The strange case of the lost NRAS mutation in a child with juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood characterized by mutations of the RAS-RAF-MAP kinase signaling pathway. We report the case of a child with a diagnosis of JMML carrying two mutations of NRAS gene (c.37G>C and c.38G>A) independently occurring in long-term culture initiating cells. However, only the former was consistently found in more mature hematopoietic cells, suggesting that cancer transformation may lead to the loss of a mutation. This case also indicates that molecular analysis on cell types other than peripheral blood leukocytes may be useful to obtain relevant biological information on JMML pathogenesis. \ua9 2011 Wiley Periodicals, Inc

<i>ACTN1</i>-related thrombocytopenia: identification of novel families for phenotypic characterization

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

ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization

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 alpha-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.This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text

Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.Fil: Noris, Patrizia. University of Pavia; ItaliaFil: Biino, Ginevra. Consiglio Nazionale Delle Ricerche. Istituto di Genetica Molecolare; ItaliaFil: Pecci, Alessandro. University of Pavia; ItaliaFil: Civaschi, Elisa. University of Pavia; ItaliaFil: Savoia, Anna. Università degli Studi di Trieste; Italia. Istituto Di Ricovero e Cura a Carattere Scientifico Burlo Garofolo; ItaliaFil: Seri, Marco. Università di Bologna; ItaliaFil: Melazzini, Federica. University of Pavia; ItaliaFil: Loffreddo, Giuseppe. Pausilipon Hospital; ItaliaFil: Russo, Giovana. Università degli Studi di Catania; ItaliaFil: Bozzi, Valeria. University of Pavia; ItaliaFil: Notarangelo, Lucia Dora. Spedali Civili. Ospedale dei Bambini; ItaliaFil: Gresele, Paolo. Università di Perugia; ItaliaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; EspañaFil: Kunishima, Shinji. National Hospital Organization Nagoya Medical Center; JapónFil: Cattaneo, Marco. Università degli Studi di Milano; ItaliaFil: Bussel, James. Cornell University; Estados UnidosFil: de Candia, Erica. Universita Cattolica del Sacro Cuore; ItaliaFil: Cagioni, Claudia. University of Pavia; ItaliaFil: Ramenghi, Ugo. Università di Torino; ItaliaFil: Barozzi, Serena. University of Pavia; ItaliaFil: Fabris, Fabrizio. Università di Padova; ItaliaFil: Balduini, Carlo L.. University of Pavia; Itali