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OCR for page 283
THE THALASSEMIA SYNDROMES* AMOZ I. CHERNOFF The thalassemia syndromes are perhaps one of the least lively defined of the hereditary hemolytic diseases from the standpoint of genetic background, classification, basic biochemical abnormalities, and clinical and hematologic findings. It is hardly necessary to mention the difficulties encountered in fitting in the varied clinical pictures of thalassemia with the simple concept of heterozygosity or homozygosity for the responsible abnormal gene. It would seem most appropriate to consider that the thalassemia group of diseases is caused by a series of multiple interrelated genetic defects, not necessarily closely linked, which in various combinations give rise to a graduated series of hematologic aberrations, starting with the mildest asymptomatic state, in which the diagnosis can often only be inferred, and ending with the severe chronic microcytic hypochromic hemolytic anemia referred to as Cooley's anemia. It seems, furthermore, entirely possible that at least one of the genes involved in this syndrome is either identical with or closely related to the gene for fetal hemoglobin. This concept gains some support from ~ series of observations which we have made on adult members of at least five families in whom a very high level of Hb F`, up to 70-80 per cent, has been encountered but with peripheral blood findings only minimally suggestive of thalassemia. Different members of the same family group may show similar or more marked changes of thalassemia with or without the alterations in the concen tration of Hb F. Comparable kinships have been brought to my attention by several investigators in the New York area as well as from other parts of the country. It seems reasonable, consequently, to consider a modified genetic scheme, based almost entirely on speculation, as to the hereditary pattern of thalassemia. HYPOTHETICAL GENETIC FACTORS IN THALASSEMIA A- Enzymatic defect: Fe- E. P. reaction B - Abnormalities of red cell morphology C- Fetal hemoglobin factor Etc. THEORETICAL COMBINATIONS ABC/ABC Cooley's Anemia ABC/abc Thalassemia trait ABc/abc Minimal thalasse- mia, no Hb F aBC/abC High Hb F. min imal symptoms Ftc FIG. 1. For the sake of discussion, we may pick out three genes, not necessarily on the same chromosome' as playing a role in these syndromes (iRg. 1~. 'A' may be related to the enzymatic defect probably responsible for the inability to * Some of the studies reported in this publication were supported by United States Public Health Service Grant No. A-1615. 283

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284 PART V. CLINICAL CHARACTERIST: :CS incorporate Fe into the erythrocyte protoporphyrin. 'B' may be assigned to the defect resulting in morphologic alterations such as anisocytosis, poikilocytosis, ovalocytosis, and target cells, and 'C' to the role played by Hb F. Other letters might be assigned to stippling, stromal defects, and so forth, although all or most of these may be involved in a single genetic aberration. The full blown heterozygote or homozygote would have all three of these hypothetical abnormalities. Others may have only the abnormalities related to 'B' and 'C' and manifest minimal symptoms with high levels of Hb F. Still others may have 'A' and 'B' present without the abnormality of 'C' and consequently demonstrate a thalassemia syndrome with normal levels of Hb F. Such a scheme would perhaps permit a better explanation for the wide spectrum of hematologic and clinical findings encountered in this group of diseases. TH ALASSEMI THALASSEMIA ~ ~ TRAIT FIG. 2.Genetics of thalas- semia enamor ( after Valentine NORMAL THALASSEMIA THALASSEMIA and Neel). MAJOR TRAIT = GENE fOR THALASSEMIA For the sake of practical discussion, however, it seems best to continue the use of the simpler genetic concept proposed by Valentine and Neel pre- sented in fig. 2. In this instance, the thalassemia trait is considered to be the heterozygote for an abnormal thalassemia gene, and Cooley's anemia, the homozygote. We will continue to recognize, however, that the situation is undoubtedly much more complex than indicated in this figure. The desir- ability for accepting this less complicated system becomes obvious when it is recalled that thalassemia may be encountered in combination with other well recognized hereditary hematologic defects such as Hbs S. C, E, H and possibly D, as well as with elliptocytosis, hereditary spherocytosis, etc. Most if not all of these abnormalities are transmitted by genes located on chromo- somes different from those involved in the thalassemia states as evidenced by family studies in which one or both abnormalities may be passed on by a single parent to his or her child. The widespread distribution of the thalassemia defect is known to you all and need not be discussed except to point out the large foci of this disorder in the Mediterranean basin and the southern part of Asia. Thalassemia, how- ever, is found in all areas of the world and we have recently been impressed with its prevalence in the American Negro. The anthropologic implications of these observations provide interesting material for discussion but cannot be dealt with here.

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THE THALASSEMIA SYNDROMESCHERNOFF 28 i The most constant feature of the thalassemia syndromes is the extreme variability, from patient to patient, of the clinical symptomatology, physical findings and hematologic picture. It would serve no useful purpose to review the wide range of observations which may be encountered in uncomplicated thalassemia patients. The findings in the thalassemia-hemoglobin diseases parallel those of the aforementioned group in regards to nature, severity, and variability of the signs and symptoms. All may present as hypochromic micro- cytic hemolytic anemias of variable severity. All may demonstrate moderate to marked splenomegaly and hepatomegaly. Only a few have unique features which help to suggest the true nature of the disease. Thus, sickling in com- bination with thalassemia suggests thalassemia-lIb S disease. Greatly in- creased numbers of target cells in an otherwise uncomplicated case of thalas- semia may point to a combination with fIb C. The absence of Hb F and the presence of inclusion bodies in the red cells points to thalassemia-Hb H disease. In most instances, only a thorough study of parents, siblings and children, coupled with careful hematologic evaluation and hemoglobin analysis, will permit one to make a definitive diagnosis of thalassemia or one of its variants. The discovery of an abnormal hemoglobin in the patient's red cells, as well as in one of the parents (except in the fIb H syndromes), is of great significance. Finally, the determination of fIb F will be of importance since all of the thalassemia variants save those due to Hb lI may have significantly increased amounts of the fetal pigment. It is of interest that in spite of the presumed heterozygosity for the thalassemia gene and the abnormal hemoglobin, Hb A is rarely found on hemoglobin analysis. This problem has been dealt with in a recent publication and the suggestion was made that the absence of lIb A may be explained on the basis of suppression of the overt effects of the gene for Hb A by the thalassemia gene either directly or by virtue of the increase in Mb }I.' Recently Schwartz and co-workers have postulated a similar mech- anism in a complex family carrying stigmata of thalassemia, Hb S and Hb G.3 Furthermore, in a recent study of a family with Hb S and a possible new hemoglobin compound, Durham lRo. 1 the same evidence of suppression of Hb A exists. Consequently, the absence ot the adult compound does not ., . ~ . . necessarily imply the homo7v~0us state for the abnormal hemoglobin and ~ . _, at, . . .. , D must be interpreted in the light of the more recent observations described above. Since the Endings in thalassemia-IIb E disease parallel those of the other syndromes mentioned above, we will discuss briefly the findings in this group of diseases.' Hb E is characterized by its unique electrophoretic mobility, occupying a position midway between that of Hb C and Hb S on paper elec- trophoresis, at an alkaline pII. In acid solution it migrates more slowly than either Hb S or C and may thus be easily identified. Hb E occurs primarily in Southeast Asia, with its peak prevalence in Thailand, but with a significant incidence in Burma, Indonesia, and the regions formerly known as Indochina. Lesser numbers of patients are seen in Ceylon, India and Persia, with sporadic

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286 PART V. CLINICAL CHARACTERISTICS reports from other areas all probably ire individuals related to the Southeast Asian group of nations. The heterozygous form of fIb E, the Hb E trait, is a completely benign situation. Homozygous . .. . . . . . . . Hb E disease is characterized as an extremely mace hemo~yt~c anemia with m~crocytic normochromic red cells and little in the way of abnormal physical findings, except minimal splenomegaly. Its most striking feature outside of the genetic and hemoglobin abnormalities is the presence of up to 60-80 per cent target cells and the consequent shift in the osmotic fragility curve to the right. Thalassemia-Hb E disease has been recognized with increasing frequency in Thailand, Burma, and Indonesia and except in a few minor respects, mimics Cooley's anemia. The severest cases are in children, but individuals in their thirties have been encountered. The physical findings of enormous hepato- megaly and splenomegaly are seen in the younger age groups, but moderate to minimal organ enlargement may be encountered in the adult. Similar varia- tions are related to observations concerning weakness, fatigue, dyspnea on effort, lack of development, icterus, signs of hemolysis and bone changes. Transfusion therapy may be required as often as in the most severe example of Cooley's anemia but tends to be less of a necessity than in the latter disease. Splenectomy has been of some help in controlling the mechanical difficulties resulting from the huge organ and may also cut down on a high transfusion requirement, although no evidence of an extra-corpuscular defect has been obtained. Finally, hemoglobin analysis usually demonstrates from 20-40 per cent Hb Fat, with the remainder being Hb E. Hb A has rarely been encoun- tered in this syndrome. In summary, we have reviewed some of the many problems related to this complex and interesting group of diseases. It is apparent that much more careful genetic, hematologic and biochemical studies will be required before our understanding of this syndrome is complete. The elucidation of the role of the abnormal hemoglobins has fortunately given an impetus to further study in this area and it is only a matter of time before we will have ~ more precise foundation upon which to base our knowledge of thalassemia. REFERENCES 1. Valentine, W. N., and Neel, J. V.: Hematologic and genetic study of transmission of thalassemia (Cooley's anemia: Mediterranean anemia), Arch. Int. Med. 74: 185-196, 1944. 2. Chernoff, A. I., Minnich, V., Na-Nakorn, S., Tuchinda, S., Kashemsant, C., and Chernod, R.: Studies on hemoglobin E. I. The clinical, hematologic, and genetic characteristics of the hemoglobin E syndromes, J. Lab. 8c Clin. Med. 47: 455- 489, 1956. 3. Schwartz, H. C., Spaet, T. H., Zuelzer, W. W., Neel, J. V., Robinson, A. R., and Kaufman, S. F.: Combinations of hemoglobin G. hemoglobin S and thalassemia occurring in one family, Blood 12: 238-250, 1957.