HEAVY-CHAIN DISEASES AND MYELOMA-ASSOCIATED FANCONI SYNDROME: AN UPDATE

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 more rare and associated to 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 a MGUS or smoldering multiple myeloma, with renal failure and evidence of osteomalacia. During follow-up, patients can develop end-stage renal disease. Chemotherapy provides little benefit on renal function.

Two Cases of Heavy Chain MGUS

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

B-cell receptors and heavy chain diseases: guilty by association?

Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.