AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. HCDs are divided according to immunoglobulin type, ie, immunoglobulin G (IgG), IgM, IgA, and IgD. No IgE HCD is yet known. The most often-studied HCD is gamma-HCD, or Franklin disease, which was first reported by Franklin in 1963. Up to a third of patients with gamma-HCD have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjögren syndrome, lupus erythematosus, autoimmune hemolytic anemia).

Pathophysiology

A mutant cell, which is derived from a normal immunoglobulin-producing cell, may produce the abnormal protein in Franklin disease. Researchers describe many different genetic alterations that affect both the constant and variable regions. Although the gamma-HCD 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. 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 tend to polymerize with each other. The synthesis of light chains is also down-regulated, suggesting either a 2-gene defect or a negative feedback effect.

Frequency

United States

The condition is uncommon.

International

The condition is uncommon.

Mortality/Morbidity

Patients with gamma-HCD 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 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

HCD reportedly occurs in whites, Asians, and blacks.

Sex

The disorder is slightly more common in males than females.

Age

Age at diagnosis ranges from 9-88 years; median age at onset is 60 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients often report a history of progressive weakness, fatigue, and intermittent fevers. Lymphadenopathy, splenomegaly, and hepatomegaly are common. Other features include parotid gland tenderness, severely sore tongue, autoimmune hemolytic anemia, and purpura. The clinical course ranges from rapidly progressive, resulting in death within a few weeks, to asymptomatic chronic disease. Because so few patients have been reported with HCD, projecting a median survival time is difficult. However, from 49 described patients, the median survival time was 12 months.

• Symptoms of gamma-HCD are variable but include the following:
• • Fevers are frequently recurrent and are secondary to impairment of both cellular and humoral immunity.
  • Malaise may be secondary to the disease state itself or to an anemia. Mild anemia is universal in patients with HCD.
  • Dysphagia is usually caused by edema of the soft palate, secondary to progressive lymphadenopathy of the Waldeyer ring. This edema may also lead to tongue soreness.
  • Recurrent upper respiratory tract infections develop because of impaired humoral and cellular immunity. Edema of the upper respiratory tract, observed when lymphoid tissue of the oropharynx enlarges, may contribute to recurrent upper respiratory tract infections by reducing the ability to rid the airway of pathogens.
  • Splenomegaly, hepatomegaly, and/or abdominal lymphadenopathy cause abdominal pain and are often associated with gamma-HCD.

Physical

• Lymphadenopathy
• • Develops in 60% of patients and may wax and wane
  • Commonly involves cervical, axillary, thoracic, and abdominal nodes
  • Also involves Waldeyer ring and mesenteric lymph nodes, often leading to an edematous tongue and soft palate
  • Becomes more pronounced as disease progresses
• Hepatosplenomegaly (60%)
• Parotid gland swelling
• Lytic lesions of the bones, similar to those observed in multiple myeloma (only occasionally)

Causes

Causes or risk factors for gamma-HCD are not known.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Plasma cell leukemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Immunoelectrophoresis or immunofixation of serum and urine
• • Conduct immunoelectrophoresis or immunofixation to detect the monoclonal gamma heavy chain without an associated light chain.
  • Immunoselection combined with immunophoresis is the most reliable test but is not available at all institutions.
• Order serum and/or urine protein electrophoresis, which often shows a more broad-based band than the typical M-spike diagnostic of a monoclonal protein. The abnormal band often migrates to the beta region and not to the gamma region.
• CBC count
• • This test may reveal a mild normochromic-normocytic anemia, which develops in virtually all patients.
  • A peripheral blood smear may demonstrate eosinophilia, neutropenia, and lymphoid plasma cells. Rouleaux formation may also be noted.
  • Creatinine level is important because renal function occasionally decreases from nodular glomerulosclerosis, precipitated by deposition of the monoclonal heavy chains.
• Uric acid level: Hyperuricemia is common in affected patients.

Procedures

• Bone marrow biopsy with aspirate: This test often reveals increased numbers of plasma cells, lymphocytes, and large immunoblasts, although biopsy and aspirate findings are sometimes normal. Eosinophilia is also a commonly recognized feature and is occasionally the only abnormality noted in the marrow.
• Lymph node biopsy
• • Even though gamma-HCD does not have specific histologic patterns, this procedure may exclude other causes of lymphadenopathy.
  • The lymph node biopsy may also reveal pleomorphic lymphocytes, plasma cells, or findings suggesting granulomatous disease.

Histologic Findings

Bone marrow biopsy and aspirate findings may be normal but often reveal increased numbers of plasma cells, lymphocytes, and large immunoblasts. Eosinophilia is also a commonly recognized feature and is sometimes the only abnormality noted in the marrow. The lymph node may reveal pleomorphic lymphocytes, plasma cells, or findings suggesting granulomatous disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treat only the symptomatic patient since chemotherapeutic results are often disappointing. Use chemotherapeutic agents that are effective in treating multiple myeloma (eg, cyclophosphamide, prednisone, vincristine, chlorambucil, doxorubicin). If remissions are achieved, they are usually short lived.

Consultations

• Oncologists
• Hematologists

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treat only symptomatic patients because results of chemotherapeutic approaches are often disappointing. Use agents that are effective in treating multiple myeloma.

Drug Category: Antineoplastic agents

Inhibit cell growth and proliferation.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Infections, especially upper respiratory tract infections: Infections are secondary to impairment of both cellular and humoral immunity. Edema of the lymphoid tissue of the oropharynx reduces the ability to rid the airway of pathogens, perhaps by impairing the cough reflex. Most patients with HCD eventually succumb to bacterial infections.
• Anemia: The anemia observed in patients with HCD may be either anemia of chronic disease or hemolytic anemia. An autoimmune hemolytic anemia is commonly seen in patients with HCD.
• Increased incidence of fractures of long bones and vertebrae: HCD, as with multiple myeloma, may be associated with lytic lesions leading to increased incidence of fractures.

Prognosis

• Prognosis is poor. The clinical course varies because some patients remain asymptomatic for months to years, while others have a waxing and waning course. Still others experience a rapidly progressive course with death occurring within months of diagnosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose and treat: Although no good treatment exists for HCD, correct diagnosis and treatment may lead to better palliative care, including prophylactic antibiotics if clinically warranted.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• 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].
• 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].
• 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].
• 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].
• 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].
• 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].
• 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].

Article Last Updated: Sep 7, 2005