Sickle Cell Genotype Research Articles

Neurocognitive screening with the Brigance Preschool screen‐II in 3‐year‐old children with sickle cell disease

Neurocognitive deficits have been described in school age children with sickle cell disease (SCD), even in the absence of stroke or silent infarcts. However, the age of onset and factors contributing to this problem have not been well studied. We hypothesized that in children with SCD the failure rate with Brigance screening would be higher than in the normal population. We reviewed retrospectively the Brigance Preschool Screen-II test results in 3-year-old children with SCD. Findings were correlated with hemoglobinopathy genotype, hemoglobin level, transcranial Doppler ultrasound (TCD) velocities, and treatment with hydroxyurea, as well as with psychosocial factors. Eighty-eight children with SCD followed by the St. Jude Sickle Cell Center (mean age 3.5 years) had neurocognitive screening during their regular clinic visits. Forty-four (50%) children had scores below the normal cut-off value for their age (twice the national failure rate of 25%). Failures were associated with less parental education (P = 0.005 for maternal and P = 0.03 for paternal education levels) and with speech deficits (P = 0.01), but were not associated with sickle cell genotype or hemoglobin concentration. These preliminary data suggest that psychosocial factors may have more profound effects on early childhood development than disease-related factors in this group of young sickle cell patients. A larger prospective study with appropriate controls is warranted to validate these findings, which have implications for the etiology and prevention of neurocognitive decline in children with SCD.

Seizures in the Jamaica cohort study of sickle cell disease

Although there is some evidence that epilepsy is more common in Sickle Cell Disease (SCD), we sought to establish the incidence rates, risk factors for and specific types of seizures in a SCD cohort followed from birth, and how seizure occurrence affects morbidity and mortality. We examined all records of persons in the Jamaica cohort Study of Sickle Cell Disease (JSSCD) clinically identified as having experienced a seizure during their lifetime. At first presentation, seizures were classified as Febrile Convulsion, Acute Symptomatic Seizure or Single Unprovoked Seizure. The seizure classification was revised to include Epilepsy if seizures recurred. Thirty-eight persons in the JSSCD (N = 543) were identified with seizures. The 5-year cumulative incidence of febrile convulsions was 2·2%. The incidence rate of epilepsy (all genotypes) was 100/100 000 person-years, 139/100 000 for the SS genotype. Despite limited availability of diagnostic investigations, clinical seizures were associated with increased all-cause mortality. Male gender (Odds Ratio [OR]: 4·0[95% confidence interval [CI]; 1·03-20·0]) and dactylitis in childhood (OR: 17·4 [95% CI; 4·82-62·85]) were associated with increased risk of developing epilepsy. Epilepsy in persons with SCD is 2-3 times more common than in non-sickle populations and is associated with increased all-cause mortality in all sickle cell genotypes.

The Number of People with Sickle Cell Disease in the United States: National and Individual State Estimates.

Abstract 1365Poster Board I-387 BackgroundAlthough sickle cell disease is a genetic disease diagnosed by state newborn screening programs, it is not a reportable condition. Therefore it is difficult to ascertain the actual number of affected individuals living with sickle cell disease in the United States. One NIH estimate puts the number between 50,000 and 75,000 while the Sickle Cell Disease Association of America estimates the number to be “over 70,000”. Without accurate estimates, clinicians, health services researchers, and policy makers are all working with incomplete information when determining the extent of the cost and health consequences of sickle cell disease. Our objective was to estimate the number of people with sickle cell disease for the United States as a whole and for each individual State, adjusting for the increased mortality of sickle cell disease. MethodsCensus estimates by age and race/ethnicity were obtained for both the United States as a whole and for each individual State from the US Census website. The prevalence of sickle cell disease for blacks was uniformly applied to the U.S. and individual states using a rate of 289 black children with sickle cell disease per 100,000 live births. Based on previously published prevalence rates for Hispanics, prevalence rates of 89.8 Hispanic children of non-Mexican ancestry with sickle cell disease per 100,000 live births and 3.14 Hispanic children of Mexican ancestry with sickle cell disease per 100,000 live births were calculated. We did not include sickle cell disease for whites or Asians in our estimate. Year 2005 was used as the baseline year for all calculations. Consistent with previous literature, at age 0, 60% of children with sickle cell disease were classified as having HgbSS/SB0 and 40% of children were classified as having HgbSC/SB+. These proportions were altered towards higher proportions of HbSC/SB+ with increasing age based on the increased mortality of the more severe forms of sickle cell disease. To adjust for mortality, we analyzed the data based on age and sickle cell type, and used published mortality data for different sickle cell genotypes to calculate survival of the population to a given age. A population multiplier was then used to adjust population estimates for the difference in population across age groups and differences in population patterns by race/ethnicity. ResultsAnalysis revealed an estimate of 89,079 (95% CI: 88,494 – 89,664) people with sickle cell disease in the United States, of which 80,151 are black and 8,928 Hispanic. The South, with a sickle cell population of 47,354 people, comprised more than 53% of all people with sickle cell disease in the United States. The five states with the highest estimated number of people with sickle cell disease were New York with 8,308; Florida with 7,539; Texas with 6,765; California with 6,474; and Georgia with 5,890. These five states comprised more than 43% of the total sickle cell population for the nation. Finally, the increased mortality for HgbSS/SB0 leads to an alteration in the relative percentages of sickle cell genotypes, with HgbSS/SB0 comprising 60% of people with sickle cell disease at birth, half of the sickle cell population at slightly over 30 years old, and only 25% of the sickle cell population by 60 years old. ConclusionThis study reveals that the sickle cell population in the United States is higher than previously reported, with almost 90,000 people with sickle cell disease. In addition, differential mortality increases the percentage of people with HbSC/SB+, such that after 40 years of age they represent the majority of the sickle cell population. The population estimates for the country as well as the individual states provide important information with regard to allocation of resources for this chronic disease which primarily affects lower income, underserved individuals. DisclosuresNo relevant conflicts of interest to declare.

Prevalence and Complications of Obesity in Sickle Cell Disease.

Background: Obesity is associated with major health problems in the pediatric population and is a fundamental risk factor for adult obesity with its concomitant morbidities. Sickle cell disease (SCD) has historically been associated with poor nutritional status rather than obesity. Children with SCD, however, have many general risk-factors and disease-specific characteristics, such as ethnic distribution and sedentary lifestyle, that may increase their risk for obesity. We hypothesized that the prevalence of obesity in children and adolescents with SCD would reflect that of the general pediatric population and that obesity would be associated with demographic and disease-specific variables.Methods: We conducted a retrospective chart review of all pediatric and young adult patients over the age of two in the Hasbro/RIH Sickle Cell clinics from 1980- 2008, collecting cross-sectional and longitudinal demographic and clinical variables. The primary outcome was the prevalence of overweight and obesity in this population. Secondary endpoints included the association of obesity with demographic and clinical variables and longitudinal growth trends. Body mass indices (BMI) were calculated for each subject, who were then categorized as underweight, healthy weight, overweight, or obese based on the International Obesity Task Force guidelines. Chi-square, Fischer exact tests, and T-tests were used to evaluate associations between overweight/obesity and the hypothesized risk factors and morbidities. Odds ratios were then calculated to determine the strength of these associations. This project was approved by the local Institutional Review Board.Results: The analysis included 149 subjects with a mean age of 13.2±6.5 years, 51% male, and a mean hemoglobin of 9.7±1.8. The mean BMI was 20.5±6.3 with a range from 13.1–49.1. Five percent of the subjects were underweight, 70% healthy weight, 12% overweight, and 13% obese. The most common morbidities included acute chest syndrome (44%), frequent (>3/yr) pain crises (34%), asthma (17%), and obstructive sleep apnea (17%). Overweight and obesity were not associated with gender, race, or insurance status in this population. The overweight/obese group was significantly older than the non-overweight group (15.3 years vs. 12.4 years, p=.02). Obesity was associated with sickle cell genotype: subjects with less severe genotypes were more likely to be obese than those with the most severe genotypes (p<.01). Likewise, the mean hemoglobin was higher in the overweight/obese group than the non-obese group (10.3 vs. 9.5, p=.01). Obesity was also associated with a higher risk of certain SCD- and obesity-related morbidities including osteonecrosis (p=.01) and hypertension (p<.01). The overweight/obese group spent more time hospitalized over the past year than the non-overweight group (9.5 days vs. 2.1 days, p<.01). Overweight/obesity did not increase the likelihood of being on hydroxyurea treatment or requiring chronic transfusions, and did not increase the risk of acute chest syndrome, pain crises, asthma, obstructive sleep apnea, priapism, splenic sequestration, stroke, or abnormal transcranial doppler studies.Conclusions: In contrast to traditional thinking, this is the first study to demonstrate a high prevalence of overweight and obesity in pediatric SCD. Indeed, the prevalence of overweight and obesity in our children with SCD parallels that of these conditions in the general pediatric population. In those with SCD, obesity is more common in patients with less severe disease and is more widespread in older children. Additionally, obesity is associated with increased risk of SCD-related morbidities such as osteonecrosis and hypertension and is associated with more hospitalizations.

Hydroxyurea Use Is Associated with Avascular Necrosis of the Femoral Head among Children with Sickle Cell Disease

Hydroxyurea therapy is associated with reduced morbidity among patients with sickle cell disease (SCD). Avascular necrosis of the femoral head (AVN) is one potentially debilitating complication of SCD. In this study, we examined the relationship between hydroxyurea use and the prevalence of AVN among children with SCD. We performed a retrospective chart review of 202 children with SCD, aged 10–21 years, followed in the pediatric hematology program at the Children's Hospital at Montefiore (Bronx, NY) between July 2007 and 2008. Abstracted data included age, ethnicity, SCD genotype, frequency of hospitalization, hip radiograph results, laboratory data and hydroxyurea use. Hip radiographs were performed prospectively as part of SCD health maintenance from 2005–2008. Forty-four patients were excluded because they did not have a screening hip radiograph. Descriptive statistics were calculated for independent variables. T-tests and chi-square tests were used to compare clinical and demographic characteristics of children with and without AVN. Multivariate logistic regressions were used to estimate the odds ratio of having AVN among SCD patients. Our final sample consisted of 158 patients whose demographic characteristics are listed in Table 1. The prevalence of AVN was 16.5% (n=26). Of the clinical variables analyzed, we identified significant associations between the presence of AVN and hydroxyurea use (p=.005), as well as older age (p=.013) (Table 1.) Children with AVN had significantly lower mean lactic dehydrogenase levels (LDH) (p=.04) and higher mean corpuscular volumes (MCV) (p=.012). (Table 2.) After controlling for gender, ethnicity, sickle cell genotype, and frequency of hospitalizations, age was also found to be associated with AVN (OR 1.15, 95% confidence interval (CI): 1.01,1.31, p=0.033). SCD patients on hydroxyurea had higher odds of having AVN compared to non-users (OR 3.51, 95% CI: 1.31, 9.38, p= 0.013). Laboratory values (MCV, Hemoglobin, LDH and Hematocrit) had a high degree of collinearity and were removed from the final model. In summary, the prevalence of AVN in our sample was 16.5%. This is substantially higher than the prevalence of approximately 6% reported by the Cooperative Study of Sickle Cell Disease for comparative age groups in a prospective study1. SCD patients exposed to hydroxyurea were three times more likely to have AVN than those not exposed to this drug. Vaso-occlusive pain crisis is a recognized risk factor for AVN, thus we could expect a higher rate of AVN among patients on hydroxyurea. However, the odds ratio of 3.5 is unexpectedly high and warrants further investigation into the role of hydroxyurea as a risk factor for AVN. Nonetheless, these preliminary results suggest that more stringent screening regimens for AVN may be indicated among this subset of patients.Table 1. Clinical characteristics of patients with and without avnNo AVN (N =132)AVN (N = 26)Age *15.7 years17.4 yearsSex Male64 (49%)17 (65%)EthnicityBlack110 (83%)23 (88%)Hispanic22 (17%)3 (12%)HgbSS84 (64%)20 (77%)HgbSC38 (29%)4 (15%)HgbSBthal05(3.8%)2 (8%)Hgb SC HgbSBthal+5 (3.8%)0On Hydroxyurea**38 (29%)15 (58%)# Hospitalizations060 (45%)10 (38%)1–564 (49%)14 (54%)>58 (6%)2 (8%)*p<0.05**p<0.01Table 2. Mean Laboratory Values for Patients With And Without AVNNo AVNAVN(N =132)(N = 26)WBC10.7 k/uL10.5 k/uLHgb9.4 gm/dL9.6 gm/dLMCV*83 fL89 fLPlatelets381 k/uL376 k/uLReticulocyte7.70%8.10%Ferritin369.8 ng/mL438.7 ng/mLLDH*471.6 U/L389 U/LCreatinine0.6 mg/dL0.6 mg/dLHgb F9.80%11.30%*p<0.05

Prise en charge de la drépanocytose en milieu pédiatrique : expérience du centre hospitalier universitaire pédiatrique Charles-de-Gaulle de Ouagadougou (Burkina Faso)

Sickle cell disease is a genetic disease most common in blacks. We retrospectively collected records for patients with sickle cell disease who were seen from January 2002 through September 2006 to assess the care provided for this disease at Charles de Gaulle University Children's Hospital of Ouagadougou. In all, 88 patients were monitored quarterly at outpatient visits for sickle cell disease, in the absence of any crisis. Their age ranged from 6 months to 16 years, with an average age of 7. There were more boys than girls, with a sex ratio of 1.44. The distribution according to sickle cell genotype showed that SC accounted for 62% of cases, while SS forms were more frequent until the age of 5. All children have received the immunizations in the standard Expanded Programme on Immunization (EPI) [diphtheria, tetanus, pertussis, polio, measles and yellow fever]. The immunization rates for non-EPI vaccines including hepatitis B, Haemophilus influenzae B, Salmonella typhi, meningitis, pneumonia and the combined vaccine against measles, mumps and rubella ranged from 94 to 100%. A prophylactic anti-anaemic agent was made with folic acid often associated with iron. In addition, patients receive malaria chemoprophylaxis. Chloroquine was initially provided, and since 2006, children have been receiving sulfadoxine-pyrimethamine. Our encouraging results deserve reinforcement in the short-term - at the local level by neonatal screening, the creation of an immunization unit, and the systematization of antibiotic prophylaxis, and in the medium-term by implementation of a National sickle cell disease programme to help meet the objective of a 40% reduction in mortality among affected children younger than 5 years by 2015, set by the Sickle Cell Disease International Organization.

Day Hospital Approach to Uncomplicated Vaso-Occlusive Crises in Children with Sickle Cell Disease.

Day hospital management for patients with sickle cell disease experiencing uncomplicated vaso-occlusive pain crises has been described in adult populations as an alternative care delivery system. To date, there are no published studies addressing the utility of this model in pediatric populations. We retrospectively studied all admissions to the Day Hospital at the Texas Children's Sickle Cell Center since its inception in 2000. A Day Hospital admission was defined as a minimum of two consecutive days of aggressive pain management as an outpatient, including intravenous hydration and analgesics, supported by home treatment over night with oral analgesic and anti-inflammatory agents. We gathered data on demographics, sickle cell genotype, incoming pain scale, provider type (physician versus nurse practitioner), home treatment with narcotics prior to presentation, average daily dose of narcotics administered during admission, length of stay, admission charges, return rate to the emergency department within 48 hrs, and transfer rate from Day Hospital to inpatient care. A total of 35 patients accounted for 80 visits during the study period (2000–2006). Approximately 83% of patients had sickle cell anemia (HbSS). The mean baseline hemoglobin for patients was 9.1 g/dl. Patients were seen equally by physicians and nurse practitioners. Approximately 93% of visits were preceded by home narcotic use within 24hrs of presentation. The mean incoming pain score was 7.9 on a scale from 1 to 10. The mean length of stay was 2.4 days. The return rate for emergency care within 48 hours was 6%. Approximately 40% of patients admitted to the Day Hospital were transferred to inpatient care for unresolved pain or increasing medical needs. We conclude that a dedicated Day Hospital facility has the potential to provide patient-centered, effective, and timely management of vaso-occlusive crises in children as well as adults. It may serve as an alternative to emergency and inpatient care for children with mild to moderate pain. Future studies should compare day hospital care to inpatient hospitalization for differences in length of stay, cost, patient satisfaction, and quality of life.

Avaliação dos produtos da degradação oxidativa da Hb S nos genótipos SS, SF (S/beta0 talassemia) e AS, em comparação com hemoglobinas normais

Sickle cell disease is a generic term used to determine a group of genetic alterations characterized by a dominance of Hb S. The main genotypes which compose the sickle cell disease group are as follows: SS, SF (S/b0 thalassemia and S/Hereditary Persistence of Fetal Hemoglobin or HPFH), SFA (S/b+ thalassemia), SC, SD and SH (S/a thalassemia). This study analyzes the products resulting from the oxidization of hemoglobin, identified by the methemoglobin concentration and by red blood cells with Heinz bodies, in two sickle cell genotypes (SS and S/b0 thalassemia) and in the sickle cell trait (AS) compared with the normal genotype (AA). Analysis of the products resulting from hemoglobin oxidative damage, characterized by an increase in the mean levels of methemoglobin and of the number of red blood cells with Heinz bodies, which are directly related to the increase in the Hb S concentration. Thus, oxidative damage of hemoglobin diminishes among the studied genotypes in the following manner: SS>SF>AS>AA. It is important to stress that these results indicate that the simple presence of Hb S in the red blood cell, as in the AS genotype, is capable of increasing the methemoglobin concentration in 52.62% of the assessed samples and inducing the precipitation of Heinz bodies in 73.68% of cases. Elucidation of the oxidative and reductive processes of the studied hemoglobins is presented in the paper. Highlighted among the presented results is the identification, by means of alkaline agarose gel electrophoresis, of the free alpha globin fraction in all SF genotype samples originating from Hb S/b0 thalassemia individuals. A hypothesis to explain the origin of free alpha globin, especially in the S/b0 thalassemia genotype is proposed, as is the importance of its identification in the laboratorial diagnosis of S/b0 thalassemia.

Frequencies of sickle cell trait and glucose-6-phosphate dehydrogenase deficiency differ in highland and nearby lowland malaria-endemic areas of Kenya

Sickle cell genotype prevalence was 26% in a malaria-holoendemic lowland area compared with 3% in a highland area of Kenya. The prevalence of glucose-6-phosphate dehydrogenase deficiency was 7% and 1 % in holoendemic lowland and highland areas, respectively. Lack of protective polymorphisms may contribute to morbidity and mortality during outbreaks of malaria in the highlands.

Coagulation changes in individuals with sickle cell trait.

Sickle cell disorders, such as Hb SS and Hb SC, are associated with a hypercoagulable state that may contribute to the vaso-occlusive episodes observed in the disorders. To what extent increased coagulation activity occurs in individuals with sickle cell trait has had limited study. Because such information may help clarify clinical and pathologic findings that may occur in these individuals and may be useful in clarifying the hypercoagulable state in sickle cell disease, we have examined individuals with Hb AS to determine the extent that increased coagulation activity does occur. We measured d-dimers, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1.2 (F1.2), absolute blood monocyte levels, proteins C and S, and isotypes of antiphospholipid antibodies in individuals with Hb AS and in matched controls (Hb AA). Results showed that d-dimers, TAT, and F1.2 were increased significantly above normal levels. Absolute blood monocyte levels were increased. The d-dimers, TAT, F1.2, and monocyte counts showed significant increasing trends through groups of increasing severity (Hb AA, Hb AS, Hb SC, and Hb SS). Our study shows that individuals with Hb AS have increased coagulation activity, with d-dimers, TAT, and F1.2 being consistent indicators. The measures of coagulation activity in Hb AS are lower than in patients with Hb SC and Hb SS disease. These results extend our previous observation that the degree of coagulation activation parallels the degree of disease severity among sickle cell genotypes. The findings suggest that monocytosis, with the possible expression of monocyte-derived tissue factor, and the associated hypercoagulable state are driven by disease severity.

Characterization of pica prevalence among patients with sickle cell disease.

To determine the prevalence of pica and its characteristics among children with sickle cell disease. Retrospective, observational study. An urban, ambulatory care, interdisciplinary center. The medical records of all 480 patients who visited the center from March 1, 1998, to June 30, 1999, were reviewed. Patients were excluded for history of stroke, long-term transfusions, pregnancy, acute illness, or age younger than 3 years. Sex, age, weight, height, Tanner stage, complete blood cell count, sickle cell genotype, pica history, and levels of iron, zinc, lead, and fetal hemoglobin (Hb). Of 395 study patients, 134 (33.9%) reported pica. Ingested items included paper, foam, and powders. There was a significantly higher prevalence of pica among patients homozygous for Hb S (Hb SS, sickle cell anemia) compared with the combined group of double heterozygous patients with Hb SC, Hb SD, and Hb Sbeta thallasemia (Sbeta(+)or Sbeta(0)) (35.6% vs 25.5%; P =.03). Within genotype, mean Hb levels were significantly lower and reticulocyte counts were significantly higher in the patients with pica. Overall, the mean age of patients with pica was significantly lower; however, the prevalence was 23.3% (27/116) among those aged 10.0 to 14.9 years and 14.8% (8/54) among those aged 15.0 to 19.0 years. Within age groups, patients with pica weighed significantly less. Pica appeared to have an unusually high prevalence in patients with sickle cell disease and a correlation with lower Hb levels. It is unclear whether pica is a specific marker of disease severity, because our review did not show a relationship to increased number and duration of hospitalizations. The association between pica and low body weight suggests a nutritional effect on its prevalence.

Ligase chain reaction assay for human mutations: the Sickle Cell by LCR assay

We can detect the beta-globin gene sickle cell mutation by using an assay based on the ligase chain reaction. The simultaneous amplification of the human growth hormone gene in the same reaction serves as a control for the amount of template DNA or amplification efficiency. Ligation products, which are biotinylated at one end and tagged with an arbitrary "tail" sequence at the other, are captured by hybridization to "tail"-complementary oligonucleotides immobilized on polystyrene microwells. The captured ligation products are detected colorimetrically by use of streptavidin-alkaline phosphatase conjugate. In a study of 24 subjects, the assay unequivocally discriminated among normal, carrier, and sickle cell genotypes.

Distribution of HbS Gene and Variability of the Index of the Opportunity for Natural Selection in a Caste Population of Western Orissa, India.

Pattern of distribution of HbS gene among the people in a caste population of India was studied through the estimation of its frequency in different isolates, age groups and generations. Crow's index of the opportunity for natural selection among the live births in completed families, based on sickle cell genotype of parents, was estimated to check the suspected superior fertility potentials of AS over AA women. It is observed that genotype frequencies are in equilibrium in each of the three isolates of the population and there exists no significant difference between isolates. Among the adults similarly, nonsignificant differences in frequency between two successive age groups and between generations are observed. Opportunity for natural selection is highest among families in which one or both of the parents are AS. Nonsignificant but lightly higher mean fertility is observed from AA × AS than AA × AA atings.

Developmental Screening in Young Children with Sickle Cell Disease

The goal of the study was to assess development in young children with sickle cell disease as part of the Cooperative Study of Sickle Cell Disease (CSSCD). The Denver Developmental Screening Test (DDST) was administered to children younger than 6 years at 12 participating institutions of the CSSCD. Trained examiners administered tests to 344 children. Tests were scored as normal in 90.4%, questionable in 6.4%, and abnormal in 1.5%; 1.7% of children were considered untestable. There was no relationship between DDST results and sickle cell genotype. Questionable and abnormal (Q/A) scores were more common in children ages 3-5 years than in younger children (12.6% versus 3.8%; P = 0.002). Because the DDST is a screening test, it should be interpreted cautiously. However, the more numerous Q/A scores in our "older" group agree with the findings of recent reports of neuropsychological impairment in school-age children with sickle cell disease. Our data suggest that development is relatively normal before age 3 years; deficits seen in older children may reflect subsequent ischemic insults.