[Show abstract][Hide abstract] ABSTRACT: The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
[Show abstract][Hide abstract] ABSTRACT: The molecular basis of α-thalassemia (α-thal) is complex. The use of multiplex ligation-dependent probe amplification (MLPA) has offered the possibility of identifying more gene deletions causing α-thal. Our objective was to determine the molecular basis of two patients with Hb H (β4) disease. By using MLPA in combination with comparative genomic hybridization (CGH) we identified two novel α-globin gene cluster deletions: a 30 kb deletion (patient 1) we refer to as – –JAL and a large 216 kb deletion (patient 2) we refer to as – –LOD. Patient 1 was a compound heterozygote for – –JAL and –α3.7 (rightward deletion). Twelve family members of patient 1 carrying the – –JAL deletion were available for evaluation: five with – –JAL/–α3.7, four with – –JAL/αHph Iα and three with – –JAL/αα. Their clinical picture of compound heterozygosity was compatible with moderate Hb H disease. In patient 2 (– –LOD/–α3.7), no additional symptoms were present despite the heterozygous deletion of seven known genes, three non coding RNAs (ncRNAs), four unknown genes and two pseudo genes. Further analysis of more patients with α-thal deletions will have implications for genetic counseling and appropriate therapy.
[Show abstract][Hide abstract] ABSTRACT: Long-term Granulocyte-Colony Stimulating Factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on the use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European Branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in six women with cyclic, 12 in five women with idiopathic neutropenia) were reported. Granulocyte-Colony Stimulating Factor was administered throughout pregnancy in 16 women and for at least one trimester in further five women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in eight men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58 percent from female and in 62 percent from male patients revealing ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, Granulocyte-Colony Stimulating Factor therapy has been shown to be safe for mothers throughout pregnancies and newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy is crucial. The acceptance of having affected children may reflect the high quality of life due to this treatment.
[Show abstract][Hide abstract] ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is caused by an excessive activation of nonmalignant macrophages. Renal lesions have been described in association with, but always after, HLH diagnosis.
We describe a previously healthy 26-month-old girl who presented originally with steroid-responsive nephrotic syndrome (NS), but after 4 months, on the first NS relapse, experienced numerous complications (many of them reported to accompany NS as single events). Clinical and laboratory signs of HLH evolved with time and led to deterioration of her condition and death, within 5 months of her original presentation.
To our knowledge, this is the first report of NS antedating the presentation of HLH.
No preview · Article · Aug 2013 · Pediatric Nephrology
[Show abstract][Hide abstract] ABSTRACT: The congenital dyserythropoietic anemias (CDAs) are hereditary disorders characterized by distinct morphological abnormalities of marrow erythroblasts. The unveiling of the genes mutated in the major CDA subgroups (I-CDAN1, II-SEC23B) has now been completed with the recent identification of the CDA III gene (KIF23). KIF23 encodes mitotic kinesin-like protein 1 which plays a critical role in cytokinesis, while the cellular role of the proteins encoded by CDAN1 and SEC23B is still unknown. CDA variants with mutations in erythroid transcription factors genes (KLF1, GATA-1) have been recently identified. Molecular diagnosis of CDA is now possible in most patients.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the predictive value of clinical features at diagnosis of immune thrombocytopenia (ITP) for resolution of disease.
Hospital records of 472 consecutive children (<18 years old) with ITP cared for at 2 participating centers were reviewed retrospectively and data related to the initial presentation were recorded. Logistic regression analysis was used for calculating prediction of resolution at 3, 6, and 12 months from diagnosis.
The most significant predictors for resolution of ITP at 3, 6, and 12 months were age at onset <10 years and abrupt onset (history of <2 weeks of bleeding). We designed a prediction rule for ITP chronicity based on these criteria. The rate of developing chronic ITP for low, intermediate, and high risk children at diagnosis of ITP was 11%, 39%, and 63%, respectively. Recovery rate at 3 months for low, intermediate, and high risk children was 72%, 43% and 30%, respectively.
We present a simple rule to predict recovery from ITP at 3, 6, and 12 months from diagnosis. For prediction of resolution at 3 months, our rule was in agreement with the more complex, previously described Nordic score. Prediction of resolution of ITP may enable practitioners to better inform children and parents at the time of diagnosis, resulting in reduced anxiety and improved quality of life.
No preview · Article · Jul 2013 · The Journal of pediatrics
[Show abstract][Hide abstract] ABSTRACT: Although the majority of children with immune thrombocytopenia (ITP) have a short duration of the disease, the very rare but significant complications of the disease often cause fear and anxiety among families of children with ITP. Added to the reduced quality of life (QoL) of those children are restrictions imposed on daily activities to avoid trauma. Treatment decisions in chronic ITP and especially regarding splenectomy are hampered by the inability to predict when recovery will take place. Identification of predictors of recovery would be beneficial for improving treatment decisions and QoL of both children and families. This literature review focuses on clinical parameters and emerging genetic biomarkers for prediction of duration of childhood ITP. Higher recovery rates were found among infants with newly diagnosed ITP. In contrast onset of the disease at adolescence was associated with worse recovery rates. Six clinical features were found to be associated with short duration of disease; the most prominent ones were abrupt onset of bleeding symptoms (<2 weeks) and age at onset≤10 years. Two genetic biomarkers have been suggested as predictors of chronic disease: overexpression of vanin-1 (VNN-1), an oxidative stress sensor, and the Q63R missense variant of the gene encoding the cannabinoid receptor type 2. To be clinically useful each of those predictors requires further validation in larger studies. Genetic biomarkers will potentially offer direct and early prognosis estimation.
Preview · Article · May 2013 · Seminars in Hematology
[Show abstract][Hide abstract] ABSTRACT: Thrombocytosis is a common finding and is a frequent cause of referral for further investigation. The MPL Baltimore (Lys39Asn) mutation has been reported as a cause of thrombocytosis in 7% of African Americans. We describe an 11-month-old Ethiopian Jewish boy referred for evaluation of thrombocytosis who was found to be homozygous for MPL Baltimore. So far, there is no indication whether patients with thrombocytosis who have this mutation, particularly homozygotes, are at increased risk of thrombotic or hemorrhagic complications. Nevertheless, this entity should be considered in the differential diagnosis of every patient with thrombocytosis, particularly those of African origin.
No preview · Article · Apr 2013 · Journal of Pediatric Hematology/Oncology
[Show abstract][Hide abstract] ABSTRACT: : We constructed an animal model to examine the possibility that erythrophagocytosis may contribute to decreased hemoglobin (Hgb) levels in acute infection in mice.
: BALB/c mice weighing 20 to 25 g were injected (intraperitoneally) with lipopolysaccharide (LPS) (Escherichia coli serotype) of some concentrations. Control mice were injected intraperitoneally with saline (0.5 mL). Two and 4 hours after LPS administration, mice were bled (0.25 mL) for complete blood count measures and tumor necrosis factor-α and interleukin-6 levels. The mice were then killed, and their spleen, liver, and bone marrow were examined microscopically for erythrophagocytosis.
: After LPS administration, mouse Hgb and hematocrit levels dropped significantly. At 4 hours after LPS injection, all Hgb and hematocrit concentrations were found to be significantly lower compared with that of controls (P=0.002 and 0.001, respectively). Significantly increased concentrations of tumor necrosis factor-α and interleukin-6 were evident after LPS injection. Prominent hepatic erythrophagocytosis was observed in the LPS-injected mice compared with controls. A significant across-group difference was observed at 4 hours, driven by significantly higher values in group 500 mcg versus controls (P=0.005) and 100 mcg (P=0.025). A significant increase in erythrophagocytes was observed at 2 to 4 hours in the 500 mcg LPS group (P=0.044).
: Erythrophagocytosis may play a role in anemia associated with acute infection in mice.
No preview · Article · Jan 2013 · Journal of Pediatric Hematology/Oncology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The epsilon gamma delta beta (εγδβ)-thalassemias are rare sporadic disorders caused by deletion of the β-globin gene cluster. The main clinical feature is marked prenatal and neonatal anemia that resolves spontaneously within a few months. Reports originating mainly from Europe have so far identified 30 such deletions The aim of the present work was to describe a novel 1.78-Mb deletion, the longest ever reported, and to detail the clinical features in 12 members of an extended Bedouin family.
The deletion was identified by globin gene multiplex ligation-dependent probe amplification (MLPA) of the β-globin cluster and further characterized by comparative genomic hybridization. Past and present clinical and laboratory data of ten symptomatic and two asymptomatic patients were collected.
A 1.78-Mb εγδβ-deletion, the largest ever described, was identified in all patients. Although other genes were included in the deletion, no other symptoms were observed. Of the ten symptomatic fetuses and neonates, three died of the disease. The remainder required packed cell transfusions during the first months of life. Pregnancy complications included intrauterine growth restriction and oligohydramnios, as well as additional neonatal complications including prematurity and persistent pulmonary hypertension of the neonate.
We suggest that εγδβ-thalassemia be added to the list of hemoglobinopathies that can cause neonatal anemia and that MLPA of the β-globin cluster be used to confirm its diagnosis. Careful surveillance during pregnancy is important to reduce neonatal mortality and morbidity, especially given the dramatic improvement that occurs later.
No preview · Article · Dec 2012 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: Congenital dyserythropoietic anemia (CDA) is a rare group of red blood cell disorders with ineffective erythropoiesis and secondary hemochromatosis. Inappropriate suppression of hepcidin and high levels of growth differentiation factor 15 (GDF15) have been described in CDA I and II patients, probably contributing to secondary hemochromatosis. Hemojuvelin (HJV) is an important regulator of serum hepcidin, while soluble form of HJV (s-HJV) competitively down-regulates hepcidin.
We determined the soluble hemojuvelin (s-HJV) levels in 17 patients with CDA I and in 17 healthy volunteers (HV) and looked for correlations with other parameters of iron overload and erythropoiesis.
Significantly higher levels of s-HJV were found in patients (2.32 ± 1.40 mg/L) compared with healthy volunteers (0. 69 ± 0.44 mg/L) (P = 0.001). Western blot analysis confirmed the presence of high levels of s-HJV in CDA I patients. s-HJV positively correlated with serum ferritin, erythropoietin, soluble transferrin receptor, and GDF15 and negatively correlated with hepcidin to ferritin ratios.
We for the first time documented high levels of serum s-HJV in CDA I patients, suggesting that it may contribute to iron loading pathology in CDA I and eventually in other anemias with ineffective erythropoiesis.
No preview · Article · Oct 2012 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: Neutral lipid storage disease (Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder of lipid metabolism, characterized by systemic accumulation of neutral lipids in multiple tissues. We report a case of a 14-year-old girl with generalized ichthyosis, liver cirrhosis, and a hearing impairment. A peripheral blood smear demonstrated marked cytoplasmatic vacuoles in most polymorphonuclear cells (Jordan's anomaly). Bone marrow examination revealed vacuoles in myeloid precursors. Genetic analysis showed that the patient was homozygous for the p.Arg312Ter mutation in the CGI-58 gene, a key enzyme in lipid metabolism. The peripheral blood smear is diagnostic, and should be performed in any patient with ichthyosis.
No preview · Article · Oct 2012 · Journal of Pediatric Hematology/Oncology