- Email: [email protected]
Essential thrombocythaemia in children in the Czech Republic
st
1. JMML and other Myeloproliferative Disorders
8Department of Paediatric Haematology-Oncology, University Hospital Motol, Prague, Czech Republic *E-mail: [email protected]
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Introduction: Essential thrombocythaemia (ET) is a Philadelphia chromosome negative chronic myeloproliferative disease characterized by increased proliferation of megakaryocytes with uncontrolled platelet production. In the majority of patients, reduced expression of c-mpl on megakaryocytic progenitors and platelets has been found. In a small cohort of paediatric patients, TPO gene mutations have been detected. In 2005, JAK-2 kinase gene mutation was discovered in 23-51% of adult patients with ET. The etiological significance of these mutations to ET has not yet been fully explained. To date, approximately 100 paediatric cases with ET have been published internationally. Patients and Methods: Eleven children were diagnosed with ET at centres of Paediatric Haematology~Oncology in the Czech Republic between 1985 and 2005. There were 6 girls and 5 boys between the ages of 6-14 years at the time of diagnosis (median 10.5 years). All patients fulfilled the diagnostic criteria established by PVSG. Platelet count at the time of diagnosis was 1230 2420• 109/1 (median 1616• 109/1). In 7/11 cases the diagnosis was established by chance during blood count analysis done for other purposes such as pre-surgical examination. Four patients had clinical signs which could be linked to thrombocytosis (headache, circulatory collapse). No patient had pathological bleeding or thrombosis. Splenomegaly was found in 6 and hepatomegaly in 4 patients. Erythropoietin levels were normal in all children and thrombopoietin levels were normal or slightly increased. Spontaneous BFU-E colony growth was demonstrated in 7/9 patients examined. Molecular-genetic analysis of TPO and JAK-2 kinase gene failed to show any mutation. One patient had received hydroxyurea and two interferon-c~ in the past. Four are treated with acetylsalicylic acid and six with anagrelide. Conclusions: ET is a very rare disease in children. The clinical picture is milder than in adults and in the majority of cases, the condition is only disclosed during routine blood analysis. In our cohort, in contrast to the literature, no JAK-2 kinase gene mutations were found. ET in childhood may have a somewhat different pathophysiology from the adult form and needs a different treatment approach. Given the rarity of ET, international collaboration in this field is essential.
E R Y T H R O C Y T O S I S IN C H I L D H O O D : W H A T GENES TO L O O K FOR?
H. Carlo*. University Children' s Hospital Ulm, Germany *E-mail: [email protected] Primary erythrocytosis (PE) is a condition in which the erythropoietic compartment is expanding independently of extrinsic influences or by responding inadequately to them. Due to the physiologic negative feedback mechanisms, PE is characterized by a low erythropoietin (Epo) concentration. The so far only molecularly characterised congenital type of PE is caused by dominant mutations in the Epo-receptor gene (PFCP). At least eleven different Epo-receptor mutations leading to a truncation of the intracellular part of the receptor have so far been reported. The truncated receptor is lacking negative feedback regulation with consecutive hypersensitivity of erythroid progenitors to circulating Epo. Secondary erythrocytosis (SE) is driven by hormonal factors (predominantly by Epo) extrinsic to the erythroid compartment. The increased Epo secretion may represent a physiologic response to tissue hypoxia, an abnormal autonomous Epo production, or a dysregulation of the oxygen-dependent Epo synthesis. The first defined congenital form of SE the abnormal hemoglobin Chesapeake was reported in 1966. Since that time, more than 200 hemoglobin variants with an increased oxygen affinity have been described, one third of them associated with SE. In 2002, the underlying genetic defect of Chuvash polycythemia (CP), the currently only known endemic form of an erythrocytosis, was identified. CP is caused by a homozygous mutation (598C>T R200W) in the von-Hippel Lindau (VHL) gene. The VHL protein is involved in the deactivating degradation of the hypoxia-inducible factor HIFlct the key regulator of the oxygen dependent expression of genes such as EPO. After the identification in Chuvash patients, the VHL598C>T and other VHL gene mutations were also detected in several individuals with sporadic or familial congenital erythrocytosis outside the Chuvash region. Very recently, a family with congenital erythrocytosis due to a heterozygous mutation in the PHD2 (prolyl hydroxylase 2) gene was reported. Under normoxic conditions, PHDs catalyze the hydroxylation of two proline residues of HIF 1ct. This hydroxylation allows modification-dependent binding of HIFlct by the pVHL ubiquitin ligase complex and the subsequent degradation process. It seems probable that defects affecting additional factors involved in the oxygen sensing process are responsible for the development of erythrocytosis in other patients with a so far unexplored underlying inherited disorder.
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E S S E N T I A L T H R O M B O C Y T H A E M I A IN CHILDREN IN THE CZECH REPUBLIC
D. Pospisilova1 *, V. Mihal 1, T. Votava 2, J. Hak 3, H. Ptoszkova4, J. Blatny5, M. Priwitzerova6, V. Divoky 6, J. Cmej lova7, R. Cmej la 7, K. Petrtylova8, J. Star')8. Departments of Paediatrics, University
Hospitals, ~Olomouc, eplzeh, 3Hradec Kralove, 40strava, Czech Republic; SDepartment of Clinical Haematology, Centre for Thrombosis and Haemostasis, University Hospital, Brno, Czech Republic; 6Department of Biology, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; 7Institute of Haematology and Blood Transfusion, Department of Cell Physiology, Prague;
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Case Forum: IDIOPATHIC M Y E L O F I B R O S I S IN CHILDREN - RARE DISEASE C U R A B L E BY BONE MARROW TRANSPLANTATION
K. Zdrahalova 1 *, P. Sedlacek 1, R. Formankova 1, H. Ptoszkova 2, K. Michalova3, G. Kerndrup 4, J. Star"S . 1Department of Pediatric
Hematology and Oncology, University Hospital Motol, Prague, Czech Republic," 2Department of Pediatrics, Teaching Hospital, Ostrava, Czech Republic," 3Centerfor Oncogenetics, 1st Medical School, Prague, Czech Republic," 4Department of Pathology, University Hospital, Odense, Denmark *E-mail: [email protected] Idiopathic myelofibrosis (IMF) is a myeloproliferative disorder characterized by myelofibrosis, extramedullary hematopoiesis, splenomegaly and pancytopenia. In children the disease is rare and variable; acute fulminant course, stable disease or spontaneous remission have been reported. Histologic pattern of myelofibrosis may be found in substantial number of patients with primary MDS and differential diagnosis can be difficult. Allogeneic hematopoietic stem cell transplantation (SCT) is a treatment option but is
1. JMML and other Myeloproliferative Disorders
8Department of Paediatric Haematology-Oncology, University Hospital Motol, Prague, Czech Republic *E-mail: [email protected]
~-]
Introduction: Essential thrombocythaemia (ET) is a Philadelphia chromosome negative chronic myeloproliferative disease characterized by increased proliferation of megakaryocytes with uncontrolled platelet production. In the majority of patients, reduced expression of c-mpl on megakaryocytic progenitors and platelets has been found. In a small cohort of paediatric patients, TPO gene mutations have been detected. In 2005, JAK-2 kinase gene mutation was discovered in 23-51% of adult patients with ET. The etiological significance of these mutations to ET has not yet been fully explained. To date, approximately 100 paediatric cases with ET have been published internationally. Patients and Methods: Eleven children were diagnosed with ET at centres of Paediatric Haematology~Oncology in the Czech Republic between 1985 and 2005. There were 6 girls and 5 boys between the ages of 6-14 years at the time of diagnosis (median 10.5 years). All patients fulfilled the diagnostic criteria established by PVSG. Platelet count at the time of diagnosis was 1230 2420• 109/1 (median 1616• 109/1). In 7/11 cases the diagnosis was established by chance during blood count analysis done for other purposes such as pre-surgical examination. Four patients had clinical signs which could be linked to thrombocytosis (headache, circulatory collapse). No patient had pathological bleeding or thrombosis. Splenomegaly was found in 6 and hepatomegaly in 4 patients. Erythropoietin levels were normal in all children and thrombopoietin levels were normal or slightly increased. Spontaneous BFU-E colony growth was demonstrated in 7/9 patients examined. Molecular-genetic analysis of TPO and JAK-2 kinase gene failed to show any mutation. One patient had received hydroxyurea and two interferon-c~ in the past. Four are treated with acetylsalicylic acid and six with anagrelide. Conclusions: ET is a very rare disease in children. The clinical picture is milder than in adults and in the majority of cases, the condition is only disclosed during routine blood analysis. In our cohort, in contrast to the literature, no JAK-2 kinase gene mutations were found. ET in childhood may have a somewhat different pathophysiology from the adult form and needs a different treatment approach. Given the rarity of ET, international collaboration in this field is essential.
E R Y T H R O C Y T O S I S IN C H I L D H O O D : W H A T GENES TO L O O K FOR?
H. Carlo*. University Children' s Hospital Ulm, Germany *E-mail: [email protected] Primary erythrocytosis (PE) is a condition in which the erythropoietic compartment is expanding independently of extrinsic influences or by responding inadequately to them. Due to the physiologic negative feedback mechanisms, PE is characterized by a low erythropoietin (Epo) concentration. The so far only molecularly characterised congenital type of PE is caused by dominant mutations in the Epo-receptor gene (PFCP). At least eleven different Epo-receptor mutations leading to a truncation of the intracellular part of the receptor have so far been reported. The truncated receptor is lacking negative feedback regulation with consecutive hypersensitivity of erythroid progenitors to circulating Epo. Secondary erythrocytosis (SE) is driven by hormonal factors (predominantly by Epo) extrinsic to the erythroid compartment. The increased Epo secretion may represent a physiologic response to tissue hypoxia, an abnormal autonomous Epo production, or a dysregulation of the oxygen-dependent Epo synthesis. The first defined congenital form of SE the abnormal hemoglobin Chesapeake was reported in 1966. Since that time, more than 200 hemoglobin variants with an increased oxygen affinity have been described, one third of them associated with SE. In 2002, the underlying genetic defect of Chuvash polycythemia (CP), the currently only known endemic form of an erythrocytosis, was identified. CP is caused by a homozygous mutation (598C>T R200W) in the von-Hippel Lindau (VHL) gene. The VHL protein is involved in the deactivating degradation of the hypoxia-inducible factor HIFlct the key regulator of the oxygen dependent expression of genes such as EPO. After the identification in Chuvash patients, the VHL598C>T and other VHL gene mutations were also detected in several individuals with sporadic or familial congenital erythrocytosis outside the Chuvash region. Very recently, a family with congenital erythrocytosis due to a heterozygous mutation in the PHD2 (prolyl hydroxylase 2) gene was reported. Under normoxic conditions, PHDs catalyze the hydroxylation of two proline residues of HIF 1ct. This hydroxylation allows modification-dependent binding of HIFlct by the pVHL ubiquitin ligase complex and the subsequent degradation process. It seems probable that defects affecting additional factors involved in the oxygen sensing process are responsible for the development of erythrocytosis in other patients with a so far unexplored underlying inherited disorder.
F•
E S S E N T I A L T H R O M B O C Y T H A E M I A IN CHILDREN IN THE CZECH REPUBLIC
D. Pospisilova1 *, V. Mihal 1, T. Votava 2, J. Hak 3, H. Ptoszkova4, J. Blatny5, M. Priwitzerova6, V. Divoky 6, J. Cmej lova7, R. Cmej la 7, K. Petrtylova8, J. Star')8. Departments of Paediatrics, University
Hospitals, ~Olomouc, eplzeh, 3Hradec Kralove, 40strava, Czech Republic; SDepartment of Clinical Haematology, Centre for Thrombosis and Haemostasis, University Hospital, Brno, Czech Republic; 6Department of Biology, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; 7Institute of Haematology and Blood Transfusion, Department of Cell Physiology, Prague;
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Case Forum: IDIOPATHIC M Y E L O F I B R O S I S IN CHILDREN - RARE DISEASE C U R A B L E BY BONE MARROW TRANSPLANTATION
K. Zdrahalova 1 *, P. Sedlacek 1, R. Formankova 1, H. Ptoszkova 2, K. Michalova3, G. Kerndrup 4, J. Star"S . 1Department of Pediatric
Hematology and Oncology, University Hospital Motol, Prague, Czech Republic," 2Department of Pediatrics, Teaching Hospital, Ostrava, Czech Republic," 3Centerfor Oncogenetics, 1st Medical School, Prague, Czech Republic," 4Department of Pathology, University Hospital, Odense, Denmark *E-mail: [email protected] Idiopathic myelofibrosis (IMF) is a myeloproliferative disorder characterized by myelofibrosis, extramedullary hematopoiesis, splenomegaly and pancytopenia. In children the disease is rare and variable; acute fulminant course, stable disease or spontaneous remission have been reported. Histologic pattern of myelofibrosis may be found in substantial number of patients with primary MDS and differential diagnosis can be difficult. Allogeneic hematopoietic stem cell transplantation (SCT) is a treatment option but is