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

被引:81
作者
Latger-Cannard, Veronique [1 ,2 ]
Philippe, Christophe [3 ]
Bouquet, Alexandre [4 ]
Baccini, Veronique [5 ,14 ]
Alessi, Marie-Christine [5 ,14 ]
Ankri, Annick [6 ]
Bauters, Anne [2 ,4 ]
Bayart, Sophie [7 ]
Cornillet-Lefebvre, Pascale [8 ]
Daliphard, Sylvie [8 ]
Mozziconacci, Marie-Joelle [9 ]
Renneville, Aline [4 ]
Ballerini, Paola [12 ,14 ]
Leverger, Guy [12 ,14 ]
Sobol, Hagay [9 ]
Jonveaux, Philippe [3 ]
Preudhomme, Claude [4 ]
Nurden, Paquita [5 ]
Lecompte, Thomas [10 ,11 ]
Favier, Remi [12 ,13 ,14 ,15 ]
机构
[1] Ctr Hosp Univ Nancy, Serv Hematol Biol, Nancy, France
[2] Ctr Competence Nord Est Pathol Plaquettaires CCPP, Nancy, France
[3] Ctr Hosp Univ Nancy, Genet Lab, Nancy, France
[4] Ctr Hosp Reg Univ Lille, Serv Hematol Biol, Ctr Biol Pathol, Lille, France
[5] Hop Enfants La Timone, Hematol Lab, Marseille, France
[6] La Pitie Salpetriere, Assistance Publ Hop Paris, Hematol Lab, Paris, France
[7] Ctr Hosp Univ Rennes, Ctr Reg Traitement Hemophiles, Rennes, France
[8] Ctr Hosp Univ Robert Debre, Hematol Lab, Reims, France
[9] Inst J Paoli I Calmettes, Ctr Rech Cancerol Marseille, Dept Biopathol, F-13009 Marseille, France
[10] Hop Cantonal Univ Geneva, Serv Hematol, Geneva, Switzerland
[11] Univ Geneva, Fac Med, Geneva, Switzerland
[12] Hop Armand Trousseau, Assistance Publ Hop Paris, Dept Hematol, Paris, France
[13] INSERM, U1170, Villejuif, France
[14] Hop Enfants La Timone, CRPP, Marseille, France
[15] Hop Enfants Armand Trousseau, Serv Hematol Biol, 26 Ave Dr Netter, F-75012 Paris, France
关键词
Thrombocytopenia; Familial platelet disorder with predisposition to acute myeloid leukaemia; RUNX1; Leukaemia; delta-granule release defect; ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; BLEEDING ASSESSMENT-TOOL; THROMBOCYTOPENIA; PROPENSITY; EXPRESSION; PREDISPOSITION; SECRETION; DIAGNOSIS; FPD/AML;
D O I
10.1186/s13023-016-0432-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 x 10(9)/L), with normal platelet volume. A functional platelet defect consistent with a delta-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 delta-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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