Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype.

Background: Constitutive inflammation and hemostatic activation have been identified as key contributors to the pathophysiology of sickle cell disease (SCD), leading to clinical consequences such as vaso-occlusive crises and stroke. Patients with hemoglobin SS (HbSS) and hemoglobin SC (HbSC) genotypes are reported to have different symptoms, as do patients in steady-state and crisis situations. Differences among these groups remain unclear in pediatric patients. Objectives: To compare hemostatic activity in HbSS and HbSC pediatric patients during steady state, in crisis, and in clinical follow-up and compare HbSS and HbSC patients with normal healthy children. Methods: Whole-blood coagulation assay thromboelastography (TEG) was used to assess hemostatic activity. In parallel, flow cytometry was used to assess procoagulant surface expression of platelets and red blood cells. Results: TEG results indicated no significant differences in clotting onset (R time), clot maximum amplitude, or maximum rate of thrombus generation among steady-state, crisis, and follow-up subgroups of HbSS and HbSC patients. TEG parameters did not differ significantly between HbSC patients and healthy children, while HbSS patients showed significantly shorter R time and greater maximum amplitude and maximum rate of thrombus generation, all indicative of a constitutive hypercoagulable state. Flow cytometry results did not detect increased platelet integrin αIIbß3 activation or red blood cell procoagulant surface expression in SCD patients compared with unaffected children. Conclusion: Our results indicate that pediatric SCD patients with the HbSS genotype have constitutively activated hemostasis relative to HbSC patients and healthy children. It remains to be determined how treatments that improve clinical outcomes in SCD patients affect this constitutively hypercoagulable state.

Identifying and Treating Severe Bone Marrow Necrosis and Fat Embolism Syndrome in Pediatric Patients With Sickle Cell Disease: A Case Report.

Fat embolism syndrome after bone marrow necrosis is an extremely rare complication in sickle cell disease associated with significant morbidity and mortality. A high index of suspicion is required for diagnosis. This case report will assist pediatric clinicians and hematologists to recognize this severe complication in patients with sickle cell disease and to promptly initiate treatment. Red flags include severe bone pain, respiratory distress, neurological impairment, decreasing platelet count, peripheral leukocyte left shift, elevated nucleated red blood cells, and significant elevation in plasma ferritin and lactate dehydrogenase. We report a pediatric patient who was diagnosed early, received urgent red cell exchange transfusion and plasma exchange, and ultimately survived this devastating complication.

Syrian Refugees and Their Impact on Health Service Delivery in the Pediatric Hematology/Oncology Clinics Across Canada.

This study examined the impact of Syrian refugees on 1 area of the Canadian health care sector. We predicted that pediatric hematology clinics across Canada would see a spike in their Syrian refugee patient population in proportion to their recent migration and, as a result, an increase in perceived workload. Data on the number of refugee patients, types of diseases, and perceived workload were gathered from hematology clinics across Canada using a clinical survey (Supplemental Digital Content 1, http://links.lww.com/JPHO/A315). The results showed that Ontario had the most Syrian refugee patients, followed by the Quebec, Western Canadian, and Atlantic regions. The results also showed that perceived workload ranged from "no increase" (4 programs) to "minimal increase" <25% (1 program), "moderate increase" 25% to 75% (4 programs), and "significant increase" >75% (3 programs, 2 of which had no transfusion-dependent thalassemia patients before the immigration).

Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).

BACKGROUND: Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN. METHODS: We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. RESULTS: We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease. CONCLUSIONS: Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

White matter integrity and core cognitive function in children diagnosed with sickle cell disease.

Children diagnosed with sickle cell disease (SCD) have an increased risk of stroke, often associated with white matter damage and neurocognitive morbidity. Growing evidence suggests that subtle changes in white matter integrity, which do not pass the threshold to be visible on a clinical magnetic resonance image and classified as stroke, may contribute to decreased cognitive performance. We used archived diffusion-weighted imaging and neurocognitive assessment data to identify associations between microstructural changes in normal-appearing white matter and cognitive performance in children with SCD. Study participants included 10 healthy children and 15 pediatric SCD patients (5 with identified lesions and 10 without lesion). After excluding lesioned tissue from analyses, we detected significant increases in apparent diffusion coefficient across the brains of patients in comparison with control children, suggesting compromise to the structure of normal-appearing white matter. Deficits in working memory and processing speed were also apparent in patients. Increased apparent diffusion coefficient and deficiencies in processing speed were again detected in a subanalysis including only the patients without lesion. Correlation analyses evidenced associations between the microstructure of the right frontal lobe and cerebellum, and processing speed. This outcome suggests a relationship between tissue integrity and cognitive morbidity in SCD patients.

Renal dysfunction in patients with thalassaemia.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary ß(2) -microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Pediatric vasoocclusive crisis and weather conditions.

BACKGROUND: Previous studies have demonstrated associations of frequency of vasoocclusive crisis with weather conditions in adults, although relationships have been inconsistent. OBJECTIVES: Our objective was to determine if there is an association between weather conditions and pediatric emergency department (ED) visits, hospital admissions, and day and severity of pain precipitation for vasoocclusive crisis (VOC). METHODS: A retrospective observational study was performed at a large tertiary care pediatric center. We reviewed health records of all VOC patients under the age of 18 years with a chief complaint of pain and performed correlations between daily and average weekly and monthly weather conditions and frequency of painful crises. RESULTS: A total of 430 visits for VOC to the ED were documented from January 2005 to December 2006. Significant correlations were noted between the daily and weekly number of painful crises and colder temperatures (ρ=-0.11, p=0.004 for daily data and r=0.25, p=0.01 weekly) and wind speed (ρ=0.13, p<0.001 and r=0.25, p=0.01). The monthly number of painful crises was moderately correlated with temperatures (r=-0.42, p=0.04). The average monthly pain score was higher in more humid months (r=0.44, p=0.03). CONCLUSION: We found significant correlations of VOC with weather conditions where colder temperatures and higher wind speed were associated with a higher incidence of VOC in children. Health care providers as well as parents should be aware of these findings and ensure that preventive measures are instituted in patients at risk.

Admission and length of stay due to painful vasoocclusive crisis in children.

PURPOSE: To identify demographic, clinical, and laboratory characteristics associated with admission and a longer length of stay (LOS) due to vasoocclusive crisis (VOC) in children with sickle cell disease (SCD). METHODS: Retrospective chart review at a large tertiary pediatric center. Patients younger than 18 years with VOC due to SCD presenting to the emergency department were included. We performed multivariate regression analyses to predict characteristics associated with admission and LOS of 4 days or more. RESULTS: A total of 428 visits for VOC were documented in 2005 to 2006. In a multivariate regression analysis higher pain score at triage (P < .001), older age (P = .04), and increased systolic blood pressure (P = .02) were predictors of admission. Higher pain score at triage (P = .046), older age (P = .002), increased polymorphonuclear count (P = .02), and homozygous SCD type (P = .03) were associated with prolonged hospital LOS. CONCLUSION: These characteristics will help healthcare providers predict and plan admission and management of children with SCD.

Initial presentation of unscreened children with sickle cell disease: the Toronto experience.

BACKGROUND: The morbidity and mortality related to sickle cell disease (SCD) has decreased since the introduction of newborn screening in the United States. Given the multicultural nature of the Canadian population and the growing African Canadian population, it is concerning that there is no national neonatal screening program for SCD in Canada. The objective of this study was to evaluate the most common manner in which SCD is diagnosed in children when neonatal screening is not available routinely. PROCEDURE: The study design was a retrospective chart review. All children aged from birth to 18 years with SCD and an admission to the Hospital for Sick Children in Toronto, Canada, between 1978 and 2004 were eligible for inclusion. RESULTS: Fifty-two percent of the children with SCD were diagnosed through some form of screening while 48% were diagnosed with symptoms suggestive of their disease. The median age at time of diagnosis was 0.75 years in the "screened" group, and 2 years in the "symptom" group (P < 0.05). The most common symptomatic presentation was with a vaso-occlusive crisis. Fifteen percent presented with more severe symptoms including acute chest syndrome (5.5%), acute splenic sequestration (5%), sepsis (3.3%), aplastic crisis (1%), priapism (0.5%), meningitis (0.5%), stroke (0.5%), and death (1%). CONCLUSIONS: Fifteen percent of children with undiagnosed SCD presented initially with severe complications of the disease. The morbidity and mortality related to undiagnosed SCD underscores the need for a national neonatal screening program in Canada.

Bone disease in thalassemia: a frequent and still unresolved problem.

Adults with beta thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, > or =6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1-75 yr), were studied. Spine and femur BMD Z-scores < -2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

Deferoxamine-related ocular toxicity: incidence and outcome in a pediatric population.

PURPOSE: Deferoxamine (DFO) is a chelating agent used widely for the treatment of transfusional hemochromatosis. DFO-related ocular toxicity has been previously reported several times, and many institutions have adopted an ophthalmic screening protocol for patients treated with DFO despite little information regarding the rate of ocular toxicity. Our study aimed to determine the incidence of DFO toxicity at a major pediatric hospital that uses regular ophthalmic screening for all DFO-treated patients. METHODS: A retrospective case series of all patients treated with DFO for transfusional hemochromatosis at The Hospital for Sick Children (Toronto, Ontario, Canada) between 1995 and 2005 inclusive. RESULTS: A total of 84 patients received regular DFO treatment for transfusional hemochromatosis related to long-term hypertransfusion. A total of 421 ophthalmic screening examinations were performed (average, 5.0 examinations per patient). DFO-related ocular toxicity was found only in one patient (1.2%). This patient had central blurriness and retinal pigmentary changes shown by examination and decreased central responses shown by electroretinography, but these changes were all found to be completely reversible after a change from intravenous to subcutaneous therapy at a reduced dose. CONCLUSIONS: In this large pediatric center, DFO-related ocular toxicity has been a rare and mild finding. Regular ophthalmic screening should be carried out for patients receiving high-dose subcutaneous or intravenous therapy, because early detection of retinal toxicity may lead to optimization of the DFO dose and thus prevention of long-term visual sequelae.

Is morphine exposure associated with acute chest syndrome in children with vaso-occlusive crisis of sickle cell disease? A 6-year case-crossover study.

BACKGROUND: Recurrent painful vaso-occlusive crises (VOC) are a hallmark of sickle cell disease (SCD), and narcotic analgesics are an effective component of therapy. However, the belief that these drugs can promote development of the acute chest syndrome (ACS) may lead to undertreatment of pain. OBJECTIVE: The aim of this study was to explore the potential association between a dose-response effect of morphine exposure and the development of ACS in children with SCD who presented with VOC. METHODS: A retrospective, self-matched, case-crossover design was used to study data from children with SCD who were treated with continuous-drip IV morphine (initial rate of 10 mug/kg . h) for VOC and subsequently developed ACS (index hospitalization) at a tertiary pediatric hospital in Toronto, Ontario, Canada, from April 1, 2000, to March 31, 2006. So that each child could serve as his or her own control for the analysis, a comparison hospitalization for VOC was identified for each child during which ACS did not develop (reference hospitalization). We determined the cumulative dose of morphine administered before ACS development (index interval) during the index hospitalization and the cumulative amount of morphine administered during the same time interval during the reference hospitalization (reference interval). RESULTS: Seventeen children (13 girls, 4 boys; index hospitalization: mean [SD] age, 8.9 [4.0] years; mean [SD] weight, 30.9 [15.2] kg; reference hospitalization: mean [SD] age, 8.6 [3.4] years; mean [SD] weight, 27.3 [11.2] kg) with SCD who met all inclusion criteria were identified. There was no significant difference in the cumulative morphine dose (mean [SD] amount, 1.24 [0.60] mg/kg) during the index interval compared with the amount administered during the reference interval (mean [SD] amount, 1.44 [0.84] mg/kg). CONCLUSION: Among these children with SCD who presented with VOC, the administration of morphine was not found to be associated with a dose-response effect on the risk for ACS.

The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the Hospital for Sick Children, Toronto.

Children born without a spleen or who have impaired splenic function, due to disease or splenectomy, are at significantly increased risk of life-threatening bacterial sepsis. The mainstays of prevention are education, immunization, and prophylactic antibiotics. The availability of conjugate 7-valent pneumococcal vaccines for use in children to age 9 years at least, as well as conjugate meningococcal C vaccine in some countries, for use beginning in infancy, appear to represent beneficial additions, but not substitutions, to previous recommendations for the use of polysaccharide 23-valent pneumococcal and quadrivalent A, C, Y, W-135 vaccines. Routine immunization against H. influenzae type b should continue with non-immunized children older than age 5 years receiving two doses 2 months apart, similar to children who have not previously received conjugate pneumococcal vaccine in infancy. Annual influenza immunization, which reduces the risk of secondary bacterial infection, is also recommended for asplenic children and their household contacts. Many experts continue prophylaxis indefinitely although prophylaxis of the penicillin allergic child remains suboptimal.

Hepatosplenic gammadelta T-cell lymphoma in a 10-year-old boy successfully treated with hematopoietic stem cell transplantation.

The authors report a 10-year-old boy with hepatosplenic gammadelta T-cell lymphoma, a rare form of lymphoma that is highly aggressive, exceedingly rare in children, and primarily seen in young men. Conventional multi-agent chemotherapy appears to be inadequate for cure. This is the first report with this type of lymphoma in a boy less than 15 years old treated with hematopoietic stem cell transplantation (HSCT).

Cardiac failure after initiation of insulin treatment in diabetic patients with beta-thalassemia major.

Diabetes mellitus is a complication of beta-thalassemia major. Two patients are described who developed severe cardiac failure after initiation or intensification of insulin treatment. We hypothesize that insulin-induced fluid retention combined with reduced cardiac reserve was responsible for the cardiac failure. Careful initiation of insulin treatment in these patients is important.

Malignant hematological disorders in children with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder attributable to a deletion at the short arm of chromosome 4. This syndrome is associated with characteristic facial appearance, multiple congenital abnormalities, mental retardation, feeding difficulties and failure to thrive. We report two girls with WHS who developed myelodysplastic syndrome (MDS). According to the "Category, Cytology, Cytogenetic (CCC)"classification of childhood MDS, patient 1 had refractory cytopenia with ring sideroblasts at the age of 6 years, while patient 2 had refractory cytopenia with dysplasia at the age of 5-1/2 years. Patient 1 progressed to refractory cytopenia with excess blasts within a year, while patient 2 progressed to acute lymphoblastic leukemia within 1 month of presentation. It is possible that allelic loss of a tumor suppressor gene such as WHSC1 and/or FGFR3 from the deleted segment 4p16.3 plays a critical role in the process of malignant transformation. To our knowledge, this is the first report of severe hematological complications like MDS and leukemia in children with WHS and may be an important genetic model for understanding malignant hematological transformation. This report also underscores the importance of evaluating children with WHS for hematopoietic dysfunction.