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Heavy Chain Disease Heavy chain disease Report of a case In 1963 and 1964, Franklin1'2 reported the first case of a rare disorder of immunoglobulin metab- olism characterized clinically by a generalized William M. Murphy, M.D.* lymphadenopathy, recurrent respiratory infec- Sharad D. Deodhar, M.D., tions, hepatosplenomegaly, and intermittent pro- Ph.D. teinuria. The serum and urine had increased amounts of protein corresponding to the heavy Department of Immunology chain fragment of IgGj-, and this disorder was John D. Battle, Jr., M.D. named "heavy chain disease." Since then 15 cases have been reported.3-5 We are reporting another Department of Hematology and case of IgG heavy chain disease which has certain Medical Oncology unusual features. Case Report A 42-year-old Negro man was first seen at the Cleveland Clinic in July 1969. Five years before he had experienced shortness of breath and a "swelling" in the left side of the neck. A diagnosis of malignant lymphoma was made from a lymph node biopsy. He received several courses of cyclophosphamide and x-ray therapy during the next few years and was essentially asymptomatic when referred for further evaluation and treat- ment. * Present address: Naval Hospital, 8750 Mountain Boule- vard, Oakland, California 94627. t IgG—immunoglobulin G; intact molecules composed of two light chains (k or X type) and two heavy chains (y). 73 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. 74 Cleveland Clinic Quarterly Vol. 39, No. 3 On physical examination the pa- vealed increased ribosomes in the tient was an obese, well-developed tumor cells indicating increased pro- man in no acute distress and with nor- tein synthesis (Fig. 2A, 2B). mal vital signs. The cervical, axillary, Clinical course. After initial evalu- submandibular, and supraclavicular ation in July 1969, the patient was lymph nodes were greatly enlarged, treated with prednisone. Vincristine varying from 2 to 8 cm in greatest sulfate was added in August 1969 and dimension. They were nontender, given until October, at which time cy- slightly firm, and matted. The liver clophosphamide was substituted. In was slightly enlarged. The remainder April 1970 he was readmitted with a of the physical examination was unre- rectal abscess. At that time corticoster- markable. oid-induced diabetes mellitus was di- Laboratory studies. Results of perti- agnosed. Chlorambucil and tolbutam- nent laboratory studies are listed in ide were added to the treatment regi- Table 1. Lymphocyte transformation men. In July 1970 x-ray films showed to phytohemagglutinin (PHA) was large abdominal lymph nodes. Only 9% (normal 50-80%), indicating an slight fluctuations in the size of the impaired cellular immune system. A peripheral lymph nodes had oc- bone marrow smear contained 34% curred, and there was no change in his mature and 4% immature plasma clinical condition. He was again ad- cells, and 2% plasmablasts. X-ray mitted in October 1970 with an epi- films of the chest, sinuses, skull, abdo- sode of cyclophosphamide-induced men, and spine showed no bony le- cystitis. At that time a complete im- sions. A supraclavicular lymph node munologic evaluation, including ex- amination of the serum obtained in biopsy was performed, and the slides July 1969 was performed (Table 2), from the original biopsy were re- and a heavy chain fragment was iden- viewed. The diagnosis of lymphocytic tified in the serum and urine. This lymphoma was confirmed (Fig. 1). Ex- protein had a different mobility from amination by electron microscopy re- Table 1.—Laboratory studies July 1969 October 1970 April 1971 Hgb (g/100 ml) 7.3 9.9 9.3 WBC/cu mm 2700 6000 18,700 Neutrophils (%) 23 32 31 Lymphocytes (%) 48 41 16 Monocytes* (%) 23 24 36 Platelets/cu mm 180,000 135,000 Normal BUN (mg/100 ml) 9 21 14 Creatinine (mg/100 ml) 1.0 1.1 Bence Jones test Negative Negative Serum protein electrophoresis Broad increase in Broad increase in 7 region 7 region Urinary protein Trace 3+ 0.97 g/100 ml Cryoglobulin Negative Cold agglutinin Negative * A few atypical cells were observed. Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. Summer 1972 Heavy chain disease 75 Fig. 1. Histology of a supraclavicular lymph node. Normal architecture of the lymph node is replaced by a uniform population of lymphocytes which infiltrate through the capsule into the surrounding adipose tissue. Hematoxylin and eosin, x80. IgG and reacted with antisera specific The patient spent most of the remain- for IgG and Fc* fragment, but did not ing 7 months of his life in the hospital react to A, Fab K or Fab Af antisera with recurrent prostatic, periprostatic, (Fig. 3). Immunoelectrophoretic com- and pelvic abscesses. The patient died parison with whole human serum in- with clinical evidence of septicemia. dicated an «-globulin mobility. A re- An autopsy was not performed. peat lymphocyte transformation to PHA was 39%. The urine continued Discussion to contain a heavy chain fragment. Heavy chain disease is a rare, al- * Fc—crystallizable fragment of IgG after though not unexpected, aberration of papain digestion; composed of fragments of IgG synthesis, in which an excess of the two heavy chains. heavy chains or portions thereof are f Fab (K or X)—antigen-binding frag- produced and secreted into the circu- ment^) of IgG after papain digestion; com- posed of portions of both light and heavy lation. The cells responsible for this chains. abnormal protein usually appear as Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. 76 Cleveland Clinic Quarterly Vol. 39, No. 3 Fig. 2. Electron microscopy of supraclavicular lymph node. A, Ultrastructural appearance of tumor cells in Figure 1 with nucleus (N) at left. The cells are larger than small lymphocytes and contain increased numbers of ribosomes, X 18,400. B, Higher magnification of the enclosed portion of the tumor cell in Figure 2A. In this area the ribosomes (R) and granular endoplasmic reticulum (ER) are particularly well developed, although the latter were not prominent features of the tissue. Uranyl acetate and lead citrate, X49,750. Table 2.—Immunologic studies Immunoelec- trophoresis Immunoglobulins Sedimentation mg/100 ml constant of Total Fc frag- abnormal protein, Specimen ment IgG GAM protein g/100 ml Serum July 1969 + -(- 9000 260 175 3.9 S 13.0 October 1970 - + 3700 240 110 8.1 Urine October 1970 -f + 2.8-3.2 S April 1971 + + 3.2 S large lymphocytes and plasma cells, sions are not seen. Examination of the and the overall clinical picture is bone marrow reveals a variable num- more closely related to a malignant ber of mature plasma and plasmacy- lymphoma than to multiple myeloma. toid cells, usually less than 30% of the Usually the patients are middle-aged total. Immature plasma cells and plas- men with lymphadenopathy that mablasts are uncommon. waxes and wanes, hepatosplen- The common feature of this disease omegaly, a peculiar uvular and pala- is the presence of an abnormal protein tal edema, and mild anemia. Bone le- in the serum and urine. This protein Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. Summer 1972 Heavy chain disease 77 migrates in the fast gamma or slow + s 0 beta region on paper electrophoresis. On immunoelectrophoresis, it precipi- tr. : - - —a tates with antisera to IgG and the Fc fragment of IgG. ft does not react © with antisera to light chains or the Fab k or Fab A fragments of fgG (Fig. 3). Ultracentrifugation of the purified protein reveals Svedberg constants © from 2.8 to 4.7 S;>o indicating the pres- ence of both heavy chain fragments ...... " d and polymers. In the few cases in which amino acid sequences have ® been studied, homology to IgG heavy chains has been demonstrated. These patients have a variable clini- cal course with death from 7 months to many years after diagnosis. Despite Fig. 3. Demonstration of heavy chain the proteinuria, which may be as fragment by immunoclectrophoresis. Wells much as 20 g/day, renal function is containing test protein(s) numbered 1 through 5. Troughs containing antisera lettered A not significantly impaired. The major through 1). Number 1—normal human complication and usual cause of death scrum; numbers 2-5—patient's urine precip- is recurrent infection, often caused by itated with ammonium sulfate and con- pneumococci. centrated 10-fold. A—Goat trivalcnt anti- serum (IgG, IgA, IgM) obtained from Hyland This patient had, in many ways, a Laboratories, Costa Mesa, California. B— typical example of heavy chain dis- Goat anti-heavy chain (Hyland). C—Goat ease. However, certain atypical fea- anti-kappa light chains obtained from Bio- tures deserve comment. Perhaps the ware, Inc., Wichita, Kansas. D—Rabbit anti- single most unusual aspect of this case lambda light chains made in the Immunology Department, Cleveland Clinic. The heavy was the presence of a large amount of chain fragment migrates toward the anode. intact IgG molecules and only a small There is no corresponding light chain pre- quantity of heavy chain fragments. It cipitin arc and no evidence of free light is possible that the abnormal protein chains. Ponceau red S. was a product of nonspecific break- down in the serum or urine, but sev- ous protein related to the Fc fragment eral facts indicated differently. The of IgG, a highly unlikely result of ran- abnormal protein obtained from spec- dom cleavage by serum or urinary en- imens collected over a period of sev- zymes. These results, viewed in the eral months had a constant mobility.
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