TY - JOUR T1 - ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. JF - Br J Haematol Y1 - 2018 A1 - Faleschini, Michela A1 - Melazzini, Federica A1 - Marconi, Caterina A1 - Giangregorio, Tania A1 - Pippucci, Tommaso A1 - Cigalini, Elena A1 - Pecci, Alessandro A1 - Bottega, Roberta A1 - Ramenghi, Ugo A1 - Siitonen, Timo A1 - Seri, Marco A1 - Pastore, Annalisa A1 - Savoia, Anna A1 - Noris, Patrizia AB -

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.

VL - 183 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30351444?dopt=Abstract ER - TY - JOUR T1 - ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. JF - Blood Y1 - 2015 A1 - Bottega, Roberta A1 - Marconi, Caterina A1 - Faleschini, Michela A1 - Baj, Gabriele A1 - Cagioni, Claudia A1 - Pecci, Alessandro A1 - Pippucci, Tommaso A1 - Ramenghi, Ugo A1 - Pardini, Simonetta A1 - Ngu, Loretta A1 - Baronci, Carlo A1 - Kunishima, Shinji A1 - Balduini, Carlo L A1 - Seri, Marco A1 - Savoia, Anna A1 - Noris, Patrizia KW - Actinin KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Platelets KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Female KW - Gene Expression KW - Genotype KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation, Missense KW - Pedigree KW - Phenotype KW - Platelet Count KW - Severity of Illness Index KW - Thrombocytopenia KW - Thrombopoiesis KW - Thrombopoietin AB -

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.

VL - 125 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25361813?dopt=Abstract ER - TY - JOUR T1 - Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. JF - Haematologica Y1 - 2014 A1 - Noris, Patrizia A1 - Schlegel, Nicole A1 - Klersy, Catherine A1 - Heller, Paula G A1 - Civaschi, Elisa A1 - Pujol-Moix, Núria A1 - Fabris, Fabrizio A1 - Favier, Rémi A1 - Gresele, Paolo A1 - Latger-Cannard, Véronique A1 - Cuker, Adam A1 - Nurden, Paquita A1 - Greinacher, Andreas A1 - Cattaneo, Marco A1 - De Candia, Erica A1 - Pecci, Alessandro A1 - Hurtaud-Roux, Marie-Françoise A1 - Glembotsky, Ana C A1 - Muñiz-Diaz, Eduardo A1 - Randi, Maria Luigia A1 - Trillot, Nathalie A1 - Bury, Loredana A1 - Lecompte, Thomas A1 - Marconi, Caterina A1 - Savoia, Anna A1 - Balduini, Carlo L A1 - Bayart, Sophie A1 - Bauters, Anne A1 - Benabdallah-Guedira, Schéhérazade A1 - Boehlen, Françoise A1 - Borg, Jeanne-Yvonne A1 - Bottega, Roberta A1 - Bussel, James A1 - De Rocco, Daniela A1 - de Maistre, Emmanuel A1 - Faleschini, Michela A1 - Falcinelli, Emanuela A1 - Ferrari, Silvia A1 - Ferster, Alina A1 - Fierro, Tiziana A1 - Fleury, Dominique A1 - Fontana, Pierre A1 - James, Chloé A1 - Lanza, Francois A1 - Le Cam Duchez, Véronique A1 - Loffredo, Giuseppe A1 - Magini, Pamela A1 - Martin-Coignard, Dominique A1 - Menard, Fanny A1 - Mercier, Sandra A1 - Mezzasoma, Annamaria A1 - Minuz, Pietro A1 - Nichele, Ilaria A1 - Notarangelo, Lucia D A1 - Pippucci, Tommaso A1 - Podda, Gian Marco A1 - Pouymayou, Catherine A1 - Rigouzzo, Agnes A1 - Royer, Bruno A1 - Sie, Pierre A1 - Siguret, Virginie A1 - Trichet, Catherine A1 - Tucci, Alessandra A1 - Saposnik, Béatrice A1 - Veneri, Dino KW - Adult KW - Female KW - Humans KW - Infant, Newborn KW - Pregnancy KW - Pregnancy Complications, Hematologic KW - Retrospective Studies KW - Thrombocytopenia KW - Young Adult AB -

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.

VL - 99 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24763399?dopt=Abstract ER -