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Gamma Heavy Chain Disease

  • Author: Guy B Faguet, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: May 19, 2014
 

Background

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. γ-HCD is a lymphoplasmacytoid lymphoma and μ-HCD clinically resembles small cell lymphoma or chronic lymphocytic leukemia.[1]

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.[2] 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).[3, 4]

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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.[5] 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[6] 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

United States

γ-HCD is very rare.

International

γ-HCD is very rare.

Mortality/Morbidity

Patients with γ-HCD usually present with a lymphomalike illness with lymphadenopathy, hepatosplenomegaly, and B symptoms.

Race

γ-HCD occurs in whites, Asians, and blacks.

Sex

γ-HCD is slightly more common in males than in females.[2]

Age

The age at diagnosis of γ-HCD ranges from 42 to 87 years with a median of 68 years.[2]

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Contributor Information and Disclosures
Author

Guy B Faguet, MD Retired Professor, Department of Medicine, Section of Hematology and Oncology, Georgia Regents University

Guy B Faguet, MD is a member of the following medical societies: American Association of Immunologists, American Society of Hematology, International Society of Hematology, New York Academy of Sciences, Southern Medical Association, Southern Society for Clinical Investigation, American Federation for Clinical Research, Southeastern Cancer Research Association, Polycythemia Vera Study Group

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Wendy Brick, MD Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group

Wendy Brick, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, and American Society of Hematology

Disclosure: Nothing to disclose.

Russell Burgess, MD (Retired) Chief, Division of Hematology/Oncology, Eastern Carolina Internal Medicine, PA

Russell Burgess, MD is a member of the following medical societies: American College of Physicians and American Medical Assocation

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. 154.

  2. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore). 2003 Jul. 82(4):236-50. [Medline].

  3. 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].

  4. Husby G. Is there a pathogenic link between gamma heavy chain disease and chronic arthritis?. Curr Opin Rheumatol. 2000 Jan. 12(1):65-70. [Medline].

  5. 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. 1977 Apr. 49(4):495-505. [Medline].

  6. Seligmann M, Mihaesco E, Preud'homme JL, Danon F, Brouet JC. Heavy chain diseases: current findings and concepts. Immunol Rev. 1979. 48:145-67. [Medline].

  7. Wester SM, Banks PM, Li CY. The histopathology of gamma heavy-chain disease. Am J Clin Pathol. 1982 Oct. 78(4):427-36. [Medline].

  8. 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. 2011 Dec 8. [Medline].

  9. Tissot JD, Tridon A, Ruivard M, et al. Electrophoretic analyses in a case of monoclonal gamma chain disease. Electrophoresis. 1998 Jul. 19(10):1771-3. [Medline].

  10. Csako G. Immunodeletrophoresis: A method with many facets. Biji T, Kurien R, Schofield H. Protein Electrophoresis and Protocols, Methods in Molecular Biology. Springer Sciences-Business Media, LLC; 2012. 869:

  11. Gale DS, Versey JM, Hobbs JR. Rocket immunoselection for detection of heavy-chain diseases. Clin Chem. 1974 Oct. 20(10):1292-4. [Medline].

  12. Takano H, Nagata K, Mikoshiba M, Nakane M, Kato A, Hamaguchi H. Combination of rituximab and chemotherapy showing anti-tumor effect in gamma heavy chain disease expressing CD20. Am J Hematol. 2008 Dec. 83(12):938-9. [Medline].

  13. Inoue D, Matsushita A, Kiuchi M, et al. Successful treatment of ?-heavy-chain disease with rituximab and fludarabine. Acta Haematol. 2012. 128(3):139-43. [Medline].

  14. Agrawal S, Abboudi Z, Matutes E, Catovsky D. First report of fludarabine in gamma-heavy chain disease. Br J Haematol. 1994 Nov. 88(3):653-5. [Medline].

  15. Yeh CH, Tseng R, Albitar M. Plasma-based detection of clonality in lymphoid malignancies. Eur J Haematol. 2009 Jun. 82(6):450-3. [Medline].

  16. 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. 2009 Apr. 26(2):196-9. [Medline].

 
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