Disease Information for Heavy chain disease (Gamma)

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Clinical Manifestations
Disease Progression
Course/Chronic disorder
Course/Chronic only
Laboratory Tests
Abnormal Lab Findings (Non Measured)
Protein electrophoresis/serum (SEP/SPE)abnormal (Lab)
Renal function abnormalities (Lab)
Abnormal Lab Findings - Decreased
Hematocrit (Lab)
Hemoglobin (Lab)
IGA/Immunoglobulin A (Lab)
IGM/Immunoglobulin M (Lab)
Platelet count (Lab)
RBC/Red Blood Count (Lab)
Vitamin B12, serum (Lab)
Abnormal Lab Findings - Increased
Eosinophiles (LAB)
BUN/Blood urea nitrogen (Lab)
Gamma globulin (Lab)
Globulin, serum (Lab)
IGA/Immunoglobulin A (Lab)
IGG/Immunoglobulin G (Lab)
IGM/Immunoglobulin M (Lab)
Plasma cells, blood (Lab)
Plasmacytosis, reactive (Lab)
Uric acid, serum (Lab)
Viscosity, serum (Lab)
Associated Diseases & Rule outs
Associated Disease & Complications
Anemia
Azotemia/Acute
Eosinophilia Hypereosinophilia
Hyperglobulinemia
Hyperuricemia
Hyperviscosity syndrome
Hypovitaminosis B12
Vitamin B12 deficiency
Hyperviscosity
Disease Mechanism & Classification
Class
CLASS/Hematologic (category)
CLASS/Leukocyte involvement/disorder (ex)
CLASS/Marrow involvement/disorder (ex)
Pathophysiology
Pathophysiology/Proteins/blood disorder (ex)
Process
PROCESS/Neoplastic (category)
PROCESS/Blood dyscrasia/leukemic process (ex)
PROCESS/Leukemia process (ex).
PROCESS/Lymphoproliferative disorder (ex)
PROCESS/Monoclonal gammopathy (ex)
Synonyms
Synonym
Gamma heavy chain disease, Gamma heavy chain disease (morphologic abnormality), disease gamma heavy chain, Franklin, FRANKLIN DIS, FRANKLIN DISEASE, FRANKLINS DIS, Franklins Disease, Franklin's Disease, GAMMA CHAIN DISEASE, gamma Chain Diseases, GAMMA HCD, Gamma heavy chain disease, Gamma heavy chain disease (clinical), Gamma heavy chain disease (disorder), Gamma heavy chain disease (dup) (disorder), Gamma heavy chain disease RETIRED, Heavy chain disease IgG type, heavy chain gamma, IGG HEAVY CHAIN DISEASE, Synonym/Franklin's disease, Synonym/IGG heavy chain disease, Synonym/IGM heavy chain disease
Definition

A disorder of immunoglobulin synthesis in which large quantities of abnormal heavy chains are excreted in the urine. The amino acid sequences of the N-(amino-) terminal regions of these chains are normal, but they have a deletion extending from part of the variable domain through the first domain of the constant region, so that they cannot form cross-links to the light chains. The defect arises through faulty coupling of the variable (V) and constant (C) region genes.

Heavy Chain Disease, Gamma

Last Updated: September 7, 2005 Wendy Brick, MD,

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.

In the US: The condition is uncommon.

Internationally: 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.

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)

DIFFERENTIALS Chronic Lymphocytic Leukemia,

Heavy Chain Disease, Mu

Lymphoma, B-Cell

Plasma cell leukemia

Chronic Lymphocytic Leukemia

Alpha Heavy chain disease

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NEJM (The New England Journal of Medicine)
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