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 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.
Service d'Hématologie Biologique, Centre Hospitalier Universitaire de Nancy, Nancy, France.|Centre de Compétence Nord-Est des Pathologies Plaquettaires (CCPP), Nancy, France.
Veronique
V
Latger-Cannard
Laboratoire de Génétique, Centre Hospitalier Universitaire de Nancy, Nancy, France.
Christophe
C
Philippe
Service d'Hématologie Biologique, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
Alexandre
A
Bouquet
Laboratoire d'Hématologie, Hôpital La Timone, Marseille, France.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France.
Veronique
V
Baccini
Laboratoire d'Hématologie, Hôpital La Timone, Marseille, France.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France.
Marie-Christine
MC
Alessi
Assistance Publique-Hôpitaux de Paris, Laboratoire d'Hématologie, La Pitié Salpetrière, Paris, France.
Annick
A
Ankri
Centre de Compétence Nord-Est des Pathologies Plaquettaires (CCPP), Nancy, France.|Service d'Hématologie Biologique, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
Anne
A
Bauters
Centre Régional de Traitement des Hémophiles, Centre Hospitalier Universitaire de Rennes, Rennes, France.
Sophie
S
Bayart
Laboratoire d'Hématologie, Centre Hospitalier Universitaire Robert Debré, Reims, France.
Pascale
P
Cornillet-Lefebvre
Laboratoire d'Hématologie, Centre Hospitalier Universitaire Robert Debré, Reims, France.
Sylvie
S
Daliphard
Département de Biopathologie, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Marie-Joelle
MJ
Mozziconacci
Service d'Hématologie Biologique, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
Aline
A
Renneville
Assistance Publique-Hôpitaux de Paris, Département d'Hématologie, Hôpital Armand Trousseau, Paris, France.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France.
Paola
P
Ballerini
Assistance Publique-Hôpitaux de Paris, Département d'Hématologie, Hôpital Armand Trousseau, Paris, France.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France.
Guy
G
Leverger
Département de Biopathologie, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Hagay
H
Sobol
Laboratoire de Génétique, Centre Hospitalier Universitaire de Nancy, Nancy, France.
Philippe
P
Jonveaux
Service d'Hématologie Biologique, Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
Claude
C
Preudhomme
Laboratoire d'Hématologie, Hôpital La Timone, Marseille, France.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France.
Paquita
P
Nurden
Service d'Hématologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland.|Faculté de Médecine, Université de Genève, Geneva, Switzerland.
Thomas
T
Lecompte
Assistance Publique-Hôpitaux de Paris, Département d'Hématologie, Hôpital Armand Trousseau, Paris, France. remi.favier@aphp.fr.|Inserm U1170, Villejuif, France. remi.favier@aphp.fr.|Centre de Référence des Pathologies Plaquettaires (CRPP), Hôpital La Timone, Marseille, France. remi.favier@aphp.fr.|Service d'Hématologie Biologique, Hôpital d'enfants Armand Trousseau, 26 Avenue du Dr Netter, 75012, Paris, France. remi.favier@aphp.fr.
Remi
R
Favier
D000293:Adolescent; D000328:Adult; D025861:Blood Coagulation Disorders, Inherited / Q000235:genetics*; D001791:Blood Platelet Disorders / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013921:Thrombocytopenia / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human
Familial platelet disorder with predisposition to acute myeloid leukaemia; Leukaemia; RUNX1; Thrombocytopenia; δ-granule release defect