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Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders

BACKGROUND: Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen i...

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Autores principales: Latger-Cannard, Veronique, Philippe, Christophe, Bouquet, Alexandre, Baccini, Veronique, Alessi, Marie-Christine, Ankri, Annick, Bauters, Anne, Bayart, Sophie, Cornillet-Lefebvre, Pascale, Daliphard, Sylvie, Mozziconacci, Marie-Joelle, Renneville, Aline, Ballerini, Paola, Leverger, Guy, Sobol, Hagay, Jonveaux, Philippe, Preudhomme, Claude, Nurden, Paquita, Lecompte, Thomas, Favier, Remi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845427/
https://www.ncbi.nlm.nih.gov/pubmed/27112265
http://dx.doi.org/10.1186/s13023-016-0432-0
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author Latger-Cannard, Veronique
Philippe, Christophe
Bouquet, Alexandre
Baccini, Veronique
Alessi, Marie-Christine
Ankri, Annick
Bauters, Anne
Bayart, Sophie
Cornillet-Lefebvre, Pascale
Daliphard, Sylvie
Mozziconacci, Marie-Joelle
Renneville, Aline
Ballerini, Paola
Leverger, Guy
Sobol, Hagay
Jonveaux, Philippe
Preudhomme, Claude
Nurden, Paquita
Lecompte, Thomas
Favier, Remi
author_facet Latger-Cannard, Veronique
Philippe, Christophe
Bouquet, Alexandre
Baccini, Veronique
Alessi, Marie-Christine
Ankri, Annick
Bauters, Anne
Bayart, Sophie
Cornillet-Lefebvre, Pascale
Daliphard, Sylvie
Mozziconacci, Marie-Joelle
Renneville, Aline
Ballerini, Paola
Leverger, Guy
Sobol, Hagay
Jonveaux, Philippe
Preudhomme, Claude
Nurden, Paquita
Lecompte, Thomas
Favier, Remi
author_sort Latger-Cannard, Veronique
collection PubMed
description BACKGROUND: Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered. METHODS: We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015. RESULTS: Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation. CONCLUSIONS: Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.
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spelling pubmed-48454272016-04-27 Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders Latger-Cannard, Veronique Philippe, Christophe Bouquet, Alexandre Baccini, Veronique Alessi, Marie-Christine Ankri, Annick Bauters, Anne Bayart, Sophie Cornillet-Lefebvre, Pascale Daliphard, Sylvie Mozziconacci, Marie-Joelle Renneville, Aline Ballerini, Paola Leverger, Guy Sobol, Hagay Jonveaux, Philippe Preudhomme, Claude Nurden, Paquita Lecompte, Thomas Favier, Remi Orphanet J Rare Dis Research BACKGROUND: Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered. METHODS: We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015. RESULTS: Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation. CONCLUSIONS: Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management. BioMed Central 2016-04-26 /pmc/articles/PMC4845427/ /pubmed/27112265 http://dx.doi.org/10.1186/s13023-016-0432-0 Text en © Latger-Cannard et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Latger-Cannard, Veronique
Philippe, Christophe
Bouquet, Alexandre
Baccini, Veronique
Alessi, Marie-Christine
Ankri, Annick
Bauters, Anne
Bayart, Sophie
Cornillet-Lefebvre, Pascale
Daliphard, Sylvie
Mozziconacci, Marie-Joelle
Renneville, Aline
Ballerini, Paola
Leverger, Guy
Sobol, Hagay
Jonveaux, Philippe
Preudhomme, Claude
Nurden, Paquita
Lecompte, Thomas
Favier, Remi
Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title_full Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title_fullStr Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title_full_unstemmed Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title_short Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders
title_sort haematological spectrum and genotype-phenotype correlations in nine unrelated families with runx1 mutations from the french network on inherited platelet disorders
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845427/
https://www.ncbi.nlm.nih.gov/pubmed/27112265
http://dx.doi.org/10.1186/s13023-016-0432-0
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