Célia Maria Silva

Growth Deficits in Children with Sickle Cell Disease

BACKGROUND Growth deficits are common in children with sickle cell disease. Few prospective studies are available and the pathophysiologic basis for the impaired growth is not clearly understood. Our objectives were to collect data on anthropomorphic measurements of children with sickle cell disease prospectively followed for 1 year and to correlate them with hematologic data. METHODS One hundred children <8 years of age (73 with homozygous SS sickle cell anemia [HbSS] and 27 with hemoglobinopathy SC [HbSC]) were included. Standardized Z scores of weight for age (waz), height for age (haz), and weight for height (whz) were compared to the National Center for Health Statistics (NCHS) reference population. RESULTS At study entry, the means (standard deviation [SD]) of waz, haz, and whz were -0.69 (1.06), -0.65 (1.11), and -0.32 (1.00), respectively. After 1 year of study, children with HbSS presented a significant decrease in waz (p = 0.01) and whz (p = 0.02); the decrease in haz was not statistically significant (p = 0.48). The effect was similar for children older or younger than 24 months of age. The decrease in waz and whz was significant for boys but not for girls. After 1 year of follow-up, lower mean waz scores were observed among patients with lower hemoglobin concentration and higher reticulocyte count (p = 0.03 and p = 0.08). Hemoglobin concentration was higher in girls. The anthropomorphic measurements did not deteriorate significantly in children with HbSC. CONCLUSIONS Growth deficits may be demonstrable in children with HbSS, even during a short period of observation. Fast red blood cell turnover may be partially responsible for the observed effect.

Coinheritance of α-Thalassemia Decreases the Risk of Cerebrovascular Disease in a Cohort of Children with Sickle Cell Anemia

The study estimated α-thalassemia (α-thal) prevalence and assessed its associations with clinical and hematological features in a random sample of Brazilian children with sickle cell anemia (208 Hb SS and 13 Hb S-β0-thal). α-Thalassemia genotyping was carried out by multiplex polymerase chain reaction (m-PCR) for seven alleles. Clinical and hematological data were retrieved from the 221 childrens medical files. Their ages ranged from 2.5 to 10.4 years. Of the Hb SS children, 27.9% carried –α3.7/αα and 1.4% –α3.7/–α3.7. The presence of α-thal was significantly associated with reduction in MCV, MCH, WBC values and reticulocyte counts. No significant association with blood transfusion or acute chest syndrome (ACS), was found. α-Thalassemia genotypes were strongly associated with reduction in risk for cerebrovascular disease (CVD) (conditional and abnormal transcranial Doppler or stroke; p = 0.007). The interaction of α-thal with other modulating factors should be investigated in order to define subphenotypes of the disease and to use them as clinical tools in the follow-up care of patients.

β-globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or Sβ⁰-thalassemia and their association with clinical and hematological features.

Background/Aims: βS-Haplotype prevalence and its associations with clinical and hematological characteristics were assessed in Brazilian children with sickle cell anemia or Sβ⁰-thalassemia. Methods: A retrospective randomized cohort study was undertaken with 208 SS and 13 Sβ⁰-thalassemia children derived from the Newborn Screening Program of the state of Minas Gerais. βS-Haplotypes were determined by PCR-RFLP. Results: Thirty-nine percent of the SS subjects had the CAR/CAR genotype, 33% had CAR/Ben, 24% had Ben/Ben, 1% had CAR/Atp, 1% had Ben/Atp, and 1% had Arab-Indian/Ben; 1% could not be characterized. Of the Sβ⁰-thalassemia children, 5 were CAR/undefined, 2 were Ben/undefined, and 1 was CAM/undefined. There was no significant association between βS-haplotypes and the total Hb, Hb F, MCV, MCH, WBC, and reticulocyte count among the SS children. Likewise, no significant association was detected between βS-haplotypes and the frequency of acute chest syndrome episodes, blood transfusions, splenic sequestration, or cerebrovascular disease (high-risk/conditional transcranial Doppler ultrasonography or clinical stroke). A limited number of Sβ⁰-thalassemia children precluded valid analyses. Conclusions: The prevalence of βS-haplotypes in this study is in agreement with the historical records of African slaves brought to the state of Minas Gerais. Furthermore, βS-haplotypes CAR and Ben were not associated with any analyzed feature of children with sickle cell anemia.

High reticulocyte count is an independent risk factor for cerebrovascular disease in children with sickle cell anemia

Transcranial Doppler ultrasonography (TCD) is an important way of detecting risk of ischemic stroke in children with sickle cell anemia.

Association of alpha-thalassemia, TNF-alpha (-308G>A) and VCAM-1 (c.1238G>C) gene polymorphisms with cerebrovascular disease in a newborn cohort of 411 children with sickle cell anemia

Cerebrovascular disease (CVD) is a severe complication associated with sickle cell anemia. Abnormal transcranial Doppler (TCD) identifies some children at high risk, but other markers would be helpful. This cohort study was aimed at evaluating the effects of genetic biomarkers on the risk of developing CVD in children from Minas Gerais, Brazil. Clinical and hematological data were retrieved from childrens records. Outcomes studied were overt ischemic stroke and CVD (overt ischemic stroke, transient ischemic attack, abnormal TCD, or abnormal cerebral angiography). Out of 411 children, 386 (93.9%) had SS genotype, 23 (5.6%) had Sβ(0)-thal and two had severe Sβ(+)-thal (0.5%). Frequency of CVD was lower in Sβ-thal group (p=0.05). No effect of VCAM-1 polymorphism on stroke or CVD risks was detected. Cumulative incidence of stroke was significantly higher for children with TNF-α A allele (p=0.02) and lower for children with HBA deletion (p=0.02). However, no association between CVD and TNF-α -308G>A was found. CVD cumulative incidence was significantly lower for children with HBA deletion (p=0.004). This study found no association between VCAM1 c.1238G>C and stroke. An association between stroke and TNF-α -308A allele has been suggested. Our results have confirmed the protective role of HBA deletion against stroke and CVD.

Association between ENPP1 K173Q and stroke in a newborn cohort of 395 Brazilian children with sickle cell anemia

To the editor: Transcranial Doppler (TCD) screening and intensification therapy may reduce the risk of stroke from 11% to 1.9% in children with sickle cell anemia (SCA).[1][1] However, the relatively low specificity of TCD screening in identifying individuals at risk of stroke[2][2] highlights the

Glucose-6-Phosphate Dehydrogenase Deficiency in Brazilian Children With Sickle Cell Anemia is not Associated With Clinical Ischemic Stroke or High-Risk Transcranial Doppler.

Stroke is a severe complication of sickle cell anemia (SCA). The role of glucose‐6‐phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is controversial.

Clinical, hematological and genetic data of a cohort of children with hemoglobin SD

Introduction The hemoglobin FSD is very uncommon in newborn screening programs for sickle cell disease. In the program of Minas Gerais, Brazil, the clinical course of children with hemoglobin SD was observed to be heterogeneous. The objective of this study was to estimate the incidence (1999–2012) and to describe the natural history of a cohort of newborns with hemoglobin SD. Methods Isoelectric focusing was the primary method used in newborn screening. Polymerase chain reaction-restriction fragment length polymorphism and gene sequencing were used to identify mutant alleles and for haplotyping. Gap-polymerase chain reaction was used to detect alpha-thalassemia. Results Eleven cases of hemoglobin S/D-Punjab and eight of Hb S-Korle Bu were detected. Other variants with hemoglobin D mobility were not identified. All hemoglobin D-Punjab and hemoglobin Korle Bu alleles were associated with haplotype I. Among the children with hemoglobin S/D-Punjab, there were four with the βS CAR haplotype, six with the Benin haplotype, and one atypical. Results of laboratory tests for hemoglobin S/D-Punjab and hemoglobin S-Korle Bu were: hemoglobin 8.0 and 12.3 g/dL (p-value <0.001), leukocyte count 13.9 × 109/L and 10.5 × 109/L (p-value = 0.003), reticulocytes 7.5% and 1.0% (p-value <0.001), hemoglobin F concentration 16.1% and 6.9% (p-value = 0.001) and oxygen saturation 91.9% and 97% (p-value = 0.002), respectively. Only hemoglobin S/D-Punjab children had acute pain crises and needed blood transfusions or hydroxyurea. Those with the Benin βS haplotype had higher total hemoglobin and hemoglobin F concentrations compared to the CAR haplotype. Transcranial Doppler was normal in all children. Conclusion The clinical course and blood cell counts of children with hemoglobin S/D-Punjab were very similar to those of hemoglobin SS children. In contrast, children with hemoglobin S-Korle Bu had clinical course and blood cell counts like children with the sickle cell trait.

Prevalence and incidence of erythrovirus B19 infection in children with sickle cell disease: The impact of viral infection in acute clinical events.

B19V infection is common during childhood. It is self‐limited in healthy individuals, but is often associated with transient aplastic crisis in children with sickle cell disease. The aim of this study was to estimate the prevalence and incidence of B19V infection in children with sickle cell disease screened by the Newborn Screening Program of Minas Gerais, Brazil, and followed‐up at Fundação Hemominas. Serum or plasma samples from 278 patients were tested for anti‐B19V IgG and IgM using commercial ELISA and for viral DNA using in‐house real‐time PCR assays; 127 negative‐children were retested about 1 year later. The median age of children at first testing was 5.9 years (0.8–12.3). The estimated prevalence of B19V was 29.5 % (95%CI 24.1–34.9 %). The incidence of B19V in those 127 negative‐children was 18.2 cases/100 patient‐years. All DNA‐positive samples were identified as genotype 1, except one sample, in which both genotypes 1 and 3 were identified. It was observed that the higher the childs age, the higher the probability of B19V infection. The analysis of clinical and hematological data showed a significant association of B19V infection with transient aplastic crisis and acute splenic sequestration, higher frequency of transfusions, and higher rate of hospitalization, but not with acute chest syndrome or stroke. These results emphasize the impact of B19V infection on the course of sickle cell disease. Strategies to prevent and monitor B19V infection in children with sickle cell disease should be considered to diminish its morbidity in this susceptible population. J. Med. Virol. 88:588–595, 2016.

The Natural History of Hb S/Hereditary Persistence of Fetal Hemoglobin in 13 Children from the State of Minas Gerais, Brazil

Abstract Children with Hb S (HBB: c.20A > T)/hereditary persistence of fetal hemoglobin (Hb S/HPFH) have a mild clinical phenotype, but some complications have been reported. The natural history of Hb S/HPFH in children from the State of Minas Gerais, Brazil newborn cohort is described. Clinical and hematological data regarding participants’ phenotypes were retrieved from medical records. The HPFH-1, HPFH-2, and HPFH-3 and α-thalassemia (α-thal) deletions were detected by gap-polymerase chain reaction (gap-PCR). Thirteen children were included, nine (69.2%) had the Hb S/HPFH-2 deletion, and four (30.8%) had Hb S/HPFH-1 deletion; 11 children (84.6%) had αα/αα, and two (15.4%) carried the αα/−α3.7 (rightward) deletion. The mean concentration of total hemoglobin (Hb) and Hb F was 12.52 ± 0.56 g/dL and 42.31% ± 1.97%, respectively. Mild microcytosis and hypochromia were observed. We found acute clinical manifestations of sickle cell disease, such as acute chest syndrome (ACS) and acute pain crisis in four children; nine (69.2%) children were completely asymptomatic during the follow-up period. All children were classified as having low-risk transcranial Doppler (TDC). In conclusion, children with Hb S/HPFH have a mild clinical phenotype of sickle cell disease, although acute clinical manifestations may occur. High Hb F levels and absence of anemia are common hematological characteristics.