Delayed diagnosis of homozygous sickle cell disease in Jamaica

In a retrospective study of symptomatically referred patients with homozygous sickle cell (SS) disease, only 26 percent were diagnosed by two years of age. Since 61 percent of subjects in a neonatally defined cohort developed symptoms specific to sickle cell disease by this age, it is clear that the diagnosis is frequently overlooked or not transmitted to the parents. The greatest mortality from SS disease occurs in the first two years of life and early diagnosis of SS disease is essential for the institution of prophylactic programmes to prevent morbidity and mortality from acute splenic sequestration, pneumococcal septicaemia, and aplastic crisis. In the majority of children despite the occurrence of specific symptoms, the diagnosis of underlying haemoglobinopathy is not made early enough for effective intervention. Neonatal screening is the preferred option but if this is impractical, education of health care workers could promote earlier diagnosis of SS disease.(AU)

Comparison of homozygous sickle cell disease in Northern Greece

The clinical and hematological features of homozygous sickle cell (SS) disease were compared in 30 Greek and 310 Jamaican patients. Deletional O-thallassaemia, which modifies SS disease, is rare among Greek patients, so only Jamaican patients with four O-globin genes were included in the control group. Greek patients had higher total haemoglobin concentration and red cell counts, and lower mean cell haemoglobin concentration (MCHC) and reticulocyte counts. They also had a more normal body build and more adults had persistent splenomegaly. Fewer had a history of leg ulceration or priapism but more reported acute chest syndrome. The comparitively mild disease in Greek patients is consistent with less haemolysis and sickling and therefore less bone marrow expansion. In the absence of amelioriating factors such as high HbF concentration or O-thalassaemia, these findings may be explained by the low MCHC. (AU)

The painful crisis of homozygous sickle cell disease: a study of the risk factors

Some epidemiologic features of the painful crisis in homozygous sickle cell disease were examined in a retrospective study of 995 painful crises. Previously reported associations with cold weather and pregnancy were confirmed. There was a striking increase in painful crises in male patients between the ages of 15 and 25 years, whereas female patients showed little age-related change. The frequency of painful crises correlated positively with hemoglobin levels and reticulocyte counts in female patients. There was a striking increase in painful crises in male patients with hemoglobin levels above 8.5 g/dL (>85 g/L). High hemoglobin levels appear to be an important risk factor for painful crises.(AU)

Interaction of the OOO globin gene haplotype and sickle haemoglobin

We have studied the interaction of the OOO/OO gene arrangements with various á globin genotypes (AA, AS, AC, SS and SC). Whereas this interaction has no detectable clinical or haematological effects in subjects with AA, SS or SC genotypes it is associated with a significantly increased level of Hb S or Hb C in heterozygotes for these variants. These findings indicate that the additional O globin gene in the OOO gene arrangement is functional (Summary)

Origin of the beta S-globin gene in blacks: the contribution of recurrent mutation or gene conversion or both

In order to investigate the origin(s) of the mutation(s) leading to the beta S-globin gene in North American populations of African ancestory, we analysed DNA polymorphisms in the beta-globin gene cluster in a large number of both beta A- and beta S-globin gene-bearing chromosomes in U.S. and Jamaican Blacks. We found 16 different haplotypes of polymorphic sites associated with 170 beta S-globin gene-bearing chromosomes. The three most common beta S haplotypes, which account for 151/170 of the beta S-globin gene-bearing chromosomes, are only rarely seen in the chromosomes bearing the beta A-globin gene in these populations (6/47). Two observations suggest multiple origins or interallelic gene conversion, or both, of the beta S mutation. First, the mutation is present in all three beta-globin gene frameworks. Second, the beta S haplotypes can be divided into four groups, each of which cannot be derived from any other by less than two crossing-over events. In summary, our observation of the beta S mutation on 16 different halotypes in African populations can be best explained by (i) a number of simple recombination events 5' to the beta-globin gene and (ii) up to four independent mutations and/or interallelic gene conversions. (AU)

Neonatal screening for sickle cell disease in the Eastern Province of Saudi Arabia

Neonatal screening for sickle cell disease has been established in three hospitals in the Eastern Province of Saudi Arabia. In the first 17 months of this programme, 5630 cord blood samples were screened with the detection of 47 babies with an FS phenotype. The sickle cell trait occurred in 4.4 percent births at Al Khobar, in 6.7 percent in Dammam and in 17.9 percent in Qatif. An apparent excess of the FS phenotype over that predicted from the observed S gene frequency occurred at all three centres. The cause of this excess remains unknown although a high prevalence of sickle cell-beta-o thalassaemia and the effects of non-random mating may be contributory factors. (Summary)

The development of haematological changes in homozygous sickle cell disease: a cohort study from birth to 6 years

A cohort study of sickle cell disease from birth has allowed observations on the disease without the symptomatic selection inherent in previous series. The development of haematological indices from birth to 6 years in male and female infants with homozygous sickle cell (SS) disease is presented and compared with values in age and sex matched controls with a normal haemoglobin (AA) genotype previously presented elsewhere. In SS disease total haemoglobin levels fell rapidly from birth to a plateau at 3-6 months before falling again to 15 months after which no age related change occured. Mean cell haemoglobin concentration fell from birth to lowest values at 15-18 months before increasing to reach the level present at birth by the age of 5 years. Red cell counts fell rapidly after birth to a plateau at 2 months, increased slightly to 2 months and then fell steadily throughout the remaining period of study. The mean cell voloume and mean cell haemoglobin also fell rapidly after birth reaching the lowest values by 6 months and then increased progressively. Female patients showed significantly higher haemoglobin levels from 15 months to 4« years. Compared to AA controls, SS patients manifested significantly lower levels of haemoglobin from 2 weeks, and red cell counts from 1 month, and significantly higher levels of MCHA from 4 months to 3 years, MCV from 8 months to 5 years, and serum iron levels from 1 to 4 years. Children with SS disease were partially protected from iron deficiency in early childhood, perhaps by increased intestinal absorption of iron, and the associated increase in intracellular haemoglobin concentration might be disadvantageous during this high risk period (Summary)

Cord blood screening for sickle hemoglobin: evidence against a female preponderance of hemoglobin S

The genes controlling á-chain synthesis in hemoglobins A, S, and C are not sex linked, and sex differences in the prevalence at birth of the various á-chain genotypes would not be expected. However, the results of a recent study in the United States appeared to conflict with this expectation. In a series of 3,976 black infants whose cord blood was examined by hemoglobin electrophoresis, electrophoretic patterns compatible with AS and SS genotypes occurred in significantly higher proportions of females than males. Moreover, the number of SS births was significantly higher than expected on the basis of the observed frequency of S genes. A similar, but much larger screening program is in progress in Jamaica; results for the first 70,000 births are presented below. There were no appreciable sex differences in the proportions with AS and SS genotypes, and the number of SS births was not significantly in excess of its expected value. It seems likely, therefore, that the findings reported previously were the result of stochastic variation. (AU)

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 O thalassaemia and the sickle cell mutation (ás) were independently segretated. Using a combination of techniques we identified two O thalassaemia phenotypes which resemble the reserve (O thalassaemia 1) and mild (O thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of O thalassaemia with the genotype in this population. Furthermore, since in each family O 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 OO/OO, -O/-O genotype who are also heterozygous for the ás mutation. Genetic analysis in these families shows that in each case subjects with the O thalassaemia 1 phenotype are homozygous for the O thalassaemia 2 defect (-O/-O). We have found no instances of the genotype --/OO in this population which may explain the rarity of the severe O thalassaemia 2 homozygotes from this population shows that the (-O/) haplotype results from a deletion of one of the linked pair of O globin and that this had probably arisen by an unequal crossover between non-homologous O genes (AU)

The liver in sickle haemoglobinopathies - abstract

Hepatic structure was reviewed in 107 of 141 (76 percent) autopsies performed on patients with sickle haemoglobinopathies at the University Hospital of the West Indies. Tissue was available from 58 males and 49 females with ages ranging from 0 - 72 (mean 18) years. Genotypes included 78 SS, 9 SC, 2 SB+ thalassaemia and 18 with sickle cell disease of undetermined aetiology. In contrast with 12-29 percent prevalence in necropsy studies from USA and Africa, cirrhosis was present in only 3 (3 percent). Hepatocellular necrosis was found in 17 (16 percent) but in none did this appear to be directly related to the sickle haemoglobinopathy. Iron storage usually of mild degree was present in 48 (45 percent) and appeared not to contribute to the other hepatic structural changes. Cholestasis was seen in 14 without cirrhosis (13 percent) and was unrelated to gallstone disease. The major changes were in the sinusoids, where extramedullary erythropoiesis was present in 13 (12 percent). In 99 (93 percent) congestion of the sinusoids by erythrocytes exhibiting a variable degree of sickling was seen. Sickled cells occurred as nodules in 19 (18 percent) overall, but only in those with definite (17) or probable (2) SS. Nodules which were frequently related to Kupffer cells, were also more common in males (14). In contrast, despite sepsis being the major cause of death in 58 (54 percent) with frequent disseminated infection, Kupffer cell hyperplasia was present in only 5. Similar findings have been demonstrated in percutaneous needle biopsy of the liver in 22 patients with sickle haemoglobinopathies undergoing investigations for increased icterus (AU)

The determinants of irreversible sickled cells in homozygous sickle cell disease

The relationship between the irreversible sickled cell (ISC) count and other haematological parameters has been investigated. Positive correlations occurred with MCH, MCHC, and with two expressions of intracellular Hb S content. Since the ISC has a high MCHC, the positive correlations with MCHC and with factors derived from the MCHC may be difficult to evaluate. Negative correlations occurred with total haemoglobin and Hb F. The MCHC was found to affect the relationship between HbF and ISC count, a low MCHC being associated with, and probably determining, lower ISC counts at any level of Hb F. It is proposed that a low MCHC may inhibit ISC formation and the practical implications of this are discussed (AU)

Intepretation of lung function tests in the sickle-cell haemoglobinopathies

Prediction equations have been evolved for the assessment of vital capacity, total lung capacity, and the single breath carbon monoxide transfer factor in haemoglobin SS and haemoglobin SC disease. These relationships take account of the growth disorder and anaemia in the sickle-cell states. The results suggest that, in the clinically stable state, and effects of alveolar capillary sickling and haemoconcentration and any altered reactivity of haemoglobins S and C with the test gas are of no significance for clinical respiratory physiology. Sex differences in lung function appear independent of haemoglobin type. (AU)

Beta-chain variants in Jamaica newborns

In an electrophoretic study of 15,661 Jamaican cord bloods, 8 rare beta-chain variants were found in 18 subjects in addition to the common beta-chain variants, Hb S and Hb C. The heterozygote frequencies for Hb S and Hb C were 10.1 percent and 3.7 percent respectively. The most frequent of the rare beta-chain variants were Hb Korle Bu (beta 73 Asp leads to Asn) (7 cases) and Hb O su-Christiansborg (beta 52 Asp leads to Asn) (3 cases). One new beta-chain variant, Hb Caribbean (beta 91 Leu leads to Arg) was found. (AU)

Variations in globin chain synthesis in hereditary persistence of fetal haemoglobin

Globin synthesis was studied in four Negro families including 10 members with Hb A-HPFH and four with Hb S-HPFH. The á/O specific activity ratios in 10 of these patients with Hb A-HPFH heterozygotes were similar to those of the control group. In two patients with Hb A-HPFH, the á/O ratio was slightly decreased in one (0.84) and clearly decreased in another (0.78). In two of the patients with Hb S-HPFH the ratios were clearly decreased (0.71 and 0.75). The extended range of á/O ratios in these 14 patients is similar to that of Negro patients with á-thalassaemia trait. These studies indicate that a decreased á/O ratio may be found in HPFH, as well as in á-thalassaemia. Bone marrow globin synthesis was measured in two patients with Hb S-HPFH and decreased peripheral blood á/O ratios, and in one with Hb A-HPFH and a normal peripheral blood á/O ratio. In each patient the (á+y)/O ratio of radioactivities as well as the á/O specific activity ratio was close to I and therefore balanced, indicating more rapid decay of á-chain synthesis relative to O-chain during red cell maturation or extremely rapid destruction of newly synthesized excess O-chains in the bone marrow.(Summary)