Congenital amegakaryocytic thrombocytopenia: Clinical and biological consequences of five novel mutations

Anna Savoia, Carlo Dufour, Franco Locatelli, Patrizia Noris, Chiara Ambaglio, Vittorio Rosti, Marco Zecca, Simona Ferrari, Filomena Di Bari, Anna Corcione, Mariateresa Di Stazio, Marco Seri, Carlo L. Balduini

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Abstract

Background and Objectives: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor. Key words: congenital amegakaryocytic thrombocytopenia, CAMT, c-MPL, thrombopoietin receptor, mutations.

Original languageEnglish
Pages (from-to)1186-1193
Number of pages8
JournalHaematologica
Volume92
Issue number9
DOIs
Publication statusPublished - Sep 2007

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Thrombopoietin Receptors
Pancytopenia
Mutation
Bone Marrow Diseases
Thrombopoietin
Hematopoietic Stem Cell Transplantation
Age of Onset
Bone Marrow Cells
Thrombocytopenia
Interferons
Congenital amegakaryocytic thrombocytopenia
Blood Platelets
Tumor Necrosis Factor-alpha
Bone Marrow
Cytokines
Mortality
Therapeutics
Serum
Genes

ASJC Scopus subject areas

  • Hematology

Cite this

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title = "Congenital amegakaryocytic thrombocytopenia: Clinical and biological consequences of five novel mutations",
abstract = "Background and Objectives: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor. Key words: congenital amegakaryocytic thrombocytopenia, CAMT, c-MPL, thrombopoietin receptor, mutations.",
author = "Anna Savoia and Carlo Dufour and Franco Locatelli and Patrizia Noris and Chiara Ambaglio and Vittorio Rosti and Marco Zecca and Simona Ferrari and {Di Bari}, Filomena and Anna Corcione and {Di Stazio}, Mariateresa and Marco Seri and Balduini, {Carlo L.}",
year = "2007",
month = "9",
doi = "10.3324/haematol.11425",
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pages = "1186--1193",
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TY - JOUR

T1 - Congenital amegakaryocytic thrombocytopenia

T2 - Clinical and biological consequences of five novel mutations

AU - Savoia, Anna

AU - Dufour, Carlo

AU - Locatelli, Franco

AU - Noris, Patrizia

AU - Ambaglio, Chiara

AU - Rosti, Vittorio

AU - Zecca, Marco

AU - Ferrari, Simona

AU - Di Bari, Filomena

AU - Corcione, Anna

AU - Di Stazio, Mariateresa

AU - Seri, Marco

AU - Balduini, Carlo L.

PY - 2007/9

Y1 - 2007/9

N2 - Background and Objectives: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor. Key words: congenital amegakaryocytic thrombocytopenia, CAMT, c-MPL, thrombopoietin receptor, mutations.

AB - Background and Objectives: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor. Key words: congenital amegakaryocytic thrombocytopenia, CAMT, c-MPL, thrombopoietin receptor, mutations.

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JO - Haematologica

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SN - 0390-6078

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