Gamma Heavy Chain Disease

Updated: Jan 17, 2017
  • Author: Guy B Faguet, MD; Chief Editor: Emmanuel C Besa, MD  more...
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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. 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. [1, 2]

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. [3]

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. [4] 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, Sjogren syndrome, lupus erythematosus, and autoimmune hemolytic anemia). [5, 6]

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)

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Pathophysiology

In γ-HCD, a mutant lymphoplasmacytoid cell clone synthesizes an abnormal IgG protein. The mutant clone involves genetic alterations, including 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. [7] 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 [8] 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.

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Epidemiology

Frequency

γ-HCD is very rare, with approximately 130 US cases reported in the literature. [9]

Race-, Sex-, and Age-related Demographics

γ-HCD occurs in whites, Asians, and blacks. γ-HCD is slightly more common in males than in females. [4] The age at diagnosis of γ-HCD ranges from 42 to 87 years with a median of 68 years. [4]

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