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

From Medical Genetics, Department of Reproductive and Developmental Science, IRCCS Burlo Garofolo Children’s Hospital, University of Trieste, Italy (AS,MDS); IRCCS G.Gaslini Childen's Hospital, Genova, Italy (CD, AC); IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy (FL, PN, CA, VR, MZ, CLB);⁴ Laboratory of Medical Genetics, Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Italy (SF, MS); Telethon Institute of Genetics and Medicine, Naples, Italy (FDB)

Corresponding author: Carlo L. Balduini, Clinica Medica III, Fondazione IRCCS Policlinico San Matteo. Università di Pavia, piazzale Golgi, 27100 Pavia, Italy. E-mail: c.balduini{at}smatteo.pv.it

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- and interferon- 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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				E. Maserati, C. Panarello, C. Morerio, R. Valli, B. Pressato, F. Patitucci, E. Tassano, A. Di Cesare-Merlone, C. Cugno, C. L. Balduini, et al. Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498) Haematologica, August 1, 2008; 93(8): 1271 - 1273. [Full Text] [PDF]

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