TY - JOUR T1 - Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry. JF - Am J Hematol Y1 - 2019 A1 - Farruggia, Piero A1 - Fioredda, Francesca A1 - Puccio, Giuseppe A1 - Onofrillo, Daniela A1 - Russo, Giovanna A1 - Barone, Angelica A1 - Bonanomi, Sonia A1 - Boscarol, Gianluca A1 - Finocchi, Andrea A1 - Ghilardi, Roberta A1 - Giordano, Paola A1 - Ladogana, Saverio A1 - Lassandro, Giuseppe A1 - Luti, Laura A1 - Lanza, Tiziana A1 - Mandaglio, Rosalba A1 - Marra, Nicoletta A1 - Martire, Baldassare A1 - Mastrodicasa, Elena A1 - Motta, Milena A1 - Notarangelo, Lucia Dora A1 - Pillon, Marta A1 - Porretti, Laura A1 - Serafinelli, Jessica A1 - Trizzino, Angela A1 - Tucci, Fabio A1 - Veltroni, Marinella A1 - Verzegnassi, Federico A1 - Ramenghi, Ugo A1 - Dufour, Carlo AB -

Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at ≤4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013).

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30456824?dopt=Abstract ER - TY - JOUR T1 - Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia. JF - Haematologica Y1 - 2018 A1 - Bottega, Roberta A1 - Nicchia, Elena A1 - Cappelli, Enrico A1 - Ravera, Silvia A1 - De Rocco, Daniela A1 - Faleschini, Michela A1 - Corsolini, Fabio A1 - Pierri, Filomena A1 - Calvillo, Michaela A1 - Russo, Giovanna A1 - Casazza, Gabriella A1 - Ramenghi, Ugo A1 - Farruggia, Piero A1 - Dufour, Carlo A1 - Savoia, Anna AB -

Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria.

VL - 103 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29269525?dopt=Abstract ER - TY - JOUR T1 - Autoimmune neutropenia of childhood secondary to other autoimmune disorders: Data from the Italian neutropenia registry. JF - Am J Hematol Y1 - 2017 A1 - Farruggia, Piero A1 - Puccio, Giuseppe A1 - Fioredda, Francesca A1 - Lanza, Tiziana A1 - Porretti, Laura A1 - Ramenghi, Ugo A1 - Barone, Angelica A1 - Bonanomi, Sonia A1 - Finocchi, Andrea A1 - Ghilardi, Roberta A1 - Ladogana, Saverio A1 - Marra, Nicoletta A1 - Martire, Baldassare A1 - Notarangelo, Lucia Dora A1 - Onofrillo, Daniela A1 - Pillon, Marta A1 - Russo, Giovanna A1 - Lo Valvo, Laura A1 - Serafinelli, Jessica A1 - Tucci, Fabio A1 - Zunica, Fiammetta A1 - Verzegnassi, Federico A1 - Dufour, Carlo KW - Autoimmune Diseases KW - Child KW - Disease Susceptibility KW - Female KW - Humans KW - Immunoglobulins, Intravenous KW - Immunosuppressive Agents KW - Infant, Newborn KW - Infant, Premature KW - Infant, Premature, Diseases KW - Italy KW - Male KW - Neutropenia KW - Prevalence KW - Registries VL - 92 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28567966?dopt=Abstract ER - TY - JOUR T1 - Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association. JF - Blood Transfus Y1 - 2017 A1 - Ladogana, Saverio A1 - Maruzzi, Matteo A1 - Samperi, Piera A1 - Perrotta, Silverio A1 - Del Vecchio, Giovanni C A1 - Notarangelo, Lucia D A1 - Farruggia, Piero A1 - Verzegnassi, Federico A1 - Masera, Nicoletta A1 - Saracco, Paola A1 - Fasoli, Silvia A1 - Miano, Maurizio A1 - Girelli, Gabriella A1 - Barcellini, Wilma A1 - Zanella, Alberto A1 - Russo, Giovanna KW - Anemia, Hemolytic, Autoimmune KW - Blood Transfusion KW - Child KW - Coombs Test KW - Disease Management KW - Hematology KW - Humans KW - Immunoglobulin M KW - Italy KW - Pediatrics KW - Societies, Medical KW - Steroids AB -

Autoimmune haemolytic anaemia is an uncommon disorder to which paediatric haematology centres take a variety of diagnostic and therapeutic approaches. The Red Cell Working Group of the Italian Association of Paediatric Onco-haematology (Associazione Italiana di Ematologia ed Oncologia Pediatrica, AIEOP) developed this document in order to collate expert opinions on the management of newly diagnosed childhood autoimmune haemolytic anaemia.The diagnostic process includes the direct and indirect antiglobulin tests; recommendations are given regarding further diagnostic tests, specifically in the cases that the direct and indirect antiglobulin tests are negative. Clear-cut definitions of clinical response are stated. Specific recommendations for treatment include: dosage of steroid therapy and tapering modality for warm autoimmune haemolytic anaemia; the choice of rituximab as first-line therapy for the rare primary transfusion-dependent cold autoimmune haemolytic anaemia; the indications for supportive therapy; the need for switching to second-line therapy. Each statement is provided with a score expressing the level of appropriateness and the agreement among participants.

VL - 15 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28151390?dopt=Abstract ER - TY - JOUR T1 - The prognostic value of biological markers in paediatric Hodgkin lymphoma. JF - Eur J Cancer Y1 - 2016 A1 - Farruggia, Piero A1 - Puccio, Giuseppe A1 - Sala, Alessandra A1 - Todesco, Alessandra A1 - Buffardi, Salvatore A1 - Garaventa, Alberto A1 - Bottigliero, Gaetano A1 - Bianchi, Maurizio A1 - Zecca, Marco A1 - Locatelli, Franco A1 - Pession, Andrea A1 - Pillon, Marta A1 - Favre, Claudio A1 - D'Amico, Salvatore A1 - Provenzi, Massimo A1 - Trizzino, Angela A1 - Zanazzo, Giulio Andrea A1 - Sau, Antonella A1 - Santoro, Nicola A1 - Murgia, Giulio A1 - Casini, Tommaso A1 - Mascarin, Maurizio A1 - Burnelli, Roberta KW - Adolescent KW - Age Factors KW - Antineoplastic Combined Chemotherapy Protocols KW - Biomarkers, Tumor KW - Blood Platelets KW - Child KW - Child, Preschool KW - Databases, Factual KW - Disease Progression KW - Disease-Free Survival KW - Eosinophils KW - Female KW - Ferritins KW - Hodgkin Disease KW - Humans KW - Infant KW - Infant, Newborn KW - Italy KW - Kaplan-Meier Estimate KW - Leukocyte Count KW - Male KW - Multivariate Analysis KW - Neoplasm Staging KW - Platelet Count KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Factors KW - Time Factors KW - Treatment Outcome AB -

BACKGROUND: Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children.

PATIENTS AND METHODS: By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens.

RESULTS: On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography.

CONCLUSION: Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

VL - 52 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26630532?dopt=Abstract ER - TY - JOUR T1 - Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Associ JF - Am J Hematol Y1 - 2016 A1 - Svahn, Johanna A1 - Bagnasco, Francesca A1 - Cappelli, Enrico A1 - Onofrillo, Daniela A1 - Caruso, Silvia A1 - Corsolini, Fabio A1 - De Rocco, Daniela A1 - Savoia, Anna A1 - Longoni, Daniela A1 - Pillon, Marta A1 - Marra, Nicoletta A1 - Ramenghi, Ugo A1 - Farruggia, Piero A1 - Locasciulli, Anna A1 - Addari, Carmen A1 - Cerri, Carla A1 - Mastrodicasa, Elena A1 - Casazza, Gabriella A1 - Verzegnassi, Federico A1 - Riccardi, Francesca A1 - Haupt, Riccardo A1 - Barone, Angelica A1 - Cesaro, Simone A1 - Cugno, Chiara A1 - Dufour, Carlo AB -

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.

VL - 91 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27013026?dopt=Abstract ER - TY - JOUR T1 - Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort. JF - Br J Haematol Y1 - 2015 A1 - Randi, Maria L A1 - Geranio, Giulia A1 - Bertozzi, Irene A1 - Micalizzi, Concetta A1 - Ramenghi, Ugo A1 - Tucci, Fabio A1 - Notarangelo, Lucia D A1 - Ladogana, Saverio A1 - Menna, Giuseppe A1 - Giordano, Paola A1 - Consarino, Caterina A1 - Farruggia, Piero A1 - Zanazzo, Giulio A A1 - Fiori, Giovanni M A1 - Burnelli, Roberta A1 - Russo, Giovanna A1 - Jankovich, Momcilo A1 - Peroni, Edoardo A1 - Duner, Elena A1 - Basso, Giuseppe A1 - Fabris, Fabrizio A1 - Putti, Maria C KW - Adolescent KW - Adult KW - Amino Acid Substitution KW - Child KW - Child, Preschool KW - Cohort Studies KW - Female KW - Hematologic Neoplasms KW - Humans KW - Infant KW - Janus Kinase 2 KW - Male KW - Mutation, Missense KW - Neoplasm Proteins KW - Thrombocythemia, Essential AB -

Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (25·8%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (74·2%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of non-clonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment.

VL - 169 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25716342?dopt=Abstract ER - TY - JOUR T1 - Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology. JF - Haematologica Y1 - 2014 A1 - De Rocco, Daniela A1 - Bottega, Roberta A1 - Cappelli, Enrico A1 - Cavani, Simona A1 - Criscuolo, Maria A1 - Nicchia, Elena A1 - Corsolini, Fabio A1 - Greco, Chiara A1 - Borriello, Adriana A1 - Svahn, Johanna A1 - Pillon, Marta A1 - Mecucci, Cristina A1 - Casazza, Gabriella A1 - Verzegnassi, Federico A1 - Cugno, Chiara A1 - Locasciulli, Anna A1 - Farruggia, Piero A1 - Longoni, Daniela A1 - Ramenghi, Ugo A1 - Barberi, Walter A1 - Tucci, Fabio A1 - Perrotta, Silverio A1 - Grammatico, Paola A1 - Hanenberg, Helmut A1 - Della Ragione, Fulvio A1 - Dufour, Carlo A1 - Savoia, Anna KW - Amino Acid Substitution KW - Cell Line KW - Cohort Studies KW - Computational Biology KW - Databases, Nucleic Acid KW - Fanconi Anemia KW - Fanconi Anemia Complementation Group Proteins KW - Founder Effect KW - Genotype KW - Humans KW - Italy KW - Mosaicism KW - Mutation KW - Polymorphism, Single Nucleotide AB -

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

VL - 99 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24584348?dopt=Abstract ER -