%0 Journal Article %J Br J Haematol %D 2018 %T ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. %A Faleschini, Michela %A Melazzini, Federica %A Marconi, Caterina %A Giangregorio, Tania %A Pippucci, Tommaso %A Cigalini, Elena %A Pecci, Alessandro %A Bottega, Roberta %A Ramenghi, Ugo %A Siitonen, Timo %A Seri, Marco %A Pastore, Annalisa %A Savoia, Anna %A Noris, Patrizia %X

The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

%B Br J Haematol %V 183 %P 276-288 %8 2018 Oct %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30351444?dopt=Abstract %R 10.1111/bjh.15531 %0 Journal Article %J Blood %D 2015 %T ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. %A Bottega, Roberta %A Marconi, Caterina %A Faleschini, Michela %A Baj, Gabriele %A Cagioni, Claudia %A Pecci, Alessandro %A Pippucci, Tommaso %A Ramenghi, Ugo %A Pardini, Simonetta %A Ngu, Loretta %A Baronci, Carlo %A Kunishima, Shinji %A Balduini, Carlo L %A Seri, Marco %A Savoia, Anna %A Noris, Patrizia %K Actinin %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Platelets %K Case-Control Studies %K Child %K Child, Preschool %K Female %K Gene Expression %K Genotype %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation, Missense %K Pedigree %K Phenotype %K Platelet Count %K Severity of Illness Index %K Thrombocytopenia %K Thrombopoiesis %K Thrombopoietin %X

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.

%B Blood %V 125 %P 869-72 %8 2015 Jan 29 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25361813?dopt=Abstract %R 10.1182/blood-2014-08-594531 %0 Journal Article %J Haematologica %D 2014 %T Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. %A Noris, Patrizia %A Schlegel, Nicole %A Klersy, Catherine %A Heller, Paula G %A Civaschi, Elisa %A Pujol-Moix, Núria %A Fabris, Fabrizio %A Favier, Rémi %A Gresele, Paolo %A Latger-Cannard, Véronique %A Cuker, Adam %A Nurden, Paquita %A Greinacher, Andreas %A Cattaneo, Marco %A De Candia, Erica %A Pecci, Alessandro %A Hurtaud-Roux, Marie-Françoise %A Glembotsky, Ana C %A Muñiz-Diaz, Eduardo %A Randi, Maria Luigia %A Trillot, Nathalie %A Bury, Loredana %A Lecompte, Thomas %A Marconi, Caterina %A Savoia, Anna %A Balduini, Carlo L %A Bayart, Sophie %A Bauters, Anne %A Benabdallah-Guedira, Schéhérazade %A Boehlen, Françoise %A Borg, Jeanne-Yvonne %A Bottega, Roberta %A Bussel, James %A De Rocco, Daniela %A de Maistre, Emmanuel %A Faleschini, Michela %A Falcinelli, Emanuela %A Ferrari, Silvia %A Ferster, Alina %A Fierro, Tiziana %A Fleury, Dominique %A Fontana, Pierre %A James, Chloé %A Lanza, Francois %A Le Cam Duchez, Véronique %A Loffredo, Giuseppe %A Magini, Pamela %A Martin-Coignard, Dominique %A Menard, Fanny %A Mercier, Sandra %A Mezzasoma, Annamaria %A Minuz, Pietro %A Nichele, Ilaria %A Notarangelo, Lucia D %A Pippucci, Tommaso %A Podda, Gian Marco %A Pouymayou, Catherine %A Rigouzzo, Agnes %A Royer, Bruno %A Sie, Pierre %A Siguret, Virginie %A Trichet, Catherine %A Tucci, Alessandra %A Saposnik, Béatrice %A Veneri, Dino %K Adult %K Female %K Humans %K Infant, Newborn %K Pregnancy %K Pregnancy Complications, Hematologic %K Retrospective Studies %K Thrombocytopenia %K Young Adult %X

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.

%B Haematologica %V 99 %P 1387-94 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24763399?dopt=Abstract %R 10.3324/haematol.2014.105924