The changing face of homozygous sickle cell disease: 102 patients over 60 years.

Earlier reports on homozygous sickle cell (SS) disease have been biased by severely affected cases. The Jamaican clinic which seeks to avoid such bias has 102 patients surviving beyond 60 years. The objective of this study was to examine the features of elderly cases and assess factors determining survival and the behaviour of this disease with advancing age. A retrospective review of all cases and prospective assessment in survivors was conducted at The Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica previously operated by the MRC Laboratories. All patients with SS disease born prior to December 31, 1943 who would, by January 2004, have passed their 60th birthday were traced and their current status ascertained. The molecular and clinical features were assessed and observations on the clinical behaviour of the disease and of haematology and biochemistry are presented. Of the 102 patients, 58 had died, four had emigrated and 40 were alive, resident in Jamaica and aged 60-87 years. Survival was associated with female gender and higher foetal haemoglobin but not with alpha-thalassaemia or beta-globin haplotype. A tendency to familial clustering among elderly survivors did not reach statistical significance. Painful crises ameliorated with age and there was a benign course in pregnancy. Mean haemoglobin levels fell with age and were generally associated with rising creatinine levels indicating the importance of renal failure. Elderly survivors present some features of intrinsic mildness but also manifest age-related amelioration of painful crises and falling haemoglobin levels from progressive renal damage.

Phenotype/genotype relationships in sickle cell disease: a pilot twin study.

The roles of genetic and non-genetic factors in the haematology, growth and clinical features of sickle cell disease have been studied in nine identical twin pairs (six homozygous sickle cell disease, three sickle cell-haemoglobin C disease). A comparison group of 350 age-gender matched sibling pairs, selected to have an age difference of <5 years, was used for assessing the concordance of numerical data. Attained height, weight at attained height, fetal haemoglobin, total haemoglobin, mean cell volume, mean cell haemoglobin and total bilirubin levels showed significantly greater correlation in identical twins than in siblings. Twins showed similarities in the prevalence and degree of splenomegaly, susceptibility to priapism, and in onset of menarche, but other clinical complications were discordant in prevalence and severity. These findings suggest that physical growth and many haematological characteristics are subject to genetic influences, but that non-genetic factors contribute to the variance in disease manifestations.

Benign clinical course in homozygous sickle cell disease: a search for predictors.

AIMS: (1) To estimate the proportion of subjects with homozygous sickle cell disease who have a benign clinical course, and (2) to assess factors that may be predictive of benign disease. MATERIAL: Subjects (n = 280) were participants in a longitudinal cohort study of sickle cell disease. They were classified as benign or control based on clinical history from birth to age 13 years old. Associations with growth, hematology, and an index of social status were investigated. RESULTS: Benign disease occurred in 43 (15%) patients. Neither growth nor social status were related to benign disease. There were only two statistically independent associations: alpha thalassemia status and average steady state fetal hemoglobin (HbF). Patients with a normal complement of alpha globin genes were 2.2 (1.0, 4.9) times more likely to have benign disease than those with gene deletion, and were less likely to have frequent painful crises, dactylitis, and bone necrosis. The odds of having benign disease were 1.09 (1.02, 1.17) times higher for each unit increase in HbF, and 44% of subjects with HbF in the top decile (HbF > 13.8%) of the distribution had benign disease. There was no evidence for a threshold effect of high HbF on benign disease. CONCLUSION: A benign clinical course of sickle cell disease may occur in Jamaica and is associated with a normal alpha globin gene complement, and high levels of HhF. Ability to predict benign disease at birth is limited.

Influence of alpha thalassaemia on the retinopathy of homozygous sickle cell disease.

Homozygous alpha+ thalassaemia (alpha-/alpha-) ameliorates some of the clinical manifestations of homozygous sickle cell (SS) disease but its effect on retinal complications remains unknown. This has been assessed by visual examination and fluorescein angiography in 39 subjects with SS disease and homozygous alpha+ thalassaemia and in 39 age/sex matched controls with SS disease but with a normal alpha globin genotype (alpha alpha/alpha alpha). The results indicate that homozygous alpha+ thalassaemia reduces the extent of peripheral retinal vessel closure but has no apparent effect on the frequency of proliferative sickle retinopathy.

The interaction of alpha thalassaemia and sickle cell-beta zero thalassaemia.

The effects of alpha thalassaemia on sickle cell-beta zero thalassaemia have been studied by comparing haematological and clinical features in four subjects homozygous for alpha thalassaemia 2 (2-gene group), 27 heterozygotes (3-gene group), and 55 with a normal alpha globin gene complement (4-gene group). Alpha thalassaemia was associated with significantly higher haemoglobin levels and lower reticulocyte counts independent of the presence of splenomegaly. Contrary to expectation, alpha thalassaemia was associated with small but significant increases in mean cell volume and mean corpuscular haemoglobin concentration. Splenomegaly at age 5 years and episodes of acute splenic sequestration were significantly more frequent in the 4-gene group. There were no significant differences in painful crises, acute chest syndrome, or other clinical features.

Haemoglobin gene frequencies in the Jamaican population: a study in 100,000 newborns.

The gene frequencies of abnormal haemoglobins have been determined in a group of 100,000 Jamaican newborns screened over a period of 8 1/2 years. The population is predominantly of West African origin and the survey represents approximately one quarter of all island deliveries within the period of the study. The common beta globin chain abnormalities beta s and beta c occurred with gene frequencies of 0.055 and 0.019 respectively; beta thalassaemia was relatively rare. In contrast, alpha thalassaemia was quite common, occurring with a gene frequency of 0.183. In addition to these common abnormalities, the frequencies of 256 rare abnormal haemoglobins are described. This survey thus represents a complete and accurate documentation of the alpha and beta globin variants that occur in the Jamaican population.

Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood.

alpha Thalassemia modifies the hematologic expression of homozygous sickle cell (SS) disease, resulting in increased total hemoglobin and HbA2 and decreased HbF, mean cell volume, reticulocytes, irreversibly sickled cells, and bilirubin levels. The age at which these changes develop in children with SS disease is unknown. Ascertainment of globin gene status in a large representative sample of children with SS disease has afforded an opportunity to study the hematologic indices in nine children homozygous for alpha thalassemia 2 (two-gene group), 90 children heterozygous for alpha thalassemia 2 (three-gene group), and 167 children with a normal alpha globin gene complement (four-gene group). The two-gene group had significantly lower mean cell volumes from birth, higher red cell counts from one month, lower reticulocytes from three months, and higher HbA2 levels from one year, as compared with the four-gene group. Children with three genes had intermediate indices but resembled more closely the four-gene group. Differences in total hemoglobin or in fetal hemoglobin between the groups were not apparent by eight years of age. The most characteristic differences of the two-gene group were the raised proportional HbA2 level and low mean cell volume, the latter having some predictive value for alpha thalassemia status at birth.

Acute splenic sequestration in homozygous sickle cell disease: natural history and management.

Of a cohort of 308 children with homozygous sickle cell disease diagnosed at birth, 89 experienced 132 clinically significant attacks of acute splenic sequestration (ASS) over a 10-year period. The age at first attack ranged from 3 months to 6 years. Survival curve analysis of the interval until first attack indicated a cumulative probability of 0.225 by 2 years, and 0.265 by 3 years, and 0.297 by 5 years of age. Thirteen events were fatal, 11 during the first attack, and all before transfusion could be instituted. Recurrences occurred in 49% of survivors of the first attacks, and there were diminishing intervals between subsequent events. Respiratory symptoms were associated with 52 of 132 events, but bacterial isolates on blood culture were less frequent, and ASS was not prevented by pneumococcal vaccine or penicillin prophylaxis. A high fetal hemoglobin level protected against attacks of ASS. A parental education program aimed at early diagnosis of ASS was followed by an increase in the incidence rate for ASS from a mean of 4.6 per 100 patient-years to 11.3 per 100 patient-years, probably reflecting increased awareness of the complication. During the same periods, the fatality rate fell from 29.4 per 100 events to 3.1 per 100 events. The improvement in outcome is likely to have resulted from improvement in medical management and earlier detection of ASS.

Clinical presentation of homozygous sickle cell disease.

The pattern of initial clinical symptoms and signs developing in a representative sample of 305 children with homozygous sickle cell (SS) disease diagnosed at birth was analyzed. Specific symptoms were present by age 6 months in 6% of the group, and had developed by the first to eighth birthdays in 32%, 61%, 78%, 86%, 90%, 92%, 94%, and 96%, respectively. Inclusion of nonspecific symptoms in the analysis led to earlier recognition by a mean of 3 months in the first year and by a mean of approximately 1 year between the ages of 2 and 4 years. Dactylitis was the most common initial symptom, noted in 40% of the group overall and in 50% in the first 2 years. Painful crisis was the first symptom in more than one fourth of the patients and was the most frequent symptom after the age of 2 years. Acute splenic sequestration led to presentation in one-fifth of the group overall and in one third of patients younger than 2 years. The most common nonspecific symptom was pneumonia. There was a significant trend of earlier presentation in children with low fetal hemoglobin levels. The age at presentation did not appear to be affected by alpha-thalassemia status.

A genetic marker for elevated levels of haemoglobin F in homozygous sickle cell disease?

Ten patients with sickle cell (SS) disease from a Jamaican family were found to have unusually high levels of haemoglobin F for this population. Each of them has inherited one sickle cell gene on a chromosome characterized by an arrangement of restriction fragment length polymorphisms (haplotype) which is very rare in the Jamaican population. Genetic analysis of the family suggests that there is a determinant linked to the beta-globin gene cluster, characterized by this haplotype, which is responsible for increased haemoglobin F production in response to anaemia. Interestingly this particular haplotype appears to be common in patients with SS disease in eastern Saudi Arabia in whom a high level of haemoglobin F is the rule rather than the exception. Hence it is possible that this haplotype (++-++) acts as a genetic marker for elevated levels of haemoglobin F in sickle cell disease.

Alpha thalassaemia and the haematology of normal Jamaican children.

Haematological indices were studied from birth to 9 years in a representative sample of 195 children with a normal haemoglobin (AA) genotype subdivided according to the number of alpha globin genes. These were 5 homozygotes for alpha-thalassaemia 2 (two-gene group), 60 heterozygotes for alpha-thalassaemia 2 (three-gene group), and 130 with a normal alpha globin gene complement (four-gene group). HbF and HbA2 showed no differences between the groups. Compared to the four-gene group, the three-gene group tended to have significantly lower levels of total haemoglobin, MCHC, MCV, and MCH, and higher levels of red cell count. These differences became apparent with increasing age in the order of MCV, RBC, MCHC, and total haemoglobin. The data suggested that haematological differences were more marked in the two-gene group but with the small numbers available, the differences were not significant.

Multiple origins of the sickle mutation: evidence from beta S globin gene cluster polymorphisms.

Restriction site polymorphisms of the beta globin gene cluster of 244 Jamaican beta S chromosomes have been studied. Various patterns of restriction site polymorphisms (haplotypes) both 5' and 3' to the beta gene have been found. These two groups of haplotypes were found to be non-randomized with respect to each other. This is in contrast to normal beta A chromosomes where the 5' and 3' haplotypes are randomized. These findings together with the large number (18) of different beta S haplotypes found indicate that the beta S mutation probably has multiple origins.

The genetics and molecular basis of alpha thalassaemia in association with Hb S in Jamaican Negroes.

We have studied seven Jamaican Negro families in whom the genes for alpha thalassaemia and the sickle cell mutation (betas) were independently segregated. Using a combination of techniques we identified two alpha thalassaemia phenotypes which resemble the severe (alpha thalassaemia 1) and mild (alpha thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of alpha thalassaemia with the genotype in this population. Furthermore, since in each family alpha thalassaemia was present in association with the gene for the sickle cell mutation we have determined the proportion of Hb S in the peripheral blood of individuals with the alpha alpha/alpha alpha, -alpha/alpha alpha and -alpha/-alpha genotype who are also heterozygous for the betas mutation. Genetic analysis in these families shows that in each case subjects with the alpha thalassaemia 1 phenotype are homozygous for the alpha thalassaemia 2 defect (-alpha/-alpha). We have found no instances of the genotype --/alpha alpha in this population which may explain the rarity of the severe alpha thalassaemia syndromes in Jamaica. Restriction mapping data in the alpha thalassaemia 2 homozygotes from this population shows that the (-alpha/) haplotype results from a deletion of one of the linked pair of alpha globin genes and that this has probably arisen by an unequal crossover between non-homologous alpha genes.

Detection of alpha thalassaemia in Negro infants.

A prospective study of 2191 Negro infants in Jamaica showed that approximately 7% of them had detectable levels of Hb Bart's (gamma 4) in the neonatal period. The red cell indices, globin chain biosynthesis and restriction endonuclease mapping of DNA from these infants were used to determine the significance of Hb Bart's at birth. The results indicate that the genotypes alpha alpha/alpha alpha, -- alpha/alpha alpha and -- alpha/ -- alpha are associated with 0%, 0.1-2%, and greater than 2% Hb Bart's respectively. Although trace amounts of Hb Bart's may be associated with the genotype -- alpha/alpha alpha this is not always the case and therefore haemoglobin analysis in the neonatal period cannot be used to diagnose this genotype with any certainty.

alpha thalassemia in black populations.

The different alpha thalassemia genotypes in American and Jamaican black populations have been defined by hematologic and globin-chain synthesis studies, alpha/beta globin messenger RNA ratios and restriction endonuclease mapping of DNA. The results indicate that the common form of alpha thalassemia in these populations is the deletion type of alpha-thalassemia 2 (- alpha/alpha alpha). The homozygous state (- alpha/alpha- alpha) is expressed at birth by the presence of more than 2--3% hemoglobin Bart's; in adult life it has the same phenotype as the heterozygous state for the deletion form of alpha-thalassemia 1 (--/alpha alpha). The heterozygous state is not always associated with detectable amounts of hemoglobin Bart's at birth or with recognizable hematologic changes in adults.