Hydroxyurea therapy for pediatric patients with hemoglobin SC disease.

PURPOSE: Hydroxyurea (HU) has laboratory and clinical efficacy in hemoglobin SS (HbSS) disease, but its benefits in hemoglobin SC (HbSC) disease are unknown. A recent adult HbSC disease pilot trial with HU therapy documented a modest laboratory benefit. Our goal was to evaluate the laboratory and clinical responses of selected pediatric patients with severe HbSC disease to HU therapy. PATIENTS AND METHODS: As part of a retrospective case series, patients were selected from the Duke Pediatric Sickle Cell Program based on the frequency and severity of their vasoocclusive events or an episode of acute chest syndrome. Oral HU therapy was started as a single daily dose and increased to the maximally tolerated dose based on myelosuppression. Laboratory evaluation was performed at baseline and monthly thereafter. Once the maximum tolerated dose was reached, laboratory data were monitored bimonthly. RESULTS: We treated six severely affected pediatric HbSC patients with HU for a median of 27 months. Mean corpuscular volume increased significantly (+26 fL) without change in hemoglobin concentration (-0.1 g/dL); neutrophils decreased significantly. Percentage of fetal hemoglobin (+8.5%) and percentage of F cells (+35.7%) increased significantly. Two experienced only mild and reversible toxicity. CONCLUSION: The laboratory responses in our pediatric patients with HbSC disease were striking, with increases in percentage of fetal hemoglobin and percentage of F-cells approaching responses observed in adult and pediatric patients with HbSS disease. All patients improved clinically. Our findings demonstrate that HU therapy benefits pediatric patients with severe HbSC disease, although larger clinical trials of HU therapy in HbSC disease are warranted.

An infant with homozygous hemoglobin D-Iran.

Hemoglobin D-Iran (Hb D-Iran, beta 22 Glu-->Gln) is a beta-chain variant that was first described in 1973. Hb D-Iran in combination with normal Hb A (Hb D-Iran trait) is a benign condition. Hb D-Iran has also been described in combination with sickle hemoglobin and beta thalassemia, but never as a homozygous mutation. The authors describe a case of homozygous Hb D-Iran in an infant of Pakistani descent. The hematologic values, hemoglobin electrophoresis, peripheral blood smear, and clinical course to date suggest that homozygous Hb D-Iran is a relatively benign condition with mild microcytic anemia, poikilocytosis, and minimal hemolysis.

Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia.

PURPOSE: Genetic mutations in the uridine diphosphate (UDP)-glucuronosyltransferase 1A (UGT1A) enzyme promoter have been associated with unconjugated hyperbilirubinemia and Gilbert syndrome. The effects of UGT1A promoter polymorphisms on serum bilirubin levels and symptomatic gallstone formation were studied in a cohort of children with sickle cell anemia (SCA). METHODS: The UGT1A promoter genotype was deterrmined for 115 consecutive children with SCA. Steady-state laboratory parameters and previous cholecystectomy for symptomatic gallstones were recorded retrospectively, then analyzed according to UGT1A genotype. RESULTS: Children with SCA had a lower frequency of the normal (TA)6 UGT1A promoter allele (0.413) than the abnormal (TA)7 allele (0.461). A previously described shorter (TA)5 allele (frequency 0.074) and longer (TA)8 allele (frequency 0.052) were also observed. Children with the 7/7 UGT1A genotype had a significantly higher mean bilirubin level (5.8 +/- 3.1 mg/dL) than those with the 6/6 (2.4 +/- 0.8 mg/dL) or 6/7 genotype (3.0 +/- 1.1 mg/dL; P < 0.001 by analysis of variance). Patients with the 7/7 genotype were more likely to have previous cholecystectomy (87.5%) than those with the 6/6 (35.7%) or the 6/7 genotype (36.1%; P = 0.002 by chi2). CONCLUSIONS: Genetic variation in the UGT1A promoter significantly influences serum bilirubin levels and the development of symptomatic cholelithiasis in children with SCA. The UGT1A promoter polymorphisms represent an important nonglobin genetic modifier of clinical disease expression in SCA.

Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease.

Children with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL, and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.

Sebaceous gland carcinoma: a subtle second malignancy following radiation therapy in patients with bilateral retinoblastoma.

BACKGROUND: Second primary malignancies are common after bilateral retinoblastoma; their estimated incidence has been as high as 51% 50 years after diagnosis. Fifteen patients who developed sebaceous gland carcinoma after radiation therapy have been reported in the literature, five of whom were treated for bilateral retinoblastoma. METHODS: The authors conducted a retrospective chart review of patients treated for bilateral retinoblastoma at Duke University Medical Center who later developed sebaceous gland carcinoma. RESULTS: This article reports two patients who developed sebaceous gland carcinoma after radiation therapy for bilateral retinoblastoma. CONCLUSIONS: Delay in diagnosis is often associated with sebaceous gland carcinoma. Because high mortality is observed with metastatic disease, the recognition of this association is important for anyone who follows patients with a history of bilateral retinoblastoma or prior cranial radiation therapy.

Successful surgical outcome in children with sickle hemoglobinopathies: the Duke University experience.

BACKGROUND/PURPOSE: Surgery in patients with sickle hemoglobinopathies can be problematic because of the potential for sickling events in the perioperative and postoperative period. The authors and others have previously reported successful surgical outcomes using an aggressive erythrocyte transfusion regimen, designed to alleviate anemia and to reduce the percentage of sickle hemoglobin to below 30%. Recently, a randomized trial compared this aggressive regimen with a more conservative transfusion regimen and found no differences in perioperative complications. The incidence of complications, however, was very high in each group (31% to 35%). METHODS: The authors therefore analyzed retrospectively their surgical experience in children with sickle hemoglobinopathies over the past 10 years to determine the efficacy of an aggressive transfusion regimen and skilled perioperative care in their patient population. RESULTS: A total of 130 surgical procedures were performed on 92 children including 54 cholecystectomies (42%), 23 splenectomies (18%), 12 ENT procedures (9%), 11 central line placements and removals (8%), 7 herniorrhaphies (5%), 7 appendectomies (5%), and 16 miscellaneous operations (13%). The mean age of the children was 10 years (range, 1 to 22 years), and the mean weight was 32.1 kg (range, 9.9 to 76.8 kg). The average hemoglobin (mean +/- 1 SD) at the time of surgery was 11.2+/-1.3 g/dL, and the average percent hemoglobin S was 21+/-11%. CONCLUSIONS: Relatively few transfusions were required to achieve these endpoints, and the complications resulting from transfusions were minimal. Similarly, the number of perioperative and postoperative events was very low.

Risky behavior in teens with cystic fibrosis or sickle cell disease: a multicenter study.

OBJECTIVE: To determine the prevalence and age of onset of common risky behaviors such as smoking and sexual activity in teens with cystic fibrosis and those with sickle cell disease and to compare their behaviors with those of adolescents in the general population. DESIGN: Survey. SETTING: All five major pediatric tertiary care centers in North Carolina (study participants with sickle cell disease or cystic fibrosis) and North Carolina public schools (comparison population). PARTICIPANTS: Three hundred twenty-one adolescents with cystic fibrosis or sickle cell disease aged 12 to 19 years (mean age, 15.6 years; 49% female). Demographically matched comparison teens for each group were selected from 2760 in-school adolescents (mean age, 16.0 years; 51% female). MAIN OUTCOMES MEASURES: Prevalence of tobacco and marijuana use, alcohol use, sexual intercourse, sexually transmitted diseases, seat belt use, weapon carrying, and age of onset of these behaviors. RESULTS: Chronically ill teens reported significantly less lifetime and current use of tobacco, marijuana, and alcohol; less sexual intercourse; less weapon carrying, less drunk driving, and more seat belt use than their peers. Nonetheless, 21% of the teens with cystic fibrosis and 30% of those with sickle cell disease had smoked; sexual intercourse was reported by 28% and 51%, respectively. Age of onset of these behaviors was frequently older for the chronically ill teens. CONCLUSION: Teens with cystic fibrosis or sickle cell disease took more potentially damaging health risks than might be expected, although the prevalence was lower than reported by their peers. Future longitudinal studies should examine the relationships between chronic illness, physical and psychosocial maturation, and risky behavior. Screening for psychosocial issues, including risky behaviors, should be incorporated into the routine health care of chronically ill teens.

Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle cell disease.

Variation in the level of fetal hemoglobin (HbF) accounts for much of the clinical heterogeneity observed in patients with sickle cell disease (SCD). The HbF level has emerged as an important prognostic factor in both sickle cell pain and mortality, and a % HbF of 10-20% has been suggested as a threshold level for diminished clinical severity. The number of erythrocytes that contain HbF (termed F cells) may also be critically important, as F cells resist intravascular sickling and have preferential in vivo survival. Since F cells can be enumerated with high accuracy using flow cytometry methods, we prospectively studied a cohort of 242 children with SCD. Children with HbS and hereditary persistence of fetal hemoglobin (S/HPFH) had essentially 100% F cells. In contrast, children with homozygous sickle cell anemia (HbSS), HbS/beta0 thalassemia, or HbS/beta+ thalassemia had significantly lower mean % F cell values (55.9, 61.6, and 51.3%, respectively; P < 0.001), and children with HbSC had even fewer F cells (27.0%; P < 0.001). There was a highly significant correlation between the % F cells and the log (% HbF), which was observed for the total population of children (r = 0.95, P < 0.001), as well as for each of the individual subgroups of children with HbSS (r = 0.94, P < 0.001), HbSC (r = 0.89, P < 0.001), or HbS/beta0 thalassemia and HbS/beta+ thalassemia (r = 0.95, P <0.001). This logarithmic correlation between % F cells and % HbF has not been previously described and has important implications for the pharmacologic manipulation of HbF in patients with SCD.

Coping strategies and laboratory pain in children with sickle cell disease.

Studies have found that coping strategies are significant predictors of pain report, health care use, and psychosocial adjustment in children with sickle cell disease (SCD); however, the mechanisms of the relationship are not clear. In this study, 41 children with SCD completed a laboratory pain task to analyze their pain perception under standardized conditions. Sensory decision theory analyses were used to analyze the pain perception data. Children and their parents also completed measures of coping strategies and adjustment. Hierarchical regression analyses controlling for the child's age indicated that children who reported using active cognitive and behavioral coping strategies had a lower tendency to report pain during the laboratory pain task. Results are discussed in terms of the utility of using laboratory pain models with children and the need for future intervention studies to target coping strategies in children with SCD pain.

Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients.

PURPOSE: This research was undertaken to determine the advantages, complications, costs, and efficacy of erythrocytapheresis in young pediatric patients who receive chronic erythrocyte transfusion therapy. PATIENTS AND METHODS: We retrospectively analyzed data for 10 children who received erythrocytapheresis for an average of 16 months. Erythrocytapheresis was compared to simple transfusion therapy with respect to annual blood unit exposure, occurrence of alloimmunization, and costs. Serum ferritin levels were compared before and after the period of erythrocytapheresis. RESULTS: Erythrocytapheresis was well tolerated, even in children as young as 5 years or as small as 20 kg. It required a greater annual unit exposure than simple transfusions, but did not increase alloimmunization. Ferritin levels decreased significantly in children receiving concurrent deferoxamine, and decreased or stabilized in those not on chelation therapy. Children started on erythrocytapheresis soon after stroke have not developed iron overload. Although the costs of erythrocytapheresis exceed that of simple transfusion, the substantial costs of deferoxamine therapy should be considered; one child on erythrocytapheresis has been able to discontinue chelation therapy following normalization of his ferritin level. CONCLUSION: Erythrocytapheresis is a safe and effective method for young patients receiving chronic erythrocyte transfusions. Erythrocytapheresis can reduce total iron burden and may obviate the need for expensive chelation therapy.

Hemoglobin C disease in infancy and childhood.

We reviewed the clinical course, physical findings, and hematologic values in 16 pediatric patients with hemoglobin C disease, all but one identified by a newborn hemoglobinopathy screening program. The patients had a few symptoms or physical findings. Height and weight percentiles were normal. Patients typically had a mild hemolytic anemia characterized by microcytosis and target cells.

Diagnosis and management of common bile duct stones in patients with sickle hemoglobinopathies.

Nine of 35 patients with sickle hemoglobinopathies and cholelithiasis were found to have concomitant common bile duct (CBD) stones. We describe the diagnosis and management of these patients with CBD stones. Historical information, physical examination, and routine laboratory tests were unable to identify accurately the patients with CBD stones. Similarly, ultrasonography of the hepatobiliary system was an insensitive method for detecting CBD stones, as only 3 of 8 patients were correctly identified. In contrast, both an intraoperative cholangiogram and endoscopic retrograde cholangiopancreatography were sensitive procedures for detection of CBD stones. We conclude that CBD stones are relatively common in patients with sickle cell disease and cholelithiasis, and clinicians should have a high index of suspicion for their presence.

Long-term management of splenic sequestration in children with sickle cell disease.

We describe our experience with 23 children with sickle cell disease and splenic sequestration crisis, emphasizing our management approaches and the patients' subsequent clinical courses. Our data illustrate that sequestration crisis may occur despite a reduction in hemoglobin S concentration to less than 30% of the total hemoglobin mass. In addition, the risk of recurrent splenic sequestration was similar for patients who received transfusion therapy and for those who were simply observed. We conclude that a short-term transfusion program to prevent recurrent splenic sequestration is of limited benefit.

Experience with minimal complications in implanted catheters in children.

Eighty-two patients, ranging in age from 11 months to 24 years, underwent the percutaneous placement of an implanted catheter in order to have improved venous access. Thirty-five patients (43%) were beginning chemotherapy for cancer, four (5%) had a chronic hematologic disorder, and the remaining 43 (52%) were on chemotherapy for cancer. The mean duration of catheter function was 168 days (range of 7-1,030 days), with a cumulative experience of 18,812 days of catheter use. Complications were minimal. Only four catheters (5%) required removal secondary to infection, infiltration, or tissue breakdown. Substantially reduced complication rates were observed as compared to other studies using implanted central venous catheters. Implanted central venous catheters were proven to be safe in patients with hematologic disorders. These catheters enhance the ability to infuse chemotherapy, hyperalimentation, blood products, anesthesia, and imaging solutions and are safe to use in patients with a hemostatic or host defense deficiency.

Elective cholecystectomy in children with sickle hemoglobinopathies. Successful outcome using a preoperative transfusion regimen.

Twenty-seven children with major sickle hemoglobinopathies underwent elective cholecystectomy for cholelithiasis. All were managed with a preoperative transfusion regimen to achieve a hemoglobin concentration of 11-14 g/dl with greater than 65% hemoglobin A. Intraoperative cholangiography revealed common bile duct stones in five patients, although only one case was diagnosed by preoperative ultrasonographic examination. Twenty-four children underwent incidental appendectomy by total intussusception. There were no vaso-occlusive events nor any other perioperative morbidity or mortality. Four months after cholecystectomy, one boy had a small bowel obstruction requiring surgical re-exploration. No patients had transfusion-acquired infection, although one boy had erythrocyte allosensitization to Lewis A antigen. This preoperative transfusion regimen and careful perioperative management permits safe elective cholecystectomy in children with sickle cell disease.