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Three Sicilian siblings had a typical cone-rod dystrophy. The same ocular anomaly was probably present in their mother and in the maternal grandmother. The three probands were also carriers of Hb S, but this last anomaly was also present in an unaffected brother. It is concluded that the cone-rod dystrophy of this family is inherited as an autosomal dominant character and that its association with sickle-cell trait is coincidental.

We describe here the screening of a small group of apparently healthy individuals belonging to the tribal communities of Koya Dora and Konda Reddi. A remarkably high incidence of deletion and nondeletion alpha + thalassemia mutants has been found with allele frequencies and distributions characteristic to each tribe. We have confirmed the strict relationship between Hb S levels and the number of alpha globin genes in double heterozygotes for the S gene and alpha thalassemia. In this population sample we did not find either heterozygous carriers of alpha 0 thalassemia (deletion of both alpha genes in "cis") or individuals showing hemolytic anemia due to inactivation of three alpha-globin genes (Hb H disease). Selection by malaria is most probably responsible for the prevalence of the various alpha + thalassemia haplotypes among the two tribal populations of Andhra Pradesh.

Northern Nigeria is an endemic area for sickle haemoglobin (HbS), and it is common practice in many hospitals to accept blood for transfusion from donors with sickle cell trait (HbAS). In 212 healthy HbAS blood donors, the proportion of HbS was found to range between 24-47%. The HbS levels less than 38% were presumably due to the interaction of sickle-cell gene with the alpha + thalassaemia gene. Low HbS levels and presumed alpha + thalassaemia were associated with significant microcytosis and relatively low Hb A2 and Hb F, but differences were minimal. Carriers of sickle cell trait, with or without alpha + thalassaemia, appear to be acceptable as blood donors. Beta thalassaemia was not detected amongst 710 blood-donors.

Probably because of an abnormality of the alternative pathway of complement activation, acute bacterial infections are common in patients with homozygous sickle cell (SS) disease. To find out whether defective immunity might also predispose to chronic bacterial infection, SS patients with indolent ulcers of the legs were studied. When compared with SS individuals who had never had ulcers the differences of serum immunoglobulin and complement component concentration were similar to those found in a comparison of ulcer patients with normal (AA) haemoglobin genotype and AA controls. Both ulcer groups had higher than normal prevalences of serum cryoprecipitates and anticomplementary activity. However, the latter was found less commonly in SS patients than AA patients, suggesting that SS patients form immune complexes which lack the ability to fix complement. They may therefore have a defect of immune elimination which could predispose to chronicity of infection even in the presence of an adequate antibody response.

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 polymorphism of a restriction endonuclease site has been used for antenatal diagnosis of sickle-cell disease. In a normal person, the beta-globin gene was contained in a Hpa I-digested D.N.A. fragment 7.6 kilobases (kb) in length. In a family where the sickle gene was contained in a variant 13.0 kb fragment, restriction endonuclease mapping was used for antenatal diagnosis. The D.N.A. from amniotic-fluid cells produced both the 7.6 and the 13.0 bk beta-globin gene fragments, indicating the diagnosis of sickle-cell trait. This confirmed the diagnosis reached after investigation of a 100% sample of fetal blood. The method is sensitive and can be performed with cells obtained from 15 ml of uncultured amniotic fluid. This approach may prove useful in antenatal diagnosis of other genetic disorders.

A family was identified which carries multi-haematological disorders including Type IIA von Willebrand's disease, vascular telangiectasia, and a haemoglobinopathy (haemoglobin S trait). In the affected individuals, the von Willebrand's disease varies in its expression from an asymptomatic form to a severe form especially in those patients with telangiectasia. Some patients have vascular telangiectasia in the mucous membranes of the mouth and lips. In two patients endoscopy disclosed telangiectasia in the mucous membranes of the gastrointestinal tract. All of the patients who had telangiectasia also had von Willebrand's disease. An incidental finding was the presence of an abnormal haemoglobin (haemoglobin S) in some family members. The pattern of inheritance of the haemoglobinopathy was unrelated to the inheritance pattern of von Willebrand's disease. The presence of haemoglobin S did not interfere with the aggregation of platelets in response to ristocetin.

A prospective study was carried out to discern the outcome of pregnancy and distribution of birth weights of infants delivered of 85 women with sickle cell trait (AS) compared with a control group of 85 women with normal hemoglobin (AA) who were matched for race, age, parity, and sex of offspring. The distribution of birth weight of offspring of primiparous and multiparous women and the proportion of low-birth-weight infants did not differ significantly between infants born to mothers with AS and those in the control group. Similarly, there was no statistically significant difference between the birth weight of infants born to primipara or multipara. Also, the overall incidence of complications among women with AS did not differ from the incidence in the control group. The findings do not support previous reports that there may be definable pathologic correlates of childbearing in women with AS.

Clinical and haematological features in 41 patients with sickle cell-beta0 thalassaemia (Sbeta0 thalassemia) and in 123 age--sex matched controls with homozygous sickle cell (SS) disease were compared. Persistence of splenomegaly was more common and fetal loss less common in Sbeta0 thalassemia but other clinical features were similar in the two genotypes. Total haemoglobin, Hb A2, PCV, CCV, and red cell count were significantly higher and MCV, MCH, MCHC, and ISC counts significantly lower in Sbeta0 thalassaemia. Proportional reticulocyte counts were significantly lower in Sbeta0 thalassaemia but there was no difference in absolute reticulocyte counts. Persistence of splenomegaly and low ISC counts are compatible with decreased intravascular sickling which may result from the lower mean cell haemoglobin S concentration in Sbeta0 thalassaemia. If beneficial effects of a low MCHC can be confirmed then a carefully monitored trial of iron deficiency in SS disease may be a logical experimental procedure.

Four cases of Hb S were seen between Jan. 1976 and June 1976; three of them were newly discovered while the fourth was previously diagnosed. Out of the four cases, two were Malays and the other Indians. The family members of one Malay case were investigated. Six members had Hb S and three had Hb CoSp. Association of Hb CoSp and Hb S was seen in two of the members. Clinically they were healthy.

The relationship between sickle cell trait and falciparum malaria was studied in the village of Djoumouna, twenty kilometers south west of Brazzaville. Malaria is characterized by a stable high intensity of transmission on the average one infective mosquito bite by night and by child contrasting with a relatively low malarial infection rate. The prevalence of carriers of an S gene (AS) does not change with age: 22.2% for children under 5 years, 22.1% for childrern between 5 and 15 years, and 22.9% in adults. Malarial infection rates are 32% in homozygous AA children under five years and 38% in AS children, an insignificant difference. Our data for this region of the Congo fail to confirm the hypothesis that the AS genotype protects the carrier against Plasmodium falciparum infection.

Sickle-cell trait, a condition present in 7% to 9% of the United States Black population, is usually considered to be a clinically benign condition. However, there is increasing evidence to indicate the contrary, that is, the clinical pathophysiology is variable, ranging from a benign condition in most cases to a relatively few cases of severe pathological involvement. Physical and intellectual growth measures were taken on 19 children with sickle-cell trait (12 boys and 7 girls) from a large study of Black same-sex twin pairs from Philadelphia, Pennsylvania, and compared to measures taken of a sample of normal Black children from 155 monozygotic and dizygotic same-sex twin pairs. Sickle-cell trait carriers were found to weigh less, have smaller upper arm circumference lesser skinfold thickness, and showed less mature skeletal age, differing significantly from normal children. Sickle-cell carriers tended to score lower on four of five intellectual measures, scoring one fifth to one third of a standard deviation lower than normal children.

Two adult sickle cell homozygotes from the eastern oases of the Kingdom of Saudi Arabia presented with severe persistent priapism. Each patient had a high Hb F of 24%, and their red cells were neither hypochromic nor microcytic. Priapism probably occurs more frequently in homozygous sickle cell disease than reported previously from this region. It would appear that a high fetal haemoglobin alone without hypochromia and microcytosis--features suggestive of co-existing alpha-thalassaemia--does not protect against this agonizing vaso-occlusive event.

Hemoglobin S is rarely found in Caucasians, especially in its homozygous expression. The authors report two cases of homozygotes for Hb S diagnosed in a Romanian family. Ten subjects were investigated, belonging to three generations of the same family, and the following results were obtained: two cases of homozygotes for Hb S; five cases of heterozygotes; three normal subjects. One of the two subjects homozygous for Hb S, a girl aged six, had a severe clinical evolution, typical for homozygous drepanocytosis. The second case, a sister of the first aged two, had a less severe evolution, without splenomegaly and thrombotic accidents. The heterozygote subjects showed no clinical symptoms. The two cases of homozygous Hb S reported are the first cases of sickle-cell disease described in Romania.

The frequencies of four major red cell genetic defects, sickle haemoglobin (Hb S), glucose 6 phosphate dehydrogenase deficiency (G6PD), and alpha and beta thalassaemia, have been determined in nearly 5000 subjects from the three major Peninsular Arab States, namely Yemen (North and South), the United Arab Emirates, and Oman. All four defects are common with an overall pattern of alpha thalassaemia greater than G6PD deficiency greater than beta thalassaemia greater than Hb A/S. However, the frequencies of these within each state varies and they are, respectively, Oman: 0.389, 0.328, 0.024, and 0.038; the United Arab Emirates: 0.165, 0.087, 0.017, and 0.019; and Yemen: 0.065, 0.062, 0.0624, and 0.0095. Two, namely alpha thalassaemia and G6PD deficiency, are extremely common, but in spite of this there appears to be a lack of observed clinical disease. For example, Hb H disease and Barts hydrops fetalis were not seen and the oxidative haemolytic syndromes are rare.

Strong correlation of F-reticulocyte levels within sib pairs with sickle cell (SS) anemia suggests that the wide-ranging levels found in the SS population are governed by genes linked to the beta S-site. Correlations between F-cell levels in parents and F-reticulocyte levels in their children indicates that these same genes regulate F-cell production in nonanemic persons. Comparison of outcrossed and inbred SS populations suggests that relative well-being arises from homozygosity for alleles dictating high F-reticulocyte response to anemia.

Variability in the clinical severity of sickle cell diseases is often genetically determined. Coexistent alpha-thalassemia decreases some, but not all, associated morbid complications. Polymorphisms within the beta-globin-like gene cluster influence disease severity by varying gamma-gene expression and the amount of Hb F within the cells. Few persons with the sickle cell trait experience adverse consequences attributable to the beta s gene. Is this also due to genetic factors? A literature search failed to answer this question. It is intriguing, however, that reported associations of sickle cell trait and splenic infarction have occurred exclusively in males and mostly in whites. Plausible but scanty data suggest that splenic infarction, hematuria, and reduced renal concentrating ability may be associated with higher amounts of Hb S. Therefore, alpha-thalassemia may be protective. No evidence was found that the amount of Hb S influenced the incidence of sudden death after exertion or that increased amounts of Hb F accounted for protection against any complications. More detailed reporting of biochemical and genetic evaluations of persons with sickle cell trait who experience related clinical events may lead to a better understanding of risks in subpopulations of persons carrying a single beta s gene.

Recent mass screening programs for sickle cell trait have been the first large-scale efforts to detect potentially deleterious genes and to provide genetic counseling to healthy carriers. In these programs, the expected prevalence of sickle hemoglobin and hemoglobin C has been found, and other mutant hemoglobin genes have also been uncovered. Many of these are not associated with disease, but simply reflect normal genetic diversity. A paradox of this finding is illustrated when, in counseling, many persons demonstrate difficulty in understanding that though they have an abnormal hemoglobin gene, they themselves are not ill or abnormal. The problem's solution lies in educating both health professionals and the public so that the normal existence of considerable genetic diversity is recognized. Since every person may carry mutant genes, whether potentially deleterious or innocuous, our definition of normal must be revised.

A rare association of three haemoglobin defects, viz: traits for deletion form of alpha-thalassaemia, beta-thalassaemia, and sickle cell gene, in a family of French West Indies origin, was studied both at phenotype and genotype levels. In this sickle cell beta-thalassaemia, interacting alpha-thalassaemia is shown to influence the foetal haemoglobin expression. A reverse relationship between the foetal haemoglobin level and the number of alpha genes was observed.

Within the very large group of sickle cell hemoglobinopathies several phenocopy clusters exist. These can be conveniently classified as: 1) conditions in which HbA and S are present, 2) disorders where HbS is the predominant hemoglobin, and 3) the HbSF phenotype. This review will focus on distinguishing the genotype of these common phenocopies as well as new potential approaches to therapy.

The sickle cell (beta s) gene occurs at a high frequency in the oasis populations of Eastern Saudi Arabia. However, as compared with the disorder in Africans, sickle cell anemia runs an unusually benign clinical course in this populations; this has been attributed in part to the relatively high levels of fetal hemoglobin (Hb F) which characterize Saudi Arabians with this condition [1, 2]. As yet, there is no satisfactory explanation for this remarkable phenomenon. To learn more about the expression of the beta s gene in Eastern Saudi Arabia, we examined its interaction with beta 0 thalassemia. We found that remarkably high levels of Hb F in this population are not restricted to individuals with sickle cell anemia but also occur in compound heterozygotes for the beta s and beta 0 thalassemia (beta 0 thal) genes. Additionally, this study has characterized sickle cell-beta 0 thalassemia (S-beta 0 thal) in Eastern Saudi Arabia for the first time.

We report the presence of sickle cell trait in several members of a white Jewish family. The trait was discovered when the propositus developed massive splenic infarction at high altitude. No erythrocyte markers characteristic of African ancestry were detected in any of the family members. This is the first bona fide documentation of sickle trait among white Jews.

Cardiac function was evaluated in 24 children from a Jamaican sickle cell cohort study. Ten patients with sickle cell disease underwent echocardiographic studies on their eighth birthday. The results were compared with 14 age- and sex-matched control children born within hours of the index patients. Left ventricular dimension index (systolic 2.89 +/- 0.31 versus 2.33 +/- 0.42 cm and diastolic 4.70 +/- 0.35 versus 3.64 +/- 0.48 cm, p = 0.001), diastolic volume (79.4 +/- 17.1 versus 60.8 +/- 7.8 ml, p = 0.01), left ventricular mass index (116.3 +/- 3.4 versus 74.3 +/- 15.2 g/m2, p = 0.001) and cardiac index (5.51 +/- 1.32 versus 3.38 +/- 0.85 liters/min per m2 p = 0.001) were significantly increased in patients with sickle cell disease compared with values in control subjects. However, there was no statistically significant difference between the two groups for ejection fraction, velocity of circumferential fiber shortening, percent fractional shortening, systolic time intervals, wall stress and ratio of wall stress-systolic volume. Although two mean ratios of wall stress-systolic volume index were lower in children with sickle cell disease as compared with control subjects (4.0 +/- 0.7 versus 5.4 +/- 1.7, p = 0.02 and 5.9 +/- 1.2 versus 8.3 +/- 2.5, p = 0.005, respectively), the range of ratios remained within normal limits (3.4 to 5.8 in children with sickle cell disease versus 2.8 to 9.5 in controls and 4.2 to 8.3 versus 3.8 to 12.5, respectively). Furthermore, only body surface area predicted group status independent of other variables (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was conducted in the Eastern Province of Saudi Arabia where both thalassaemia and Hb S genes occur at a high frequency. In 171 Saudi Hb S heterozygotes, the range for Hb S was found to be 17-45% with a mean of 31.0%. Frequency distribution histograms showed a trimodal distribution. Peak A, B and C had 18-28, 28-35 and 35-45% Hb S values, respectively. Determination of alpha/beta ratio showed that these findings result from interaction of Hb S with the alpha-thalassaemia gene. Peak C with mean for Hb S of 40% consisted of a majority of individuals with no thalassaemia gene, and the alpha/beta ratio was 0.98% +/- 0.06. Peak B individuals were heterozygous for alpha-thalassaemia 2 with an alpha/beta ratio of 0.80% +/- 0.06 and peak A individuals were homozygous to alpha-thalassaemia 2 with an alpha/beta ratio of 0.58 +/- 0.08. The presence of alpha-thalassaemia 2 in homozygotes results in hypochromia and microcytosis, with little effect on haematological parameters.