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HEMOGLOBIN C DISEASES HELEN M. RANNEY The electrophoretic properties of hemoglobin C were described in 1950 by Itano and Neel,5 and the clinical findings accompanying the presence of this abnormal hemoglobin in the heterozygous state and in combination with sickle cell hemoglobin were reported by Kaplan, Zuelzer and Neel.7 The in- troduction of kilter paper electrophoresis greatly facilitated the identification of hemoglobin C, and the occurrence of this abnormal hemoglobin in four con~- binations has been described. These combinations are: (1) hemoglobin C trait, where hemoglobin C is found together with normal adult hemoglobin, (~) sickle cell-hemoglobi~2 C disease, in which hemoglobin C and hemoglobin S occur in approximately equal amounts, (3) hemoglobin C disease where vir- tually all the hemoglobin is of this abnormal variety and (4) hemoglobin C- thalassemia in which the hemoglobin electrophoretic pattern resembles that of hemoglobin C disease, but in which the affected individual has a single genetic factor for hemoglobin C in addition to a gene for thalassemia. This report is concerned with the clinical manifestations associated with the presence of hemoglobin C in hemoglobin C trait, hemoglobin C disease, and hemoglobin C-thalassemia. Little will be said about sickle-cell hemoglobin C disease, since Dr. E. W. Smith has already covered the important aspects of that disorder. Hemoglobin C trait. The combination of hemoglobin C and normal adult hemoglobin in asymptomatic individuals was first detected in family studies;7 however, large scale surveys for abnormal hemoglobins revealed hemoglobin C trait in 2 to 3 per cent of American Negroes. A Very high ~ncidences of hemoglobin C were detected in certain areas of West Africa; indeed, in some communities of the northern Gold Coast (now Ghana), more than 20 per cent of the individuals studied were found to have hemoglobin C.9 No clinical symptoms have been associated with hemoglobin C trait; the only observed abnormality in these individuals has been an increased number of target cells on blood smears. We have encountered a single patient with hemoglobin Cal trait and unexplained hematuria, but the association was probably fortuitous. The hemoglobin of individuals with hemoglobin C trait has been tom- posed of approximately 30 to 45 per cent hemoglobin C, with the larger re- maining fraction being normal adult hemoglobin. No significant increase in alkali-denaturable hemoglobin has been observed. Sickle cell-hemoglobin C disease. In terms of the frequency of the disease and the severity of symptoms, sickle cell-hemoglobin C disease is the most important of the disorders associated with the presence of hemoglobin C. ~ This study has been supported by Grant A-1017 of the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service. 287

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288 PART V. CLINICAL CHARACTERISTICS The large number of reported cases attests to the fact that this is a common disorder in American Negroes. An increased incidence of crises during preg- nancy, bone infarcts, particularly in the femoral head, and ocular changes have been encountered. Our particular interest in patients with sickle cell-hemo- globin C disease has been a study of the mode of inheritance of hemoglobin C and sickle cell hemoglobin. Studies of eight offspring of sickle cell and normal individuals revealed only hemoglobin C trait or sickle cell trait in the off- spring (figs. 1 and 2~; it seems probable that genes responsible for sickle cell hemoglobin and hemoglobin C are allelic or are closely linked.~3 FIGS. 1 and 2. Filter paper electrophoretic patterns of hemoglobin. Veronal buffer, pH 8.6. Offspring of S/C x A/A had either hemoglobin C trait or sickle cell trait. Hemoglobin C disease. The term "hemoglobin C disease" in this report refers to the clinical manifestations of the patient who is, or who is pre- sumed to be, homozygous for the gene for hemoglobin C. Hemoglobin C disease, therefore, occurs in approximately one-quarter of the offspring of marriages of two individuals, each possessing a single gene for hemoglobin C (fig. 3~; most commonly, of course, each parent would be expected to have hemoglobin C trait. Since many of the patients with hemoglobin C disease were first detected in adult life, genetic proof of homozygosity has been fre- quently lacking in reported cases. The offspring of the marriage of an indi- vidual with hemoglobin C disease to an individual levity normal hemoglobin FIG. 3. Child with hemoglobin C disease and increased fetal hemo- globin ( rapid component ) .~3 Note resemblance of pattern to that of propositus in figure 7.

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HEMOGLOBIN C DISEASESRANNEY 289 have shown ire every reported instance hemoglobin C trait (fig. 4~. The finding of hemoglobin C trait in offspring does not prove homozygosity, but the absence of hemoglobin C in offspring would prove heterozygosity of the parent with hemoglobin C. The analysis of the hemoglobin of parents and offspring of individuals with hemoglobin C disease is the most reliable method of distinguishing hemoglobin C disease from hemoglobin C-thalas- semia. FIG. 4.Hemoglobin C disease in mother. Each child had hemoglobin C trait. :. ~ The following observations on hemoglobin C disease are based upon data from 34 patients;], 3, 4' 6, s, 1o-l7, 10 '1-'' all but one have previously been reported in the American or British literature. The outstanding features of hemoglobin C disease may be summarized as follows: 1) splenomegaly, 2) a mild hemolytic process, with or without an attendant anemia? and 3) large renumbers of target cells in the stained smears. Most of the cases have been detected in the course of evaluation for complaints unrelated to hemoglobin C disease or were found incidental to the investigation of hemoglobin patterns of families. It may properly be inferred, therefore, that this is a benign disorder. The electrophoretic pattern of hemoglobin in hemoglobin C disease consists virtually entirely of hemoglobin C; two casesS 13 have shown an increase in fetal hemoglobin (figs. 3 and 4~. In table I are summarized some of the features of hemoglobin C disease. The age range extended from 4 to 79 years; in view of sampling bias such as might be introduced by the study of patients at Veterans' hospitals, the pre- dominance of males is of doubtful significance. The occurrence of hemo- globin C disease in non-Negro populations was noted by Diggs et al., who observed the disease in a male of Italian extraction and by Lewis and co- workers,l1 who reported three cases in a white South African family. W have recently observed another South African man of Dutch and French ancestry with hemoglobin C disease. Anemia, as indicated above, in uncomplicated hemoglobin C disease is mild or absent in the reported cases; the only reported case with severe

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290 PART V. CLINICAL CHARACTERISTICS TABLE I HE~CGECBIN C DISEASE ( 34 cases ) Ages: 4-79 yrs. Males 23 Females 1 1 Dutch West South Race or Negro Italian Indian -African White Nationality 27 1 2 4 Anemia: Severe Mild None Splenomegaly: 32 of 34 cases Male Female 3 19 Approximately one-third had normoblasts on smear; target cells were a constant feature, varying from 10 to 90~o. anemia was a 79-year-old man with an infection.~5 In table I most of the patients with anemia are women; this finding may be related to the fact that hemoglobin values are normally lower in women than in men, and perhaps hemolytic process may become manifest as anemia more readily in females. Studies of the survival time of erythrocytes in hemoglobin C disease have invariably disclosed a hemolytic mechanism despite the absence of anemia (table II). Erythrocyte survival times of 40 to 60 days, with one-half survival times of 13 to 24 days were observed.S' 15, i7, 2~, 9~, 94 The data are consistent with the assumption that the shortened survival time is related to an intra- corpuscular defect. The only exception to the latter statement is the second patient of Lange and co-workers;S their patient had an infection during the course of the erythrocyte survival study. TABLE II ERYTHRCCYTE SURVIVAL IN HEMOGLOBIN C DISEASE Author Method Pt. cells Normal Pt. cells to normal cells to in pt. recipient pt. recipient days days days Spaet Ashby ct al. agglut. 55 Singers' Ashby mean 13 et al. agglut. Weinstein Cry half19 et al.04 Terry Ashby 42 106 et al.20 Hb. sep. LangeS Cry normal av. 21 et al. short av. 24

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HEMOGLOBIN C DISEASES RANNEY 291 The more readily available laboratory tests for a hemolytic process usually have yielded less impressive data. Reticulocytosis has, in general, been less than 5 per cent, although normoblastic hyperplasia of the bone marrow has been found. Nucleated erythrocytes have been found in many of the peripheral blood smears. The most impressive finding on blood smear was the increased number of target cells, frequently with erythrocyte "folding" (fig. 5~. How- ever, in some cases the target cells have comprised only 10 to 30 per cent of the erythrocytes. Obviously the number of target cells carrot be used to distinguish hemoglobin C disease from hemoglobin C trait, since 20 to 30 per cent target cells have been seen in hemn~lohin (A frnit :-- :. F`IG. 5.Blood smear of patient with hemoglobin C disease. Note target cells and erythrocyte "folding." F`IG. 6."Intra-erythrocytic crystals" in a patient with hemoglobin C disease after splenectomy (Diggs et al.~). Shown at higher magnification than slide in figure 5. Splenomegaly is an almost constant feature of hemoglobin C disease. Only twos 93 of the thirty-four cases summarized in this review lacked a palpable spleen, and one of these was a child of three and a half years. Spl~enectomy was carried out in four cases of hemoglobin C disease:' id, ]7, 25 in three, the procedure was done for mechanical enlargement of the organ, and in the fourth'' a mild anemia and significant thrombocytopenia were relieved by splenectomy. In two of the four patients subjected to splenectomy an extra- ordinary appearance of some of the erythrocytes was noted following splenec- tomy Wing. 6~. The exact nature of these hemoglobin masses in erythrocytes is Dracula to ascertain; they are believed to represent hemoglobin crystals by

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292 PART V. CLINICAL CHARACTERISTICS Riggs and co-workers.4 Wheby et al.>' have noted similar changes in the blood smear of a patient with hemoglobin C disease following splenectomy. The mechanism of the effects of splenectomy upon formed elements of the circulating blood is little understood, and these Endings add another intriguing observation in that held. In summary, hemoglobin C disease is a benign hemolytic disorder, occurring chiefly but not entirely in Negroes. Splenomegaly and target cells are more constant findings than is anemia. Only one patient has developed evidence of "hypersplenism"; patients with anemia and thrombocytopenia returned to normal following splenectomy. Hemoglobin C-~halassemia. The combination of thalassemia and hemo- globin C has been described in several patients. Is _6 The diagnosis for four of the reported cases has rested upon the demonstration of thalassemia in one parent of the affected individual and hemoglobin C trait in the other parent (fig. 7 ). The clinical picture which accompanies this combination of genetic factors has been quite variable. Anemia is a prominent feature in two cases and FIG. 7. Propositus whose hemo- globin was mostly of the C variety had hemoglobin C-thalassemia. Note absence of abnormal hemo- globin of father who had thalas- semia minor with an increased A.' - hemoglobin. . ~ FIG. 8. Blood smear of patient with hemoglobin C-thalassemia. Hypochromia, target cells and nucleated erythrocytes are seen.

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HEMOGLOBIN C DISEASES RANNEY 293 splenomegaly is seen in three cases. Microcytosis, hypochromia, target cells (fig. 8), arid, in some cases, microspherocytosis is seen on smears. Ire table III are summarized the findings of reported cases of hemoglobin C-thalassemia. Three of the cases occurred in Negroes and the remaining three in patients of Italian extraction. Reticulocytosis was usually not prominent feature except during a hemolytic episode in the author's case. A great variation in the amount of hemoglobin C was noted. The case of Zuelzer and Kaplan'' was the most severely anemic but showed only 29 per cereal hemoglobin C with no increase in fetal hemoglobin. Values of more than 90 per cent hemoglobin C were noted by Erlandson et al.;2 their patients had hemoglobin electrc~pl~oretic patterns indistinguishable from those of patier~ts with hemoglobin C disease. While most of the reported patients have had some increment of normal adult hemoglobin in addition to hemoglobins C' and A, the amount of hemoglobin A nary be so small tot accurate determi- nation is difficult. Consequently, a study of the hemoglobin of other members of the family is a more reliable way of establishing the diagnosis of hemoglobin C-thalassemia than analysis of the hemoglobin of the affected individual alone. The sixth case was ire many respects unusual. The patient was initially seen at the Presbyterian Hospital in 1941, at which time splenomegaly, a severe hemolytic anemia with 32 per cent reticulocytosis and a decreased osmotic fragility were found. Following; splenectomy, her hemoglobin stabi- lized at 8 to ~ O grams per cent with 2 to 4 per cent reticulocytes. The large amount of hemoglobin C (78 per cent) in this patient has been ac- companied by the appearance of occasional "intraerythrocytic" crystals. Hemoglobin C-thalassemia is an uncommon disorder associated with the simultaneous presence of genetic factors for hemoglobin C and thalassemia. While all the patients showed microcytosis and target cells, splenomegaly appeared in only half the cases, and two of the six cases were markedly anemic. TABLE III HEMOGLOBIN C-THALASSEMIA DISEASE Zuelzer and"; Singer e! alit Kaplan Erlandson e' alp Ranney Age: 68 29 6 10 14 36 Race or Nationality of parents: Negro Negro Negro Italian Italian Italian ( Sicily) ( Sicily) Splenomegaly: 0 0 0 yes yes yes spl enectoms Hemoglobin, gum/,,: 12.7 11.5 6.1 9-11 9-11 5-10 Microcytic: yes yes yes yes yes yes Reticulocytes, C/G 3.8 2.0 3.6 2.3 2.3 32-0.5 Osmotic fragility: deer. deer. deer. deer. deer. deer. Hemoglobin C, %: 77 74 29 93 90 78 Fetal hemoglobin, /: 0 2.7 <2 1.4 0.4 5

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294 PART V. CLINICAL CHARACTERISTICS A severe hemolytic anemia in one case was alleviated by splenectomy. In view of the variation in clinical symptoms and in the amounts of hemoglobin C present, hematologic studies of the family are usually needed to establish the diagnosis. Summary. 1. Hemoglobin C trait is art asymptomatic state occurring in 2 to 3 per cent of American Negroes, with much higher incidence in certain areas of Africa. 2. Hemoglobin C disease is a mild disorder occurring predominantly in Negroes. Splenomegaly' target cells on blood smears, and a mild hemolyti~ process with or without anemia are prominent features. The hemoglobin is virtually all of the "C" variety. 3. Hemoglobin C-thalassemia is accompanied by greater variability in the clinical findings than hemoglobin C disease. The amount of hemoglobin C in this rare disorder has varied from 29 per cent to over 90 per cent; conse- quently, family studies are recommended for distinguishing between hemo- globin C disease and hemoglobin C-thalassemia. ~1ckrzowledgments: Figures 1, 2, 3 and 4 were reproduced by permission from the Journal of Clinical Investigation 33: pp. 1636 and 1637, ~ 954. Figure 6 was reproduced by permission from the article by Dr. L. W. Diggs en al., Blood 9: p. 1174, 1954. REF~EREN CES 2. 3. 4. 7. 1. Diggs, L. W., Kraus, A. P., Morrison, D. B., and Rudnicki, R. P. T.: Intraery- throcytic crystals in a white patient with hemoglobin C in the absence of other types of hemoglobin, Blood 9: 1172, 1954. Erlandson, M., Smith, C. H., and Schulman, I.: Thalassemia-hemoglobin C disease in white siblings, Pediatrics, 17: 740, 1956. Hartz, W. H., and Schwartz, S. O.: Hemoglobin C disease, Blood 10: 235, 1955. Huisman, T. H. J., van der Schaaf, P. C., and van der Sar, A.: Some characteristic properties of hemoglobin C, Blood 10: 1079, 1955. Itano, H. A., and Neel, J. V.: A new inherited abnormality of human hemoglobin, Proc. Nat. Acad. Sci. 56: 613, 1950. Jensen, W. N., Schoefield, R. A., and Agner, R.: Clinical and necropsy findings in hemoglobin C disease, Blood 12: 74, 1957. Kaplan, E., Zuelzer, W. W., and Peel, J. V.: A new inherited abnormality of hemoglobin and its interaction with sickle cell hemoglobin, Blood 6: 1240, 1951. 8. Lange, R. D., and Hagen, P. S.: Hemoglobin C disease in identical twins, Am. J. Med. Sci. 229: 655, 1955. 9. Lehmann, H.: Distribution of abnormal hemoglobins, J. Clin. Path. 9: 180, 1956. 10. Levin, W. C., Schneider, R. G., Cudd, J. A., and Johnson, J. E., Jr.: A family with homozygous hemoglobin C and sickle cell trait union. A clinical, hematological and electrophoretic study, J. Lab. and Clin. Med. 42: 918, 1953. 1 1. Lewis, S. M., Anderson, C. G., and Baskind, E.: Homozygous haemoglobin-C disease in a white family with special reference to blood autolysis studies, Brit. J. Haemat. 3: 68, 1957. _. Motulsky, A. G., Paul, M. H., and Durrum, E. L.: Paper electrophoresis of abnormal hemoglobins and its clinical applications, Blood 9: 897, 1954.