To determine the incidence and relative risk (RR) of cancer in children with Beckwith-Wiedemann syndrome (BWS), children with BWS were followed up from birth until death, diagnosis of cancer, fourth ...birthday, or last day of follow-up. A total of 183 children with BWS were followed up for 482 person-years. The end points were incidence of cancer, RR of cancer, and RR associated with specific BWS phenotypic features. Thirteen children were identified with cancers before the fourth year of life in comparison with fewer than one cancer expected in this group on the basis of general population rates over the same period. The average annual incidence of cancer in the first 4 years of life was 0.027 cancer per person-year. The RR of Wilms tumor (RR = 816; 95% confidence interval CI, 359-1156), neuroblastoma (RR = 197; 95% CI, 22-711), and hepatoblastoma (RR = 2280; 95% CI, 928-11,656) were statistically significant. Asymmetry of the limbs (hemihypertrophy) was the only clinical feature associated with an increased RR of cancer (RR = 4.6; 95% CI, 1.5-14.2). Given the high incidence of cancer in infancy and early childhood of patients with BWS, a prospective study is warranted to address the utility of screening for cancer. (J Pediatr 1998;132:398-400)
Abstract
Objective
To provide a comprehensive quantitative review of biological, environmental, and behavioral correlates across domains of cognitive function in sickle cell disease (SCD).
Methods
...Forty-seven studies were identified in PubMed, MedLine, and PsycINFO involving 2573 participants with SCD.
Results
Meta-analytic findings across all identified samples indicate that hemoglobin and hematocrit were positively correlated with Full Scale IQ FSIQ; r = .15, 95% confidence interval (CI) = .10 to .21, language and verbal reasoning (r = .18, 95% CI = .11 to .24), and executive function (r = .10, 95% CI = .01 to .19) with small effects and significant heterogeneity. Transcranial Doppler velocity was negatively associated with visual spatial and perceptual reasoning (r = −.18, 95% CI = −.31 to −.05). Socioeconomic status was positively associated with FSIQ (r = .23, 95% CI = .17 to .28), language and verbal reasoning (r = .28, 95% CI = .09 to .45), visual spatial and perceptual reasoning (r = .26, 95% CI = .09 to .41), and executive function (r = .18, 95% CI = .07 to .28) with small to medium effects. Finally, total behavioral problems were negatively associated with FSIQ (r = −.12, 95% CI = −.21 to −.02) such that participants with lower FSIQ exhibited greater behavioral and emotional problems.
Conclusions
Findings provide evidence for biological, environmental, and psychosocial corelates across multiple domains of cognitive function in SCD. More research on more specific cognitive domains and psychosocial correlates is needed in addition to assessments of interactional models among risk factors.
Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, ...BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ∼13% (rs7606173) and ∼11% (rs766432), whereas, together they explain ∼16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation.
Background Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for ...future clinical trials focused on stroke prevention. Our 3‐center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults. Methods and Results This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow‐up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time‐to‐event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow‐up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient‐years (6.17–20.88) versus 3.74 per 100 patient‐years (1.21–8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 95% CI, 1.05–11.39; P =0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 95% CI, 1.16–9.51; P =0.025). Conclusions Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.
An analysis of a prospective cohort of individuals with sickle cell anemia (SCA), enrolled from birth through adulthood, was conducted to determine if asthma is a risk factor for death in SCA. ...All-cause mortality was determined for participants after adjusting for known risk factors for death in SCA. The study included 1,963 individuals who were followed for 18,495 patient-years. After controlling for established risk factors, individuals with SCA and asthma had a more than two-fold higher risk of mortality (hazard ratio 2.36, 95% CI 1.21 to 4.62, p=0.01). To summarize, asthma is a risk factor for death in SCA.
Pulmonary complications result in mortality in adults with sickle cell anemia (SCA). We tested the hypothesis that abnormal pulmonary function was associated with earlier death. A prospective cohort ...of adults with SCA, followed in the Cooperative Study for Sickle Cell Disease, was constructed using the first pulmonary function test at >21 years of age. Spirometry measures: forced expiratory volume in 1 second (FEV1), forced vital capacity, and total lung capacity were categorized based on age, gender, height, and race. Pulmonary function patterns were categorized based on the American Thoracic Society guidelines using both spirometry and lung volumes. A cohort of 430 adults with SCA, mean age 32.6 ± 9.5 (range, 21.0-67.8) years at time of first pulmonary function test, and a median follow-up of 5.5 years, was evaluated. A total of 63 deaths occurred. At baseline, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% nonspecific lung function patterns. In the final multivariable model, lower FEV1 percent predicted was associated with increased hazard ratio of death (HR per % predicted 1.02; 95% confidence interval CI 1.00-1.04; P = .037), as was older age (HR 1.07; 95% CI 1.04-1.10; P < .001), male sex (HR 2.09; 95% CI 1.20-3.65; P = .010), higher lactate dehydrogenase levels (HR per mg/dL 1.002; 95% CI 1.00-1.003; P = .015), and higher acute chest syndrome incidence rate (HR per event/year 10.4; 95% CI 3.11-34.8; P < .001). Presence of obstructive (HR 1.18; 95% CI: 0.44-3.20; P = .740) and restrictive (HR 1.31; 95% CI: 0.64-2.32; P = .557) pulmonary function patterns were not associated with earlier death. Understanding the pathophysiology of a low FEV1 percent predicted in individuals with SCA is warranted, enabling early intervention for those at risk.
•Among adults with SCA, decreased FEV1 percent predicted was associated with earlier death.•Obstructive and restrictive pulmonary function patterns do not predict earlier death in adults with SCA.
Silent cerebral infarcts (SCI) in sickle cell anemia (SCA) are associated with future strokes and cognitive impairment, warranting early diagnosis and treatment. Detection of SCI, however, is limited ...by their small size, especially when neuroradiologists are unavailable. We hypothesized that deep learning may permit automated SCI detection in children and young adults with SCA as a tool to identify the presence and extent of SCI in clinical and research settings.
We utilized UNet-a deep learning model-for fully automated SCI segmentation. We trained and optimized UNet using brain magnetic resonance imaging from the SIT trial (Silent Infarct Transfusion). Neuroradiologists provided the ground truth for SCI diagnosis, while a vascular neurologist manually delineated SCI on fluid-attenuated inversion recovery and provided the ground truth for SCI segmentation. UNet was optimized for the highest spatial overlap between automatic and manual delineation (dice similarity coefficient). The optimized UNet was externally validated using an independent single-center prospective cohort of SCA participants. Model performance was evaluated through sensitivity and accuracy (%correct cases) for SCI diagnosis, dice similarity coefficient, intraclass correlation coefficient (metric of volumetric agreement), and Spearman correlation.
The SIT trial (n=926; 31% with SCI; median age, 8.9 years) and external validation (n=80; 50% with SCI; age, 11.5 years) cohorts had small median lesion volumes of 0.40 and 0.25 mL, respectively. Compared with the neuroradiology diagnosis, UNet predicted SCI presence with 100% sensitivity and 74% accuracy. In magnetic resonance imaging with SCI, UNet reached a moderate spatial agreement (dice similarity coefficient, 0.48) and high volumetric agreement (intraclass correlation coefficient, 0.76; ρ=0.72;
<0.001) between automatic and manual segmentations.
UNet, trained using a large pediatric SCA magnetic resonance imaging data set, sensitively detected small SCI in children and young adults with SCA. While additional training is needed, UNet may be integrated into the clinical workflow as a screening tool, aiding in SCI diagnosis.
Energy metabolism in RBCs is characterized by O2-responsive variations in flux through the Embden Meyerhof pathway (EMP) or the hexose monophosphate pathway (HMP). Therefore, the generation of ATP, ...NADH, and 2,3-DPG (EMP) or NADPH (HMP) shift with RBC O2 content because of competition between deoxyhemoglobin and key EMP enzymes for binding to the cytoplasmic domain of the Band 3 membrane protein (cdB3). Enzyme inactivation by cdB3 sequestration in oxygenated RBCs favors HMP flux and NADPH generation (maximizing glutathione-based antioxidant systems). We tested the hypothesis that sickle hemoglobin disrupts cdB3-based regulatory protein complex assembly, creating vulnerability to oxidative stress. In RBCs from patients with sickle cell anemia, we demonstrate in the present study constrained HMP flux, NADPH, and glutathione recycling and reduced resilience to oxidative stress manifested by membrane protein oxidation and membrane fragility. Using a novel, inverted membrane-on-bead model, we illustrate abnormal (O2-dependent) association of sickle hemoglobin to RBC membrane that interferes with sequestration/inactivation of the EMP enzyme GAPDH. This finding was confirmed by immunofluorescent imaging during RBC O2 loading/unloading. Moreover, selective inhibition of inappropriately dispersed GAPDH rescues antioxidant capacity. Such disturbance of cdB3-based linkage between O2 gradients and RBC metabolism suggests a novel mechanism by which hypoxia may influence the sickle cell anemia phenotype.
•Hb-conformation–dependent interaction with band 3 protein regulates glycolysis in RBCs.•In hypoxia, HbS disrupts this system, disabling RBC antioxidant defense.
Despite priapism being one of the most frequent complications of sickle cell anemia (SCA) in male individuals, little has been reported about the impact of priapism in this population. The authors ...used a sequential independent mixed-methods design, which used both international multicenter focus group discussions (n=35) and a quantitative patient-reported outcome measure (n=131) to determine the impact of priapism on men with SCA in Nigeria and the United States. The authors analyzed data from focus groups using an iterative inductive-deductive approach. Comparison of the Priapism Impact Profile data was done using the Kruskal-Wallis H test. Our result showed that priapism, across cultures, is associated with shame and embarrassment. These emotions interfere with timely clinical and family communication about priapism symptoms and complications. Participants were dissatisfied with the quality of care at emergency facilities. The quality of life and physical wellness of men with SCA-related priapism were significantly different for the 3 groups: (1) priapism condition getting better, (2) priapism condition getting worse, and (3) priapism condition remain the same (P=0.002 and P=0.019, respectively). Psychological, sexual, and physical wellbeing are all adversely affected by priapism. Evidence-based methods are necessary for adequate medical, educational, and psychological treatment for recurrent priapism.
We aimed to test the hypothesis that in children with sickle cell anemia (SCA), silent cerebral infarcts (SCIs), and normal transcranial Doppler (TCD) velocities, baseline intracranial vasculopathy ...(defined by magnetic resonance angiography (MRA)) is associated with cerebral infarct recurrence. A total of 110 children with median age of 9.4 years (range 5 to 14 years), enrolled in the Silent Cerebral Infarct Transfusion (SIT) Trial, had MRAs performed at baseline; vasculopathy was present in 2% (2 of 110). Due to the low prevalence, MRA-defined intracranial vasculopathy is not a predictor of cerebral infarct recurrence in children with SCA, SCIs, and normal TCD velocities.
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