Hereditary persistence of foetal haemoglobin: A family study suggesting allelism of the F gene to the S and C haemoglobin genes

A large family is described in which the inheritance of a gene responsible for high levels of foetal haemoglobin (the F gene) and its interaction with the gene for haemoglobin-S is followed through three generations. Four cases of SF combination are reported. An example of the the CF combination is described. Evidence is produced that the F gene is situated at the same locus as the S and C genes and the gene for classical thalassaemia, and that it is therefore an allele of them. As an altenative explanation it is suggested that the high levels of foetal haemoglobin may not result from direct gene action but may be due to a failure of inheritance of normal haemoglobin following a deletion at the A-S-C locus (or a mutation lethal for beta-chain production), with a consequent revival of the dormant mechanism of foetal haemoglobin synthesis. Sickle-cell anaemia and the SF combination are phenotypically indistinguishable, and the difficulties in explaining the very marked clinical difference between them are discussed (Summary)

The aplastic crisis in sickle-cell anaemia

Of 12 patients with aplastic crisis associated sickle-cell disease, eleven were children with sickle-cell anaemia, and one was an adult with sickle-cell haemoglobin-C disease. Ten of the cases were seen over a period of less than 7 months, and the syndrome may be commoner than has previously been supposed. Evidence is given to support the hypothesis that the distribution of sickle-cell and foetal haemoglobins in the erythrocytes in sickle-cell anaemia is not homogeneous. The fact that seven of the cases belonged to three families implies that infection may play an important aetiological role. This view is supported by the clinical presentation, and by the fact that one patient apparently had infectious mononucleosis. Bacterial and viral studies fail to demonstrate any aetiological agent in these cases (Summary)

Thalassemia in the West Indies

Data are presented on seven cases of thalassemia major (six of whom were negroes) and 32 cases ofthalassemia minor of whom eight had high levels (20-26 per cent) of fetal hemoglobin. Two families with hemoglobin H disease are presented, in whom the presence of thalassemia minor could be demonstrated. The mode of inheritance of hemoglobin H disease is discussed. Two families with an inherited double A2 fraction of hemoglobin are presented. In one of these thalassemia was also found, in the other ellitocytos is occured concurrently. On the basis of these findings the existence of at least five different types of thalassemia is postulated. A study on 93 healthy students suggests a high incidence (above 3 per) of thalassemia minor in the West Indies. (Summary)

Pernicious anaemia in Jamaica

Clinical and laboratory details are given on 10 negro patients with pernicious anaemia admitted to the University College Hospital in Jamaica in the 30 months from January, 1958, to June, 1960. All showed the usual clinical and laboratory features of pernicious anaemia; and in the patients on whom these tests were carried out the Schilling test and gastric biopsy findings were characteristic. Anorexia and loss of weight were conspicuous features. It is thought that the rarity of this disease in the negro has been overemphasized and that hospital statitics may be misleading in this respect. The literature on pernicious anaemia in other parts of the tropics is briefly reviewed. There is evidence that, in addition to the basic gastric lesion, dietary and economic factors may play a part in the genesis of the disease (AU)

Sickle-cell disease in pregnancy

17 patients with sickle-cell disease were followed through pregnancy. 9 of them had sickle-cell anaemia, 7 had sickle-cell/haemoglobin-C disease, and one had an unusual form of sickle-cell thalassaemia. The maternal and foetal hazards are discussed, and seem to be considerably less serious than in most other reports. Complications were more frequent in the puerperium. 5 out of 7 cases of sickle-cell/haemoglobin-C disease had no complications at any time. The birth-weight of the infants in this series was very much below average. The incidence of sickle-cell disease amongst pregnant women in Jamaica seems to be very similar to the incidence in the general population (Summary)

The nature of severe anaemic episodes in sickle cell disease (abstract only)

The belief that haemolytic crises in sickle cell anaemia are common is widely held. There is little or no evidence for this view. In general, patients with sickle cell anaemia maintain a stable haemoglobin level of about 7.5g/100ml. over long periods and this level is seldom affected by crises. The reserve capacity of the bone marrow is able to compensate partially for the constantly increased destruction of red cells by the reticuloendothelial system. Episodes of severe anaemia have, however, been observed in two groups of patients with sickle cell anaemia. In the first group the anaemia is due to folic acid deficiency and treatment with folic acid restores the haemoglobin level to a value which is normal for the disease. Six infants under the age of two years have been presenting this picture. In the second group consisting of six older children and one adult with sickle cell haemoglobin "C" disease the anaemic episode is attributable to an arrest of erythropoiesis at the stem cell level. There was no evidence of folic acid deficiency in these cases and recovery occured rapidly although blood transfusion was required in each case. This aplastic crisis is immediately preceded by fever and is thought to be due to infection. Further support for this view is furnished by the fact that three of the cases occured successively in one family at intervals of 15 to 20 days. It is suggested that aplastic crisis in sickle cell anaemia are much commoner than is generally recognised (AU)

Folic acid and vitamin B12 studies in megaloblastic anaemia of infancy (abstract only)

The clinical and haematological features of megaloblastic anaemia of infants are briefly reviewed. The results of assays of urinary formiminoglutamic acid on 12 infants are presented. Folic acid is required for the normal degradation of formiminoglutamic to glutamic acid and consequently in folic acid deficiency elevated levels of formiminoglutamic acid are found. The results indicate clearly that the disease is due to a deficiency of folic acid, and this is confirmed by the demonstration of normal vitamin B12 levels in the six infants in whom this assay was performed (AU)

Megaloblastic anaemia of infancy in Jamaica

The literature on megaloblastic anaemia of infancy is briefly reviewed with particular reference to its occurence with protein malnutrition (kwashiorkor). The clinical, haematological and other laboratory findings in 50 cases of megaloblastic anaemia of infancy are presented. From a clinical point of view the most striking feature is that almost all the infants were malnourished and grossly underweight. The bone marrow morphology is described, and the diagnostic value of special changes in the granulocyte series is stressed. An interesting pathological finding was the presence of extramedullary erythropoesis in the liver. This was found at necropsy in three out of six cases and on liver biopsy in seven out of ten cases. Although not constantly present, extramadullary erythropoesis is thought to be pathognomonic of the disease. Of the fifty cases in the series 45 were given folic acid and five received vitamin B12. Six of the folic acid treated cases died. The response to both folic acid and vitamin B12 in the remaining cases was excellent. No response to antibiotics was noted. The pathogenesis of the disease is discussed in some detail and illustrated with cases. Although there is no doubt of the importance of ascorbic acid deficiency and of infection in the aetiology of megaloblastic amaemia of infancy, it seems probable that a dietary deficiency of essential haemopoietic factors is the major cause. Whether the main deficiency is of folic acid or of vitamin B12 is uncertain at the present time, although in our view a deficiency of folic acid seems to likely to be the more important (Summary)

Sickle-cell anaemia complicated by megaloblastic anaemia in infancy

In a series of fifty cases of megaloblastic anaemia of infancy five cases with associated sickle-cell anaemia were seen. These cases presented with unusually low haemoglobin and reticulocyte levels for sickle-cell anaemia, and the bone marrows were megaloblastic. Folic-acid therapy produced a dramatic increase in reticulocytes and a raise in haemoglobin to the level normally seen in sickle-cell anaemia. Some degree of associated iron deficiency was present in all cases. In one of the cases described it was possible to measure the half-life of transfused erythrocytes with reasonable accuracy. The cell survival was found to be normal. The question of crisis in sickle-cell anaemia is discussed (Summary)

Some clinical aspects of abnormal haemoglobins

A short survey will be given of the different possible clinical consequences of the possession of abnormal haemoglobins both in the heterozygous and in the homozygous states. Haematuria, the crisis in sickle cell anaemia and related conditions and jaundice will be discussed in somewhat greater detail (AU)

The bone changes in sickle cell anaemia and its genetic variants

The bone changes are described in fifty-one cases of sickle cell anaemia, nineteen cases of sickle cell haemoglobin C disease and two cases of sickle cell thalassaemia. Avascular necrosis of the head of the femur has been found in all three types of sickle cell disease. These responded to treatment. The changes found in six cases of Perthes' disease in the negro compared with the changes in avascular necrosis of the head of the femur in sickle cell disease. Hyperplastic bone changes are seen only in true sickle cell anaemia and not in the variants. Secondary osteomyelitis appears to be fairly common in sickle cell anaemia. Organisms of the salmonella group have often been found in these cases (Summary)

Megaloblastic anaemia of infancy in Jamaica

The terms "megaloblast" and "megaloblastic anaemia" are defined. The megaloblast is a pathological cell and it is only found, specifically, in anaemias which are attributable to a deficiency of certain essential haemopoietic factors present in liver. The morphology of normoblasts and of megaloblasts, i.e. a cell with some of the characteristics of both a megaloblast and a normoblast, is discussed. The charateristic changes in the granulocytic series of cells, which are seen in megaloblastic anaemias, are discussed. The development of knowledge with regard to the essential haemopoietic factors present in liver is described, and the possible roles, and interrelationships of folic acid, folinic acid and vitamin B12 are discussed. It is concluded that, although their precise functions are still uncertain, there is no doubt as to their importance in nucleic acid synthesis. The literature on megaloblastic anaemia of infancy is reviewed. The rather rare association between infantile malnutrition and megaloblastic anaemia are discussed, and the fact that anaemia of any severe degree is unusual in kwashiorkor is stressed. The few available bone-marrow studies in kwashiorkor are described. A megaloblastic bone marrow has not very commonly been seen in kwashiorkor except in Durban, South Africa. A condition which resembles kwashiorkor very closely has been reported from Sicily. These infants are often very anaemic and a megaloblastic bone marrow is commonly seen. The clinical, haematological and other laboratory findings on fifty cases of megaloblastic anaemia of infancy are presented. From the clinical point of view the most striking feature was that all the infants were very malnourished and grossly under-weight. On haematological examination the best valuable finding from a diagnostic point of view was found to be the haemoglobin level. If this is below 7.0 g percent the anaemia is almost certainly going to be megaloblastic. A full blood count with determination of mean corpuscular volume, and haemoglobin concentration is rarely helpful since the anaemia is usually normocytic and normochronic. A certain diagnosis can be made by bone marrow puncture. Of the 50 cases, 45 were tested with folic acid, and 5 received vitamin B12. Six of the folic acid treated cases died. In the 39 folic acid treated who recovered, the haematological and clinical response was excellent. The 5 cases treated with vitamin B12 also showed a good haemotological and clinical response, although the dosage used was large. The majority of cases received antibiotics, and some received several, but in no case was a haematological response observed. The morphology of the bone marrow in haemaloblastic anaemia of infancy is described and extensively illustrated. In addition to typical megaloblasts, erythroblasts of intermediate type were commonly observed. The characteristic white cell abnormalities are also described. Changes in the nuclear chromatin structure of the megakaryocytes were also noted, which resemble the changes seen in megaloblasts quite closely. The post-mortem findings in the six fetal cases are summarized. Extramedullary erythropoiesis was observed in the livers of three cases, and in two a severe chronic fatty change was presented. In one case an acute fatty change was seen. The results of liver biopsies carried out on twelve other infants are also reported. Extra-medullary erythropoiesis was found in seven out of the ten specimens which were sectioned histologically. This finding of extra-medullary erythropoiesis is regarded as being pathognomonic of the disease, although it is not invariably present. Five cases of sickle cell anaemia with associated megaloblastic anaemia are described. This association has only been reported once before in infancy. Three other instances are recorded in the literature in older children. The association is highly significant, since a total of five cases out of fifty exceeds the expected incidence by no less than 3 times. An unexpected and unexplained finding was that three of these cases were also demonstrably iron deficient. The pathogenesis of the disease is considered in detail. It is thought that dietary deficiency is the most important factor, but whether of folic acid or vitamin B12 is uncertain. A deficiency of folic acid seems more likely. The possible significance of ascorbic acid deficiency in the aetiology of the disease is discussed, and the literature on the experimental production of megaloblastic anaemia in monkeys by means of a diet low in folic acid and deficient in ascorbic acid is reviewed. Only one infant in the present series had frank scurvy, and in this case ascorbic acid was required in addition to folic acid to produce a satisfactory haematological and clinical response. The importance of infection in the causation of the disease is discussed. Infections of various types were extremely common especially upper respiratory infections and gastro-enteritis. The role of gastro-enteritis is illustrated by six case in which specific pathogens were isolated from the stools. The possible mechanisms, which may be of importance in the causation of the disease, are listed: (1) A dietary deficiency of haemopoietic substance is thought to be the most significant factor. (2) An intrinsic factor deficiency is suggested speculatively as possibly playing a part. (3) Impaired absorption of haemopoietic factors due to diarrhoea is undoubtedly important. (4) Excessive utilization of haemopoietic factors by an abnormal bacterial flora in the intestine may contribute to a deficiency. (5) Diminished synthesis of haemopoietic factors by an abnormal bacterial flora in the intestine may also play a part. In conclusion some possible lines of future investigation of the disease are discussed (Summary)

Sickle-cell/haemoglobin-J disease

A case of sickle-cell/haemoglobin-J disease is reported. The interaction between the genes for haemoglobin S and J is not marked, resulting in a mild well-compensated haemolytic anaemia. Family studies suggest that the haemoglobin J was contributed by a Caucasian from North America.(AU)

Sickle-cell anaemia in adults and its differentiation from sickle-cell thalassaemia

It is relatively easy in Jamaica to separate adult cases of sickle-cell anaemia from sickle-cell thalassaemia. We present evidence to show that the great majority of our 49 adult cases of sickle-cell anaemia had the true genotype SS. We have always been able to distiguish our cases of sickle-cell thalassaemia from those with sickle-cell anaemia before family studies. The blood morphology is appreciably different in the two diseases. We were able to prove in one family that patients with sickle-cell anaemia can reach adult life and have children. Our family studies in sickle-cell anaemia have also shown the presence of an S gene in all parents and in all children of SS homozygotes. In the two years of our study we have seen only three deaths in our series of 114 cases of sickle-cell anaemia. We think that in Jamaica the true natural history of the disease presents itself, whereas in Africa it may be obscured by parasitic and other tropical diseases. This will tend to eliminate early in life those whose resistance is weakened by severe anaemia. In sickle-cell thalassaemia at least three groups of patients could be distinguished, depending on the race of the parent who had contributed the thalassaemia gene.(AU)

Megaloblastic anaemia of infancy, and the anaemia of malnutrition in Jamaica. 1 Haematological aspects. 11 Clinical aspects (abstract only)

Anaemia of any severe degree is unusual in protein malnutrition in children under two years of age, and when present it is generally attributable to parasite infestation, malaria or sickle-cell disease. A moderate degree of anaemia is however the rule, and the mean haemoglobin level of cases on admission - culled from reports all over the world - shows a remarkable constancy of 9-10g per cent. Examination of the peripheral blood is of little help as the anaemia may be macrocytic, normocytic or microcytic, and normochromic or hypochromic. There are only a few bone marrow studies reported in the literature, and with the exception of a series of cases described in Durban by Walt, Holman & Hendricks (1956), a megaloblastic bone marrow pattern has only been reported in isolated instances. In Jamaica, by contrast, we have seen over 50 cases of severe anaemia with haemoglobin levels on admission ranging from 1.5 to 7g per cent in malnourished infants under two years old. All these children had a megaloblastic bone marrow pattern with bizarre and striking changes in the myeloid cells identical to those described in infants in the United States twelve years ago by Zuelzer & Ogden. All our cases responded dramatically to folic acid therapy alone with a striking reticulocyte crisis and rapid rise in haemoglobin. In 1957 these cases constituted 6.3 per cent of all admissions to the paediatric ward or 25.6 per cent of all cases of uncomplicated malnutrition in children under two years of age. Any malnourished child in Jamaica with a haemoglobin level below 7g per cent is almost certainly suffering from megaloblastic anaemia of infancy, and we feel that folic acid should always be included in the treatment of such cases (AU)

Further observations on abnormal haemoglobins in Jamaica

The laboratory findings on 75 cases of sickle cell anaemia (genotype SS), 32 cases of sickle cell-haemoglobin C disease (genotype SC) and 11 case of sickle cell-thalassaemia disease are described. With cases reported earlier this makes a total of 114 cases of sickle cell anaemia and 45 cases of sickle cell-haemoglobin C disease which we have seen in the last two years. Approximately half our cases of sickle cell anaemia are 15 years of age or over, including three cases in one large family. Reasons are given for regarding these as cases of homozygous sickle cell anaemia. The haematological findings and foetal haemoglobin levels in these three conditions are discussed with special reference to their value in differential diagnosis. The apparent shortage of cases of sickle cell-haemoglobin C disease as compared with cases of sickle cell anaemia is discussed. A case of sickle cell anaemia responding well to splenoctomy is reported.(AU)

Sickle cell-thalassemia disease in Jamaica

Two cases of sickle-cell thalassemia disease are described in young women of mixed Chinese and African parentage. On hemoglobin electrophoresis, a complete suppression of hemoglobin A was found, giving a picture indistinguishable from that seen in sickle-cell anemia. The findings in these two cases are contrasted with those in other examples of this disease which we have studied in Jamaica. The importance of these findings in relation to the diagnosis of sickle cell anaemia is discussed (Summary)

An unusual type of hemoglobinopathy resembling sickle cell-thalassemia disease in a Jamaican family

Three generations of a Jamaican family of African extraction are desribed, in several members of which an abnormal gene is carried. This gene produces high levels of fetal hemoglobin unassociated with the usual stigmata of thalassemia. It is found in all three generations of the family associated with hemoglobin A only and is also found in at least two members of the family interacting with hemoglobin S. In the latter combination little or no disability results. The mode of inheritance of this abnormal gene is discussed, and reasons are put forward for a possible protective effect of high fetal hemogobin levels due to inhibition of sickling. The findings in the cord blood of the youngest child, including an unusually high percentage of sickling, are discussed, together with follow-up studies to the age of 25 weeks.(AU)