Practice Essentials
Heavy chain diseases (HCDs) are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains: alpha, gamma, or mu. Clinical manifestations vary based on the heavy chain isotype involved, and range from an asymptomatic presentation to aggressive lymphoma. [1]
HCDs characteristically involve production of a mutated immunoglobulin heavy chain that is incapable of either partnering with light chains to form a complete immunoglobulin molecule or being eliminated via proteasomal degradation. Their defining feature is the presence of an abnormal heavy chain in the serum and/or urine without an associated light chain. [2]
Normal immunoglobulin molecules are symmetrical and consist of 2 pairs of polypeptide chains, designated the light and heavy chains, which are interconnected by disulfide bonds (see the image below). The heavy chains comprise the larger polypeptide subunits; and are specific and distinctive structures that distinguish the major classes of immunoglobulins.
Normal immunoglobulin molecules consist of 2 pairs of polypeptide chains, designated the light and heavy chains, which are interconnected by disulfide bonds. Courtesy of OpenStax (Rice University).
B cell proliferative disorders that are characterized by an anomalous serum, and sometimes urinary, protein (from free light chain) that is immunochemically related to the Fc fragment of the immunoglobulin molecule are known as HCDs. The isotype of the mutated immunoglobulin heavy chain (α, γ, or µ) determines the HCD subtype. When the anomalous protein structurally resembles the heavy chain fragment of the immunoglobulin M (IgM) molecule, it is designated as mu-HCD. Ballard and colleagues first described this entity in 1970. [3]
This article focuses on mu-HCD; other heavy chain diseases are described elsewhere (see Gamma Heavy Chain Disease).
Pathophysiology
The pathogenesis of mu-HCD is not completely understood. No viruses, chemical, physical, or genetic factors have been identified. [4] Most patients have a concurrent lymphoproliferative disorder resembling chronic lymphocytic leukemia/ small lymphocytic leukemia. There are also single reports of mu-HCD associated with myelodysplastic syndrome, amyloidosis, and diffuse large B cell lymphoma.
In mu-HCD the altered heavy chains contain deletions, insertions, and point mutations that are acquired during the process of somatic hypermutation. These alterations typically result in loss of a large portion of the constant-1 (CH1) domain of the heavy chain, which is responsible for light chain binding. Additionally, this abnormal CH1 domain is unable to bind to the heat-shock protein 78 (hsp78), which would otherwise promote proteosomal degradation of the aberrant, unbound heavy chain. The heavy chain thus bypasses elimination and is secreted into the serum, where it can be detected. [2, 5, 6]
Epidemiology
Mu-HCD is the least common of the HCDs. Fewer than 50 cases have been reported in the literature. [7] However, many cases likely have not been reported, especially in the past decade. Given the difficulty in diagnosing this disorder, most reports are from the United States, Western Europe, and Scandinavia.
Mu-HCD is predominantly reported in white men in the 5th or 6th decade of life. However, reports also exist in black and Asian patients, with ages of diagnosis ranging from 15-80 years.
Prognosis
The course of mu-HCD is variable. Survival ranges from a few months to several years, with a median survival of 24 months in well-studied cases. [8] Possible complications include pathologic fracture secondary to osteolytic lesions. Renal insufficiency occasionally is associated with mu-HCD. Etiologies include cast glomerulopathy, nodular glomerulosclerosis, and amyloidosis. Cytopenias requiring transfusion are possible in advanced disease.
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Normal immunoglobulin molecules consist of 2 pairs of polypeptide chains, designated the light and heavy chains, which are interconnected by disulfide bonds. Courtesy of OpenStax (Rice University).
