Gamma Heavy Chain Disease: 2 Cases

Case Report

Ann Hematol Oncol. 2018; 5(3): 1198.

Gamma Heavy Chain Disease: 2 Cases

Ramasamy I¹* and Rudzki Z²

¹Department of Biochemistry, Worcester Royal Hospital, UK

²Consultant Histopathologist, Heart of England NHS Trust, UK

*Corresponding author: Ramasamy I, Department of Biochemistry, Worcester Royal Hospital, UK; Email: [email protected]

Received: March 18, 2018; Accepted: April 17, 2018; Published: May 07, 2018


Gamma heavy chain disease (gHCD) is a rare lymphoproliferative disorder characterized by the production of a truncated immunoglobulin heavy chain. Fewer than 200 cases have been reported in the literature. In some cases gHCD occurs with other lymphoid neoplasms. This study reports clinical, biochemical, haematological and histological findings in two cases gHCD. The first case is a 88 year old woman with gHCD. The second case is a 81 year old woman who developed gHCD during treatment for Waldenstrom’smacroglobulinemia. In the second patient histopathology identified a separate clone responsible for the secretion of gamma heavy chain. Studies on the clonal evolution of the disease may provide insight into therapeutic implications and the genomic complexity of the disease.

Keywords: Gamma heavy chain disease; Franklin’s disease; Waldenstrom’smacroglobulinemia


Gamma heavy chain disease (gHCD) is also called Franklin’s disease after the author of the first report in 1964. The disease is defined as a neoplasm of lymphocytes, plasmacytoid lymphocytes and plasma cells characterized by the production of an abnormally truncated gamma heavy-chain protein that lacks associated light chains. Since Franklin first reported the case fewer than 200 cases have been described in the literature. A wide variety of disorders have been associated with gHCD. In some cases gHCD occurs with other lymphoid neoplasms or with a history of autoimmune disorder. gHCD shows a wide clinical spectrum ranging from completely asymptomatic to progressively malignant forms.

Normal heavy chains not associated with light chains have not been detected in serum of healthy individuals. In gHCD abnormally short truncated heavy chains can be isolated from patient’s serum without associated light chains. In several instances where the gene encoding the shortened heavy chain gene has been characterized the truncation originated from deletions and /or insertions within the rearranged variable region genes (V) that in addition harbor somatic point mutations. One possibility is that several types of oncogene translocations happen as a byproduct of somatic hypermutation [1]. It has been established the gHCD immunoglobulins are the products of aberrant biosynthesis eg deletions, splice site correction and amino-terminal proteolysis [2]. Structural analysis of the defective gamma heavy chain in 23 patients showed some common features. In most cases the variable region sequence was short and interrupted by large deletions, usually including the CH1 domain. Normal sequence began at the hinge region or at the CH2 domain [3].

Genetic subtypes of multiple myeloma (MM) have been identified which have different biological features and heterogeneity in clinical outcomes [4]. New gene sequencing techniques have yielded new insights into the pathogenesis and evolution of the disease and potential individualized treatment by novel targeted approaches [5].

We report two cases of gHCD; one in a patient with lymphadenopathy and a second case in a patient with a history of Waldenstrom’s macroglobulinemia (WM). Further we review previous case series on gHCD. These two cases were diagnosed using the techniques of capillary zone electrophoresis, immunofixation and ‘HevyLite’ measurement. In one patient there was no evidence of previous chemotherapy. The second patient developed gHCD during treatment for WM.

Case Presentation

Case 1

A88 year old woman presented with a change in bowel habit. A colonoscopy showed some diverticular disease. A CT scan showed splenomegaly and some lymphadenopathy particularly in the region of the splenic hilum. Liver, kidney, pancreas and adrenals were normal. She had a past history of osteopenia, type II diabetes and fragility fracture. She was taking vitamin B12, vitamin D and bisphosphonates. There was no history of sweating, weight loss, bruising or recent infections. Her biochemistry and hematology at diagnosis and 3 months post-diagnosis are summarized in Table 1A,1B).

Gel protein electrophoresis and immunofixation (Figure 1A) and capillary zone electrophoresis and immunotyping (Figure 3A, 3B) (Sebia UK) identified 2 gamma heavy chains. Both methods were negative for kappa and lambda light chains. Differing sensitivities of heavy and light chain reagents can cause false negative results for light chain immunofixation and the results were confirmed by a second gel electrophoresis (Helena UK) method. Urine immunofixation identified a gamma heavy chain (Figure 2A).