John J. Strouse

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

Pediatric Melanoma: Risk Factor and Survival Analysis of the Surveillance, Epidemiology and End Results Database

PURPOSE To evaluate risk factors for the development of and factors influencing survival in pediatric melanoma. PATIENTS AND METHODS We evaluated 1,255 children (age < 20 years) and 2,673 young adults (age 20 to 24 years) with melanoma in the 2001 National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. We estimated exposure to UV radiation based on Environmental Protection Agency (EPA) measurements. RESULTS The incidence of pediatric melanoma increased 46% (95% CI, 40 to 52) per year of age and 2.9% (95% CI, 2.1 to 3.6) per year from 1973 to 2001. Incidence rates were lower in black patients (-95%; 95% CI, -98 to -90) compared with white patients and in male patients (-39%; 95% CI -46 to -31) compared with females. Increased ambient UV radiation was associated with elevated risk (19% per kJ; 95% CI, 9 to 30). Children with melanoma had a 5-year melanoma-specific survival of 93.6% (95% CI, 91.9 to 94.9), which improved from 1973 to 2001. The hazard ratio of death from melanoma increased with male sex; older age; advanced disease; location of the primary other than extremities or torso; earlier year of diagnosis; and previous cancer. CONCLUSION The incidence of melanoma in the United States is increasing rapidly in children. Risk factors for pediatric melanoma include being white, being female, increasing age, and environmental UV radiation. Survival is decreased for children and adolescents with unfavorable prognostic factors (male sex, unfavorable site, and/or second primary or regional or distant metastasis). More effective therapeutic strategies are needed for these groups.

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children.

CONTEXT. Hydroxyurea is the only approved medication for the treatment of sickle cell disease in adults; there are no approved drugs for children. OBJECTIVE. Our goal was to synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea in children with sickle cell disease. METHODS. Medline, Embase, TOXLine, and the Cumulative Index to Nursing and Allied Health Literature through June 2007 were used as data sources. We selected randomized trials, observational studies, and case reports (English language only) that evaluated the efficacy and toxicity of hydroxyurea in children with sickle cell disease. Two reviewers abstracted data sequentially on study design, patient characteristics, and outcomes and assessed study quality independently. RESULTS. We included 26 articles describing 1 randomized, controlled trial, 22 observational studies (11 with overlapping participants), and 3 case reports. Almost all study participants had sickle cell anemia. Fetal hemoglobin levels increased from 5%–10% to 15%–20% on hydroxyurea. Hemoglobin concentration increased modestly (∼1 g/L) but significantly across studies. The rate of hospitalization decreased in the single randomized, controlled trial and 5 observational studies by 56% to 87%, whereas the frequency of pain crisis decreased in 3 of 4 pediatric studies. New and recurrent neurologic events were decreased in 3 observational studies of hydroxyurea compared with historical controls. Common adverse events were reversible mild-to-moderate neutropenia, mild thrombocytopenia, severe anemia, rash or nail changes (10%), and headache (5%). Severe adverse events were rare and not clearly attributable to hydroxyurea. CONCLUSIONS. Hydroxyurea reduces hospitalization and increases total and fetal hemoglobin levels in children with severe sickle cell anemia. There was inadequate evidence to assess the efficacy of hydroxyurea in other groups. The small number of children in long-term studies limits conclusions about late toxicities.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Primary Hemorrhagic Stroke in Children With Sickle Cell Disease Is Associated With Recent Transfusion and Use of Corticosteroids

OBJECTIVES. Primary hemorrhagic stroke is an uncommon complication of sickle cell disease, with reported mortality rates of 24% to 65%. Most reported cases are in adults; little is known about its occurrence in children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. We performed a retrospective case-control study to evaluate risk and prognostic factors for primary hemorrhagic stroke among children with sickle cell disease. PATIENTS AND METHODS. Case subjects (sickle cell disease and primary hemorrhagic stroke) and control subjects (sickle cell disease and ischemic stroke) were identified at 2 children’s hospitals from January 1979 to December 2004 by reviewing divisional records and the discharge databases. RESULTS. We identified 15 case subjects (mean age: 10.4 ± 1.3 years) and 29 control subjects (mean age: 5.2 ± 0.4 years). An increased risk of hemorrhagic stroke was associated with a history of hypertension and recent (in the last 14 days) transfusion, treatment with corticosteroids, and possibly nonsteroidal antiinflammatory drugs. Average blood pressures at well visits (adjusted for age and gender) were similar between the 2 groups, suggesting that hypertension was intermittent CONCLUSIONS. In this group of children with sickle cell disease, hemorrhagic stroke was associated with a history of hypertension or antecedent events including transfusion or treatment with corticosteroids. Improved understanding of risk and prognostic factors, especially those that are modifiable, may help prevent this devastating complication in children with sickle cell disease.

DESIGN OF THE SILENT CEREBRAL INFARCT TRANSFUSION (SIT) TRIAL

Background: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. Procedure: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12–18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. Conclusion: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.

Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease

Acute chest syndrome (ACS) is a frequent cause of hospitalization and mortality in children with sickle cell disease. Transfusion is often required to prevent respiratory failure and treatment with dexamethasone may reduce the length of admission and the need for transfusions. We performed a retrospective cohort study to evaluate risk factors for readmission and prolonged hospitalization after different treatments for ACS.

Hydroxyurea for the treatment of sickle cell disease: Efficacy, barriers, toxicity, and management in children†

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on‐going and planned studies in children. Pediatr Blood Cancer 2012;59:365–371.

The excess burden of stroke in hospitalized adults with sickle cell disease.

This report compares the relative rates and risk factors associated with stroke in adults versus children with sickle cell disease (SCD) in the United States over the last decade. We identified incident strokes in patients with SCD using ICD‐9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD. We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD‐related complications from 1998 to 2007. The rate of stroke in children [<18 years old (310/100,000 person‐years)] was similar to young adults [18–34 years old (360/100,000 person‐years)], but much higher in middle‐aged [35–64 years old (1,160/100,000 person‐years)] and elderly adults [≥65 years old (4,700/100,000 person‐years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in‐hospital deaths from stroke (91%) occurred in adults. Our results suggest that the rate of stroke in SCD peaks in older adults and is three‐fold higher than rates previously reported in African‐Americans of similar age (35–64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed. Am. J. Hematol. 2009.