Background
The heavy chain diseases (HCDs) are lymphoplasmacytic proliferative disorders characterized by the uncontrolled production of abnormal, often structurally incomplete, immunoglobulin heavy chains. These heavy chains are produced uncoupled from light chains and may exist in serum, urine, or both.
The heavy chain diseases are divided according to immunoglobulin type (ie, immunoglobulin (Ig) G, IgM, IgA, IgD). No IgE heavy chain disease is yet known. Although alpha-heavy chain disease is the most commonly reported heavy chain disease, which tends to occur in younger patients (median age at diagnosis: 30-40 y), the most often studied heavy chain disease is gamma-heavy chain disease, or Franklin disease, which was first reported by Franklin in 1963. Up to one third of patients with gamma-heavy chain disease (Franklin disease) have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjogren syndrome, lupus erythematosus, autoimmune hemolytic anemia).[1, 2]
Pathophysiology
A mutant cell, which is derived from a normal immunoglobulin-producing cell, may produce the abnormal protein in gamma-heavy chain disease (Franklin disease). Researchers describe many different genetic alterations that affect both the constant and variable regions. Although the gamma-heavy chain disease (Franklin disease) proteins may be complete, most have deletions, causing reductions in the heavy chain length. Missing portions of the protein consist of 2 major types.
The first type is characterized by deletions of parts of the V (variable) region and CH1 (constant) domain, leaving a normal hinge region.[3] The second type of deletion encompasses the hinge region. The aberrant chains produced are often 50-66% the length of a normal heavy chain, and they tend to polymerize with each other. The synthesis of light chains is also downregulated, suggesting either a 2-gene defect or a negative feedback effect.
Epidemiology
Frequency
United States
Gamma-heavy chain disease (Franklin disease) is uncommon.
International
Gamma-heavy chain disease (Franklin disease) is uncommon.
Mortality/Morbidity
Patients with gamma-heavy chain disease (Franklin disease) usually present with a lymphomalike illness with lymphadenopathy, hepatosplenomegaly, and sometimes B symptoms. Although researchers note long, uneventful clinical courses in a few patients, most have an unfavorable prognosis.
The course of gamma-heavy chain disease (Franklin disease) is generally malignant, with expected survival of only months to 5 years, depending on the disease state at diagnosis. The disease may rapidly progress or wax and wane. Most patients eventually succumb to bacterial infections.
Race
Heavy chain disease reportedly occurs in whites, Asians, and blacks.
Sex
Gamma-heavy chain disease (Franklin disease) is slightly more common in males than females.
Age
The age at diagnosis of gamma-heavy chain disease (Franklin disease) ranges from 9 to 88 years; the median age at onset is 60 years.
Husby G, Blichfeldt P, Brinch L, et al. Chronic arthritis and gamma heavy chain disease: coincidence or pathogenic link?. Scand J Rheumatol. 1998;27(4):257-64. [Medline].
Husby G. Is there a pathogenic link between gamma heavy chain disease and chronic arthritis?. Curr Opin Rheumatol. Jan 2000;12(1):65-70. [Medline].
Faguet GB, Barton BP, Smith LL, Garver FA. Gamma heavy chain disease: clinical aspects and characterization of a deleted, noncovalently linked gamma1 heavy chain dimer (BAZ). Blood. Apr 1977;49(4):495-505. [Medline]. [Full Text].
Nasr SH, Valeri AM, Cornell LD, Fidler ME, Sethi S, D'Agati VD, et al. Renal Monoclonal Immunoglobulin Deposition Disease: A Report of 64 Patients from a Single Institution. Clin J Am Soc Nephrol. Dec 8 2011;[Medline].
Agrawal S, Abboudi Z, Matutes E, Catovsky D. First report of fludarabine in gamma-heavy chain disease. Br J Haematol. Nov 1994;88(3):653-5. [Medline].
Bloch KJ, Lee L, Mills JA, Haber E. Gamma heavy chain disease--an expanding clinical and laboratory spectrum. Am J Med. Jul 1973;55(1):61-70. [Medline].
Erikci AA, Karagoz B, Ozyurt M, et al. HLA-G expression in B chronic lymphocytic leukemia: a new prognostic marker?. Hematology. Apr 2009;14(2):101-5. [Medline].
Franklin EC. Some impacts of clinical investigation on immunology. Surface IgD, IgE, and heavy-chain variants. N Engl J Med. Mar 4 1976;294(10):531-7. [Medline].
Herzenberg AM, Lien J, Magil AB. Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case. Am J Kidney Dis. Jul 1996;28(1):128-31. [Medline].
Lee MT, Parwani A, Humphrey R, et al. Gamma heavy chain disease in a patient with diabetes and chronic renal insufficiency: diagnostic assessment of the heavy chain fragment. J Clin Lab Anal. 2008;22(2):146-50. [Medline].
Lyons RM, Chaplin H, Tillack TW, Majerus PW. Gamma heavy chain disease: rapid, sustained response to cyclophosphamide and prednisone. Blood. Jul 1975;46(1):1-9. [Medline]. [Full Text].
Osserman EF, Merlini G, Butler VP Jr. Multiple myeloma and related plasma cell dyscrasias. JAMA. Nov 27 1987;258(20):2930-7. [Medline].
Tissot JD, Tridon A, Ruivard M, et al. Electrophoretic analyses in a case of monoclonal gamma chain disease. Electrophoresis. Jul 1998;19(10):1771-3. [Medline].
Yeh CH, Tseng R, Albitar M. Plasma-based detection of clonality in lymphoid malignancies. Eur J Haematol. Jan 29 2009;epub ahead of print. [Medline].
Zhang Y, Chen L, Xu W, et al. [Immunoglobulin variable heavy chain region genetic constitution and mutation status in Chinese patients with chronic lymphocytic leukemia] [Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. Apr 2009;26(2):196-9. [Medline].
Print
