crystal accumulation.FLCs of the VkI subgroup are most frequently found, 61,62 although cases associated with lambda-FLCs have also been reported. 71he diagnosis of FS can be made when a patient with a monoclonal plasma cell disorder presents with hypophosphatemia, hypouricemia, aminoaciduria, phosphaturia, and glycosuria.Bence Jones proteinuria is usually present and is almost always of the kappa type.Crystal-storing histiocytosis, an intra-lysosomal accumulation of monoclonal LCs that aggregate in crystals, is observed in association with both plasma cell and lymphoid disorders. 72,73Although the type of LCs involved is almost exclusively kappa, there is no consistent association with a particular heavy chain.Crystals can form either in histiocytes in soft tissues or parenchymal cells in bone marrow, lymph nodes, spleen, liver, stomach, adrenal glands, proximal renal tubules, and thyroid follicles.The initial clinical presentation depends on the site of crystal formation and is, therefore, variable.Some patients present with soft tissue masses in which predominantly histiocytes, but also fibroblasts, contain crystals.The crystal formation in proximal renal tubules is the fundamental diagnostic criterion of MAFS.
The main laboratory abnormalities include aminoaciduria, renal glycosuria, hypophosphatemia, hyperchloremic metabolic acidosis, hypokalemia, proteinuria of tubular origin, and hypouricemia.The primary manifestations include osteomalacia, polyuria, chronic acidosis, and episodes of dehydration.FS frequently evolves into end-stage renal failure.Very few series of LC-associated FS have been published, and the efficacy of the so-called novel anti-myeloma agents, such as proteasome inhibitors and immunomodulatory drugs (IMiDs), has not been evaluated.In most cases, FS appears to progress toward end-stage renal disease slowly and rarely results in symptomatic myeloma. 74ccordingly, therapeutic decisions should take into account treatment side effects, particularly the potential risk of secondary myelodysplastic syndrome from alkylating agents. 75ll patients with an associated overt lymphoid disorder should receive appropriate chemotherapy, and treatment choices should be adapted to the degree of renal failure.In patients with stages 1 to 3 chronic kidney disease, bortezomib-based chemotherapy should be considered because of high rates of both anti-myeloma response and recovery of renal function.In addition, cyclophosphamide-or IMIDs-based regimens are good options to treat bortezomib-refractory myeloma.Bendamustine may also be used.Highdose melphalan/autologous stem cell transplantation (HDM/ASCT) may be performed in selected non-responding patients, although the benefit of this strategy remains to be proven.In the relapsed/refractory setting, additional treatment options such as carfilzomib, pomalidomide and monoclonal antibodies are now available.However, limited data have been reported as regards their effects on patients with renal impairment. 76n patients with stages 4 to 5 chronic kidney disease who are eligible for renal allograft, chemotherapy, including HDM/ASCT, should be considered either before or after transplantation.In patients who are not candidates for renal transplantation, administration of chemotherapy does not result in particular benefits. 76

Figure 1 .
Figure 1.Clinicopathologic features in a case of IPSID with α-HCD.A) Immunofixation and B) immunoelectrophoresis positivity for the anti-IgA antiserum; C) plasma cells and marginal zone cells express monoclonal cytoplasmic α-chain at immunofluorescence; D) Radiologic studies of the gastrointestinal apparatus showing diameter alterations (dilations and strictures); E), F) and G) histological features of intestinal infiltration by α-HCD cells (10X, 20X and 100X respectively).
Treatment and prognosis.The prognosis in terms of survival is good in the absence of an overt malignancy.Treatment includes symptomatic measures to prevent osteomalacia by supplementation with phosphorus, calcium, and vitamin D. Chemotherapy may benefit patients with rapidly progressive renal failure or symptomatic malignancy.

Table 1 .
Clinicopathologic features of heavy chain disease.