@article {8503, title = {Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia.}, journal = {Haematologica}, year = {2016}, month = {2016 Jun 30}, abstract = {

ETV6-related thrombocytopenia (ETV6-RT) is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematological malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 ETV6-RT patients from 7 pedigrees. They have 5 different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-RT resulted 2.6\% in the whole case series and 4.6\% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of ETV6-RT patients were mild, but 4 subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly increased incidence compared to the general population. Clinical and laboratory findings did not identify any peculiar defects that can be used to suspect this disorder by routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelet size was not enlarged. In vitro studies revealed that patients megakaryocytes have defective maturation and impaired proplatelet formation. Moreover, ETV6-RT platelets have reduced ability to spread on fibrinogen. Since also the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are characterized by normal platelet size and predispose to hematological malignancies, we suggest that mutation screening of ETV6, RUNX1 and ANKRD26 should be performed in all the subjects with autosomal dominant thrombocytopenia and normal platelet size.

}, issn = {1592-8721}, doi = {10.3324/haematol.2016.147496}, author = {Melazzini, Federica and Palombo, Flavia and Balduini, Alessandra and De Rocco, Daniela and Marconi, Caterina and Noris, Patrizia and Gnan, Chiara and Pippucci, Tommaso and Bozzi, Valeria and Faleschini, Michela and Barozzi, Serena and Doubek, Michael and Di Buduo, Christian A and Stano Kozubik, Katerina and Radova, Lenka and Loffredo, Giuseppe and Pospisilova, Sarka and Alfano, Caterina and Seri, Marco and Balduini, Carlo L and Pecci, Alessandro and Savoia, Anna} } @article {1922, title = {Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation).}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Jan}, pages = {82-8}, abstract = {

BACKGROUND: Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbβ, or GPIX and is typically inherited as a recessive disease. However, some years ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients.

DESIGN AND METHODS: Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin.

RESULTS: We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases.

CONCLUSIONS: Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20\% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Bernard-Soulier Syndrome, Child, Child, Preschool, Family Health, Female, Heterozygote, Humans, Infant, Italy, Male, Membrane Glycoproteins, Middle Aged, Mutation, Missense, Platelet Aggregation, Platelet Count, Platelet Glycoprotein GPIb-IX Complex, Polymorphism, Genetic, Thrombocytopenia, Thrombopoietin, Tubulin, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2011.050682}, author = {Noris, Patrizia and Perrotta, Silverio and Bottega, Roberta and Pecci, Alessandro and Melazzini, Federica and Civaschi, Elisa and Russo, Sabina and Magrin, Silvana and Loffredo, Giuseppe and Di Salvo, Veronica and Russo, Giovanna and Casale, Maddalena and De Rocco, Daniela and Grignani, Claudio and Cattaneo, Marco and Baronci, Carlo and Dragani, Alfredo and Albano, Veronica and Jankovic, Momcilo and Scianguetta, Saverio and Savoia, Anna and Balduini, Carlo L} } @article {1697, title = {Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations.}, journal = {Haematologica}, volume = {96}, year = {2011}, month = {2011 Mar}, pages = {417-23}, abstract = {

BACKGROUND: Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.

DESIGN AND METHODS: Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.

RESULTS: Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10\% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.

CONCLUSIONS: Regardless of mutations identified, the patients{\textquoteright} bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Bernard-Soulier Syndrome, Blood Platelets, Cell Shape, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Markers, Hemorrhage, Homozygote, Humans, Italy, Male, Membrane Glycoproteins, Middle Aged, Molecular Sequence Data, Platelet Aggregation, Platelet Count, Platelet Glycoprotein GPIb-IX Complex, Point Mutation, Polymerase Chain Reaction, Ristocetin, Thrombocytopenia, von Willebrand Factor, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2010.032631}, author = {Savoia, Anna and Pastore, Annalisa and De Rocco, Daniela and Civaschi, Elisa and Di Stazio, Mariateresa and Bottega, Roberta and Melazzini, Federica and Bozzi, Valeria and Pecci, Alessandro and Magrin, Silvana and Balduini, Carlo L and Noris, Patrizia} }