Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The heavy chain diseases

S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD


The heavy chain diseases (HCDs) are rare B cell proliferative disorders characterized by the production of a monoclonal (M) protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain [1-6]. The heavy chain in HCD is often incomplete or truncated and a sharp, localized peak may not be seen on the electrophoretic tracing of serum or urine.

The HCDs will be reviewed here. Heavy chain deposition disease is a different disorder that is discussed in detail elsewhere, in which abnormal heavy chains or short (truncated) heavy chains cause fibrillar or granular tissue deposits. (See "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases" and "Prognosis and treatment of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases".)


Three types of HCDs are recognized, based upon the class of immunoglobulin heavy chain produced (eg, alpha, gamma, mu) by the malignant cell [3,5,6]:

Alpha HCD is a form of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) that is also called immunoproliferative small intestinal disease (IPSID), Mediterranean lymphoma, or Seligmann disease. (See 'Alpha HCD' below and "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine' and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Gamma HCD (Franklin's disease) is typically associated with the presence of a systemic lymphoma, often of mixed lymphoid-plasmacytic character. (See 'Gamma HCD' below.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Aug 02, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Grogan TM, Van Camp B, Kyle RA, et al. Plasma cell neoplasms. In: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds), IARC Press, Lyon 2001. p.142.
  2. Wahner-Roedler DL, Kyle RA. Heavy chain diseases. Best Pract Res Clin Haematol 2005; 18:729.
  3. Munshi NC, Digumarthy S, Rahemtullah A. Case records of the Massachusetts General Hospital. Case 13-2008. A 46-year-old man with rheumatoid arthritis and lymphadenopathy. N Engl J Med 2008; 358:1838.
  4. Corcos D, Osborn MJ, Matheson LS. B-cell receptors and heavy chain diseases: guilty by association? Blood 2011; 117:6991.
  5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  6. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  7. Haas IG, Wabl M. Immunoglobulin heavy chain binding protein. Nature 1983; 306:387.
  8. Alexander A, Anicito I, Buxbaum J. Gamma heavy chain disease in man. Genomic sequence reveals two noncontiguous deletions in a single gene. J Clin Invest 1988; 82:1244.
  9. Hendershot L, Bole D, Köhler G, Kearney JF. Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain-binding protein. J Cell Biol 1987; 104:761.
  10. Prelli F, Frangione B. Franklin's disease: Ig gamma 2 H chain mutant BUR. J Immunol 1992; 148:949.
  11. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore) 2003; 82:236.
  12. Husby G, Blichfeldt P, Brinch L, et al. Chronic arthritis and gamma heavy chain disease: coincidence or pathogenic link? Scand J Rheumatol 1998; 27:257.
  14. Fermand JP, Brouet JC. Heavy-chain diseases. Hematol Oncol Clin North Am 1999; 13:1281.
  15. Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as a benign monoclonal gammopathy. Am J Hematol 1992; 40:56.
  16. Agrawal S, Abboudi Z, Matutes E, Catovsky D. First report of fludarabine in gamma-heavy chain disease. Br J Haematol 1994; 88:653.
  17. Bianchi G, Anderson KC, Harris NL, Sohani AR. The heavy chain diseases: clinical and pathologic features. Oncology (Williston Park) 2014; 28:45.
  18. Preud'homme JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu heavy chain disease. Clin Nephrol 1997; 48:118.
  19. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemic amyloidosis. Hematology 2004; 9:135.
  20. Zucker-Franklin D, Franklin EC. Ultrastructural and immunofluorescence studies of the cells associated with mu-chain disease. Blood 1971; 37:257.
  21. Yanai M, Maeda A, Watanabe N, et al. Successful treatment of mu-heavy chain disease with fludarabine monophosphate: a case report. Int J Hematol 2004; 79:174.