Gamma Heavy Chain Disease 

Updated: Feb 12, 2020
Author: Guy B Faguet, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

The heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by production of abnormal, structurally incomplete, immunoglobulin heavy chains without the corresponding light chains.[1] The abnormal HCD proteins are the result of gene mutations, deletions, or insertions.

The HCDs are classified according to immunoglobulin (Ig) class involved, of which α-HCD (IgA), γ-HCD (IgG), and μ-HCD (IgM) have been described, with a frequency ranging from rare to very rare. No case of ε-HCD (IgE) or δ-HCD (IgD) has been reported to date. α-HCD frequently presents as an extranodal marginal-zone lymphoma of the mucosa-associated lymphoid tissue (MALT), considered a variant of MALT lymphoma, and is the only HCD that can transform into diffuse large B-cell lymphoma. μ-HCD clinically resembles small cell lymphoma or chronic lymphocytic leukemia.[2, 3]

γ-HCD is morphologically heterogeneous. Some cases resemble splenic marginal zone lymphoma or extranodal MALT lymphoma, while others are similar to lymphoplasmacytoid lymphoma (LPL). However, γ-HCD and LPL may be unrelated disorders. Hamadeh et al reported that γ-HCD lacks the MYD88 L265P mutation that is characteristic of the vast majority of cases of LPL.[4]

While α-HCD is most commonly reported in young adults (median age at diagnosis, 30-40 years), especially of Arab or Jewish ethnicity from the Mediterranean area or the Middle East, γ-HCD or Franklin disease is the most often studied and occurs in middle-aged patients.[5] Since first described by Franklin in 1964, approximately 130 cases of γ-HCD have been reported throughout the world. Up to one third of patients with γ-HCD have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjögren syndrome, lupus erythematosus, and autoimmune hemolytic anemia).[6, 7]

Watchful observation is warranted in asymptomatic patients who have low serum IgG levels and no additional evidence of disease. Management of symptomatic disease focuses on palliative care, as disease treatment has been disappointing. (See Treatment,Medication, and Follow-up)

Pathophysiology

In γ-HCD, a mutant lymphoplasmacytoid cell clone synthesizes an abnormal IgG protein. The genetic alterations in these clones include mutations, deletions, or insertions that affect both the constant and variable regions. Alterations usually involve the V (variable) and the CH 1 (constant) domains. In the first case, the hinge region usually remains intact.[8] The second type of deletion encompasses the hinge region. In either case, the resulting γ chain is usually one half to three quarters the normal length[9] and has a tendency to polymerize. The synthesis of light chains is down-regulated, suggesting either a 2-gene defect or a negative feedback effect.

Epidemiology

Epidemiologic features of γ-HCD include the following:

  • Frequency – γ-HCD is very rare, with approximately 130 US cases reported in the literature. [10]
  • Race – γ-HCD occurs in whites, Asians, and blacks.
  • Sex – γ-HCD is slightly more common in males than in females. [5]
  • Age – The age at diagnosis of γ-HCD ranges from 42 to 87 years, with a median of 68 years. [5]

     

 

Presentation

History and Physical Examination

It has been suggested that approximately 25% of patients with γ–heavy chain disease (HCD) present with localized disease, whereas two thirds exhibit disseminated disease, including medullary and extramedullary involvement, with the remainder showing gammopathy only.[11] Patients with disseminated γ-HCD present with a lymphomalike illness that includes lymphadenopathy, splenomegaly, and hepatomegaly, and often involves progressive weakness, fatigue, and intermittent fevers. Hepatosplenomegaly is present in 60% of patients.

Lymphadenopathy is present at the onset in approximately two thirds of patients with disseminated disease. It commonly involves cervical, axillary, thoracic, and abdominal nodes. It also involves the Waldeyer ring and mesenteric lymph nodes, often leading to an edematous tongue and soft palate. Lymphadenopathy becomes more pronounced as the disease progresses. Other features may include parotid gland tenderness, soreness of the tongue, autoimmune hemolytic anemia, and purpura. Skeletal involvement and hypercalcemia are rare but kidney, adrenal, and central nervous system lymphoid infiltration have been reported postmortem.

The course of γ-HCD varies from an asymptomatic presence of a nonprogressive monoclonal heavy chain in serum or urine that occasionally resolves spontaneously, to a rapidly progressive illness. A small percentage of γ-HCD exhibits a phase of monoclonal gammopathy of undetermined significance (MGUS). Most patients with progressive disease eventually succumb to bacterial infections. A series of 23 patients reported a median survival of 7.4 years.[5]

Signs and symptoms of γ-HCD are variable but include the following:

  • Fevers are frequently recurrent and resemble that of lymphoproliferative disorders.

  • Malaise may be secondary to the disease state itself or to anemia. Mild anemia is universal in patients with disseminated γ-HCD.

  • Dysphagia is usually caused by edema of the soft palate, secondary to progressive lymphadenopathy of the Waldeyer ring. This edema may also lead to tongue soreness.

  • Recurrent upper respiratory tract infections develop because of impaired humoral and cellular immunity, although other factors also can contribute, including lymphoid hyperplasia of the oropharynx that can reduce clearance of airway pathogens.

  • Abdominal pain can be present and is caused by splenomegaly (see the image below), hepatomegaly, and/or abdominal lymphadenopathy.

    The margins of this massive spleen were palpated e The margins of this massive spleen were palpated easily preoperatively. Medially, the 3.18-kg (7-lb) spleen crosses the midline. Inferiorly, it extends into the pelvis.

Causes

The causes of γ-HCD are unknown. Approximately 25% of γ-HCD patients have a history of an autoimmune disorder, as follows[10] :

  • Rheumatoid arthritis (most frequent)
  • Sjögren syndrome
  • Systemic lupus erythematosus
  • Myasthenia gravis
  • Autoimmune cytopenias (eg, immune thrombocytopenia)
 

DDx

 

Workup

Laboratory Studies

Complete blood cell (CBC) count may reveal a mild normochromic-normocytic anemia, which develops in virtually all patients. The leukocyte count and differential cell count are usually normal, although leukopenia and leukocytosis may be present. Eosinophilia and thrombocytopenia, secondary to an autoimmune process or hypersplenism, can occur.

Peripheral blood smear may demonstrate eosinophilia, neutropenia, and lymphoid plasma cells. If present, rouleaux formation suggests a high serum level of ϒ-protein.

Measurement of the creatinine level is important because renal function occasionally decreases from nodular glomerulosclerosis, precipitated by deposition of the monoclonal heavy chains.[12] Hyperuricemia is common in patients with advanced disease.

Serum protein electrophoresis (SPE) is indicated. A monoclonal spike, with an electrophoretic mobility in the α-γ regions, is detected in approximately 75% of patients. In the remainder, SPE reveals either hypogammaglobulinemia or polyclonal hyperglobulinemia migrating in the β region of the spectrum.

Urine electrophoresis often detects small amounts of ϒ-protein.[13] The Bence Jones heat test is usually negative.

Special protein studies (not universally available) include immunoelectrophoresis (IEP), immunofixation (IF), and rocket immunoselection of serum and urine. These tests, which identify and characterize the immunoglobulin class and subclass (in this case IgG1, IgG2, IgG3, and IgG4), are highly specialized tests beyond the scope of this overview. For details, readers are referred to two reviews of the subject.[14, 15]

Imaging Studies

Radiographs may show lytic lesions of bone in approximately 10% of patients (see images below). Osteoporosis is rare.

Lateral radiograph of the skull. This image demons Lateral radiograph of the skull. This image demonstrates numerous lytic lesions, which are typical for the appearance of widespread myeloma.
Radiograph of the right femur. This image demonstr Radiograph of the right femur. This image demonstrates the typical appearance of a single myeloma lesion as a well-circumscribed lucency in the intertrochanteric region. Smaller lesions are seen at the greater trochanter.

Procedures

Bone marrow biopsy with aspirate often reveals increased numbers of plasma cells, lymphocytes, and plasmacytoid lymphocytes, but results are sometimes normal. A marked increase in erythropoiesis is classic in cases associated with hemolytic anemia. Eosinophilia, mastocytosis, lymphocytosis, and other abnormalities have been noted but are rare. See the images below.

Bone marrow biopsy specimen. Bone marrow biopsy specimen.
Bone marrow biopsy specimen in fixative solution. Bone marrow biopsy specimen in fixative solution.
Bone marrow aspiration and biopsy slides before st Bone marrow aspiration and biopsy slides before staining.
Histology of eosinophilic granuloma. Histology of eosinophilic granuloma.

Lymph node biopsy can be valuable to exclude a gammopathy associated with amyloidosis, non-Hodgkin lymphoma, or granulomatous disease.

 

Treatment

Medical Care

Watchful observation is warranted in asymptomatic patients who have low serum IgG levels and no additional evidence of disease (monoclonal gammopathy of undetermined significance [MGUS]–like presentation).

Management of γ-heavy chain disease (HCD) should focus on palliative care, as disease treatment has been disappointing.

Chemotherapy, mostly using agents efficacious in lymphoma and multiple myeloma (eg, cyclophosphamide, prednisone, vincristine, chlorambucil, doxorubicin), has been disappointing. However, partial and short-lived responses have been reported using fludarabine and/or rituximab.[16, 17, 18]

Intravenous immunoglobulin (IVIg) has been used in select patients with severe hypogammaglobulinemia, although no clinical studies support the practice.

Management of complications is as follows:

  • Antibiotics for infections
  • Complication-specific management of autoimmune disorders, hemolytic anemia, and other conditions
  • Splenectomy or surgical debulking of massive, symptomatic lymphadenopathy (rarely necessary)

Consultations

Possible consultations may include oncologists, hematologists, and/or oncologic surgeons.

 

Medication

Medication Summary

Chemotherapy is typically ineffective in γ-heavy chain disease (HCD). Agents that are effective in lymphoma and multiple myeloma have generally been used, but results have been disappointing. Treatment with fludarabine and/or rituximab has resulted in partial, short-lived responses.

Antineoplastic Agents

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Fludarabine (Fludara, Oforta)

Fludarabine is a purine analogue that interferes with DNA synthesis by inhibiting ribonucleotide reductase. It is also incorporated into RNA, causing inhibition of RNA and protein synthesis; however, its primary effect may result from activation of apoptosis.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an immunoglobulin G1 (IgG1) kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Vincristine (Oncovin, Vincasar PFS)

Vincristine is a vesicant agent that blocks mitosis by arresting cells in metaphase.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline and antimicrobial compound produced by Streptomyces in culture, which causes topoisomerase-II–dependent DNA cleavage and intercalation with the DNA double helix.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is a nitrogen-mustard alkylating compound that produces highly reactive carbonium ions, which react with electron-rich areas of susceptible molecules. It is used to treat a large number of malignancies.

Chlorambucil (Leukeran)

Chlorambucil is a nitrogen-mustard alkylating agent, generally used for the treatment of chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and as a second- or third-line therapy for patients with lymphomas. It alkylates cross-link the strands of DNA, inhibiting DNA replication and RNA transcription. It may be given as a single agent or as part of a multidrug treatment regimen; depending on protocol of choice, the dose and schedule of administration are decided.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Sterapred, Orasone)

Prednisone suppresses mRNA synthesis and causes lysis of lymphoid tumors. Cell death results from cell fragmentation.

 

Follow-up

Complications

Infections, especially upper respiratory tract infections, are a complication of γ-heavy chain disease (HCD). Infections are secondary to impairment of both cellular and humoral immunity. Edema of the lymphoid tissue of the oropharynx reduces the ability to rid the airway of pathogens, perhaps by impairing the cough reflex. Most patients with γ-HCD eventually succumb to bacterial infections.

The anemia observed in patients with γ-HCD may be either anemia of chronic disease or hemolytic anemia. An autoimmune hemolytic anemia is commonly seen in patients with γ-HCD.

Like multiple myeloma, γ-HCD may cause lytic lesions of bone, which may result in fractures of long bones and vertebrae. See the images below.

Lateral radiograph of the skull. This image demons Lateral radiograph of the skull. This image demonstrates numerous lytic lesions, which are typical for the appearance of widespread myeloma.
Radiograph of the right femur. This image demonstr Radiograph of the right femur. This image demonstrates the typical appearance of a single myeloma lesion as a well-circumscribed lucency in the intertrochanteric region. Smaller lesions are seen at the greater trochanter.

Prognosis

The prognosis for patients with γ-HCD is poor. The clinical course varies: some patients remain asymptomatic for months to years; others have a waxing and waning course; and still others experience a rapidly progressive course, with death occurring within months of diagnosis.

 

Questions & Answers