Two cases of sickle cell disease presumably due to the combination of the genes for thalassemia and sickle cell hemoglobin

A family of Greek derivation is described in which 2 out of 6 children examinedexhibited a sickle cell type of anemia. The father of these children was found tohave thalassemia minor and the mother the sickle cell trait. It is presumed thatthe anemia in the two children was due to simultaneous heterozygosity for thesickling and thalassemia genes. Biochemical studies with reference to the occurrence and amounts of normal, sickle cell, and fetal hemoglobin were carriedout on the parents and the 6 children. The theoretic interpretation of the biochemical findings is discussed.

Submitted on November 8, 1952 Accepted on January 6, 1953     

Alpha-thalassemia is related to prolonged survival in sickle cell anemia

We have determined the frequency of deletional alpha-thalassemia in black populations in the USA and Africa that harbor sickle cell anemia. In normals, the frequency of the chromosome bearing a deletion of one of the two normal alpha gene loci, designated (-alpha), ranged from 0.12 to 0.16, and in sickle trait subjects, the frequency ranged from 0.18 to 0.20. By contrast, in sickle cell anemia subjects, the frequency was significantly greater and ranged from 0.22 to 0.33. Analysis demonstrated that the greater frequency in the last group was primarily a result of an increased number of subjects with alpha- thalassemia trait (also called homozygous alpha-thalassemia-2). In addition, the frequency of the (-alpha) chromosome was found to increase progressively with age, supporting the hypothesis that alpha- thalassemia is favorable to the survival of subjects with sickle cell anemia. Thus, individuals who inherit alpha-thalassemia and sickle cell anemia may represent a subgroup of patients with a longer life expectancy.     

Beta s gene in Central Iran is in linkage disequilibrium with the Indian-Arab haplotype

Sickle cell anemia is not considered to be a significant disease in Iran, although the sickle cell trait is estimated to have a high incidence in the Southern provinces. Since 1977, when the presence of a mild sickle cell anemia was reported in this country, there have been no further investigations published giving precise data on the incidence and origins of the sickle cell mutation in Iran. We report here the finding of patients with the sickle cell trait, sickle cell anemia, and sickle-beta thalassemia in Central Iran. A survey of 300 individuals from a village in Southeast Esfahan revealed an incidence of the sickle cell trait of 8.33%. "Cascade screening" enabled 96 relatives in four surrounding villages to be tested, and the at-risk couples were offered counseling as a "sickle cell control program." The hematological indices and HbF levels of the affected patients were determined. The HbF levels were unusually high, ranging from 18% to 41.4%, and SS patients with the highest levels were asymptomatic. Linkage analysis revealed the betaS gene haplotype in this population to be the Indian-Arab haplotype.     

Thrombophilic mutations among Southern Iranian patients with sickle cell disease: high prevalence of factor V Leiden

BACKGROUND: A hypercoagulable state in sickle cell disease (SCD) and beta thalassemia has been established and thrombosis is an important aspect of the clinical spectrum of sickle cell disease. In a case-control study, the prevalence of factor V Leiden and prothrombin G20210A mutations were investigated among SCD patients from Southern Iran. METHODS: Patients comprised 60 individuals with SCD; of them 35 were with sickle cell anemia (SS) including 21 males and 14 females aged 17.2+/-8.3 years, 15 were sickle cell trait (AS) consisted of nine males and six females aged 30+/-15.4 years and 10 were sickle/beta thalassemia (S/Thal) (three males and seven females) aged 24.6+/-10.4 years. The control group were 126 apparently healthy individuals (50 males and 76 females) aged 20.1+/-9.8 years. Genotyping was done by polymerase chain reaction restriction fragment-length polymorphism (PCR-RFLP) using Mnl I and Hind III for factor V Leiden and prothrombin G20210A, respectively. RESULTS: Heterozygous factor V Leiden mutation was found in five of 35 (14.3%) SS patients, two of 15 (13.3%) AS individuals, one (a sickle/beta-zero thalassemia patient with IVSII.1 G-->A mutation) of 10 S/Thal patients (10%), and two of 126 (1.6%) control subjects (P<0.05). However, only one AS individual (6.7%) was found to be a carrier for prothrombin G20210A compared to five of 126 (4%) healthy individuals. Adjusted logistic regression analysis for the effects of age and sex was performed and a significant association was found between factor V Leiden mutation and sickle cell anemia with odds ratios (OR) of 6.5 (95% confidence intervals [CI] 1.19-35.33, P=0.03) in SS patients. However, increased prevalence of the factor V Leiden in AS individuals and S/Thal patients was not statistically significant compared to controls (OR 3.84, 95% CI 0.49-29.9, P=0.19 and OR 3.77, 95% CI 0.31-45.9, P=0.29, respectively). CONCLUSIONS: Our findings indicate a significant correlation between factor V Leiden and sickle cell anemia among Iranian patients. Association between venous thrombophilia and factor V Leiden mutation in Iranians with sickle cell anemia should be further studied.     

Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia

Acute splenic sequestration crisis is a potentially fatal condition mostly seen in children with sickle cell anemia (HbSS) up to 6 years of age. Sickle cell-beta thalassemia has been associated with development of splenic sequestration crisis in rare reports. There have also been rare reports of the development of fatal acute splenic sequestration crisis together with severe multiorgan failure in adult patients with sickle cell-beta thalassemia. We describe a case of fatal splenic sequestration crisis together with multiorgan failure in a 34-year-old African-American woman with sickle cell-beta thalassemia syndrome.     

Nutritional iron status in children with alpha+ thalassemia and the sickle cell trait in a malaria endemic area on the coast of Kenya

Although hemoglobinopathies such as alpha+ thalassemia and the sickle cell trait might contribute to anemia in African children, we hypothesized that they might also enhance iron absorption under circumstances of critical availability, and that this could attenuate their hematologic effects. We found no support for this hypothesis in a cohort of children living on the coast of Kenya.     

Toxicity of D-penicillamine in rheumatoid arthritis: A report of 63 patients including two with aplastic anemia and one with the nephrotic syndrome

To assess toxicity of D-penicillamine a retrospective chart review was performed on 63 patients with rheumatoid arthritis receiving penicillamine. These patients had a total of 83 courses of therapy.The mean age of patients was 52 years and the mean duration of disease was 10.07 years. Laboratory data showed an increase in hematocrit values from 36 per cent to 40 per cent and a decrease in the erythrocyte sedimentation rate from an average of 50 to 29 mm/hour. The platelet count also decreased with treatment from 394,000 to 267,000/mm³.The over-all complication rate was 53 per cent. Life-threatening complications occurred in two patients including one case of aplastic anemia and one case of nephrotic syndrome. One additional patient was referred with aplastic anemia. Minor complications include rash in 18 per cent, loss of taste in 6 per cent, dyspepsia in 11 per cent, oral ulceration in 7 per cent and proteinuria of less than 3 g/day in 8 per cent.In summary, 53 per cent of the courses of penicillamine were associated with toxicity including one episode of aplastic anemia and one case of nephrotic syndrome. Therapy was stopped due to complications in 39 per cent of the patients in this series.     

5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia

We previously demonstrated that 5-azacytidine can selectively increase gamma-globin synthesis in a patient with beta +-thalassemia, prompting us to treat two patients with sickle cell anemia and two additional patients with beta + thalassemia. 5-Azacytidine (2 mg/kg/day) was continuously infused for 7 days with no apparent clinical toxicity. The gamma/beta-globin biosynthetic ratio increased fourfold to sixfold in the bone marrow cells of each patient after treatment and remained elevated for 7-14 additional days. Hypomethylation of DNA near the gamma-globin genes in bone marrow cells was demonstrated 2 days after beginning the 5-azacytidine infusion. The peripheral blood fetal hemoglobin (HbF) level increased from 6.0% to 13.7% in one patient with sickle cell anemia and from 1.6% to 8.9% in the second. Stractan gradient analyses of peripheral blood from patients with sickle cell anemia revealed a marked decrease in the percentage of dense cells (cells that contain increased amounts of HbS polymer when deoxygenated) following treatment. These observations provide an impetus to investigate the effects of repeated courses of 5-azacytidine in a small group of severely ill patients to determine whether this drug may have a role in the treatment of patients with sickle cell anemia and beta- thalassemia.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

Kidney transplant nephrotic syndrome

The incidence and clinical spectrum of nephrotic syndrome following kidney transplantation was evaluated in 81 patients who received a transplant between 1963 and 1971, and whose transplant functioned more than 10 months. The nephrotic syndrome developed in 24 patients (29.6 per cent). Eighteen patients received kidneys from living related donors, and six from cadaver donors. The original kidney disease was chronic glomerulonephritis in 15 patients and nonimmunologic diseases in 9. The over-all incidence of the transplant nephrotic syndrome did not differ between these two groups of patients. However, in patients with chronic glomerulonephritis, who had the nephrotic syndrome in the course of their original disease, the incidence of transplant nephrotic syndrome was higher than in those without a history of nephrotic syndrome. Most patients had one or more episodes of rejection prior to the onset of the nephrotic syndrome, and in about two thirds of the patients the nephrotic syndrome developed within 1 year after transplantation. Pathologic studies suggest that chronic rejection is the most common cause of the transplant nephrotic syndrome.The majority of patients had hypoalbuminemia and hyperlipidemia with increased beta lipoprotein, but urine protein was fairly selective, and the patients had minimal edema. Creatinine clearance at the beginning of the nephrotic syndrome was 10 to 70 ml/min (average 47 ml/min). Thirteen patients continued to do well for 16 to 94 months (average 51 months) after receiving their transplant with an average creatinine clearance of 47 ml/ min. There was no significant difference in graft or patient survival between transplant recipients who had the nephrotic syndrome and those who did not. Once the nephrotic syndrome is established, it appears to persist regardless of steroid or other immunosuppressive therapy.     

Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyper-uricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrarinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazlnamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.     

Chronic hemolytic anemia associated with thalassemia and sickling traits

The family history, case history and genealogy of a 6 year old girl sufferingfrom a chronic hemolytic anemia is presented. The disease, resulting from herinheritance of both the gene for sickle trait and that for thalassemia trait, iscompared to a similar case in a 38 year old male reported by Powell, et al.

To date the child has had no clinical evidence of an hemolytic anemia, exceptfor an enlarged spleen. Hematologically, however, all findings indicate the presence of a brisk hemolytic process.

Electrophoretic analysis of the patienst’s hemoglobin reveals a unique patternintermediate between the usual sickle cell trait and sickle anemia patterns.

Submitted on August 20, 1951 Accepted on November 7, 1951     

Increased HbF in sickle cell anemia is determined by a factor linked to the beta S gene from one parent

Members of 7 large families, containing 20 patients with sickle cell anemia (SS) characterized by high levels of fetal hemoglobin (HbF), were studied using immunofluorescence to count F cells and a radioimmunoassay to measure small amounts of HbF. In five of these families, one of the sickle cell trait (AS) parents had a much higher HbF and F-cell count than the other; in one family, both parents had a marked increase in HbF and F cells; in the remaining family, HbF and F cells were at borderline values in both parents. Seven of 14 AS siblings, but only 1 of 8 normal hemoglobin (AA) siblings, also had HbF and F-cell counts above the "normal" range. It seems that a factor for increased F cells, linked to the beta S gene of one parent, is segregating in these families and is responsible for the greatly increased HbF and F cells in the SS subjects. HbF per F cell in AS parents and siblings was the same as that of normal AA subjects, whereas in the SS offspring it was greatly increased, suggesting that it was the result of marrow hyperplasia associated with their hemolytic anemia. The similarity of this "increased F-cell gene" to heterocellular hereditary persistence of fetal hemoglobin (HPFH). Swiss type, is discussed, and it is suggested that it may control the persistent synthesis of HbF in sickle cell anemia by its presence in early infancy.     

Pulmonary infarction in sickle cell trait.

A young black man presented with unexplained pleuritic chest pain. A hematologic evaluation revealed sickle cell trait, Chest roentgenograms, ventilation/perfusion lung scanning and a pleural-parenchymal lung biopsy documented pulmonary infarction. Sickle cell trait with resultant pulmonary infarction should be considered in black subjects with unexplained pulmonary diseases.     

Microdrepanocytic disease in Greece

Among the 57 patients with the hematologic picture of sickle cell anemia, examination of the parents revealed that 44 were suffering from the microdrepanocytic disease and 13 from sickle cell anemia. The much more frequent occurrenceof microdrepanocytic disease was expected since the microcytemia trait appearsto be much more frequent in Greece than the sickle cell trait.

Most patients with sickle cell anemia originated from areas where the traithas been found in a very high frequency. In contrast, the geographical distribution of patients with microdrepanocytic disease is much wider.

Submitted on June 25, 1956 Accepted on October 24, 1956     

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

Fetal hemoglobin (HbF) level and the HbF responses to hydroxyurea (HU) vary among patients with sickle cell disease and are, at least in part, genetically regulated. We hypothesized that siblings with sickle cell disease are likely to share the same parental beta-like globin gene clusters with their cis-acting regulatory sequences and therefore, if regulation of this response is linked to the beta-globin gene cluster, might have concordant HbF responses to HU. Accordingly, we studied 26 families (30 sib pairings), 20 with sickle cell anemia (three families had three siblings) and 6 families with HbS-beta-thalassemia (one family had three siblings, and one family consisted of monozygotic twins), to see if siblings with sickle cell disease had discordant or concordant changes in HbF during HU treatment. Intraclass correlation coefficients (r) showed a high, positive correlation between sibs for HbF levels before and during HU treatment and a concordant change in HbF response from baseline to treatment-associated levels. Changes in mean corpuscular volume (MCV) paralleled HbF levels, while the expected correlations between treatment-associated fall in leukocyte count and increase in MCV were also present. Our results provide additional evidence that some elements that regulate HbF expression are linked to the beta-globin gene cluster.     

Diagnostic value of anemia, red blood cell morphology, and reticulocyte count for sickle cell disease.

STUDY OBJECTIVE: To determine the diagnostic value of anemia, RBC morphology, and reticulocyte count for differentiating patients with sickle cell trait from those with sickle cell disease, who have acute medical or surgical conditions and a positive sickle cell screen. DESIGN: Retrospective chart review. SETTING: A midwest urban children's hospital with 220 beds and 36,000 emergency department visits per year. PARTICIPANTS: One hundred six patients with sickle cell trait and 152 patients with sickle cell hemoglobinopathies. RESULTS: Anemia was observed significantly more often in patients with sickle cell disease compared with sickle cell trait (P less than .001) at all ages 3 months and older. However, anemia alone as a diagnostic test lacked high sensitivity and specificity in children less than 4 years old. Sensitivity approached 100% with the presence of anemia, abnormal RBC morphology, or reticulocyte count of more than 2%. CONCLUSION: Absence of anemia alone does not exclude the diagnosis of sickle cell disease in children less than 4 years old. To differentiate trait from sickle cell disease, we recommend determination of not only hemoglobin adjusted for age but also of RBC morphology and reticulocyte count on all children presenting with acute medical and surgical conditions and a positive sickle cell screen.     

Hereditary Aspects of Autoimmune Hemolytic Anemia; a Retrospective Analysis

Summary. A family with three siblings involved in autoimmune hemolytic anemia is presented. One sibling had an idiopathic variety of the Evans' syndrome type of autoimmune hemolytic anemia. The other two siblings had secondary forms of autoimmune hemolytic anemia, with plasma cell myeloma present in one and systemic lupus erythematosus in the other. A retrospective analysis of the family histories of forty-four patients with idiopathic autoimmune hemolytic anemia revealed that 20 % had family members involved in clinically detectable autoimmune disease.
The hypothesis is presented that autoimmune hemolytic anemia results from a fundamental aberration of the immune apparatus which prevents the establishment of a normal immune homeostatic mechanism. This abnormality appears to be transmitted on a familial basis, and is not primarily related to erythrocyte immune homeostasis. As such, the concept of 'idiopathic' autoimmune hemolytic anemia may be illusory and simply represent a partial diagnosis of a more generalized medical disorder.     

Hemoglobin S-G (S-D) syndrome

Two subjects are described who had positive sickle cell preparations and routine alkaline electrophoretic patterns showing only hemoglobins S, F and A₂. Although this combination suggests sickle cell anemia, their hemoglobin separated into two major bands on agar gel electrophoresis using a citrate buffer, pH 6.2. The non-S hemoglobins were identified as Osu-Christiansborg [β52 Asp → Asn (D3)] in one instance and as G_Galvestonton [β43 Glu → Ala (CD2)] in the other. By most criteria, including exercise testing for one and red cell survival studies for both, these patients resembled patients with sickle cell trait. Careful study and diagnosis are essential to avoid unfairly stigmatizing subjects with benign laboratory phenomena as having sickle cell anemia or even sickle cell disease.     

Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments]

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.