RESUMO
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.
Assuntos
Actinina/genética , Plaquetas/metabolismo , Mutação de Sentido Incorreto , Fenótipo , Trombocitopenia/genética , Actinina/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Expressão Gênica , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Contagem de Plaquetas , Índice de Gravidade de Doença , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombocitopenia/fisiopatologia , Trombopoese/genética , Trombopoetina/sangueRESUMO
Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients.
Assuntos
Subpopulações de Linfócitos B/imunologia , Memória Imunológica , Infecções Pneumocócicas/imunologia , Baço/imunologia , Esplenectomia , Vacinação/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Polissacarídeos Bacterianos/imunologia , Tétano/imunologia , Adulto JovemRESUMO
BACKGROUND: Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbß, 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.
Assuntos
Síndrome de Bernard-Soulier/genética , Heterozigoto , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Bernard-Soulier/diagnóstico , Criança , Pré-Escolar , Saúde da Família , Feminino , Humanos , Lactente , Itália , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de Plaquetas , Polimorfismo Genético , Trombocitopenia/terapia , Trombopoetina/sangue , Tubulina (Proteína)/genética , Adulto JovemRESUMO
BACKGROUND: The eradication of Helicobacter pylori has been associated with remission of immune thrombocytopenia (ITP) in approximately half of eradicated patients. Data on children are limited to small case series. PROCEDURE: Children from 16 centers in Italy, who were less than 18 years of age and diagnosed with chronic ITP (cITP), were screened for H. pylori infection. Positive patients underwent standard triple therapy with amoxicillin, clarithromycin, and omeprazole. The eradication response was defined as follows: complete response, platelet (PLT) count ≥ 150 × 10(9) /L; partial response, PLT count of at least 50 × 10(9) /L; no response, PLT count <50 × 10(9) /L. RESULTS: Of 244 screened patients, 50 (20%) had H. pylori infection, 37 of which received eradication therapy and completed follow-up. Eradication was successful in 33/37 patients (89%). PLT recovery was demonstrated in 13/33 patients after eradication (39%), whereas spontaneous remission was observed in 17/166 (10%) H. pylori-negative patients (P < 0.005). Responders more often required second line eradication (9/13), whereas a second cycle was required in 3/20 non-responders (P < 0.005). CONCLUSIONS: Among the large cohort of patients, those who underwent successful H. pylori eradication showed a significantly higher PLT response. Therefore, it may be appropriate to look for H. pylori and eventually eradicate it in children with cITP.
Assuntos
Plaquetas/efeitos dos fármacos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/microbiologia , Adolescente , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Antiulcerosos/uso terapêutico , Criança , Doença Crônica , Claritromicina/uso terapêutico , Feminino , Helicobacter pylori , Humanos , Masculino , Omeprazol/uso terapêutico , Contagem de PlaquetasRESUMO
BACKGROUND: The presenting features and treatment outcome of 120 patients with Down syndrome (DS) and childhood acute lymphoblastic leukemia (ALL) were compared with 6237 non-DS patients treated in the same years. METHODS: We reviewed the database of 6 consecutive Italian Association of Pediatric Hematology and Oncology (AIEOP)-ALL trials conducted between 1982 and 2004. Features of DS patients were compared with those of non-DS patients. RESULTS: The 120 DS patients (1.9%) were more often girls (P = .027), aged > or = 10 years (P = .014), and high risk according to National Cancer Institute (NCI) criteria (P = .045). The distribution of white blood cell count did not differ (P = .32). DS patients belonged less frequently to the current high-risk group (P = .017). In all but 1 case they demonstrated B-cell precursor (BCP) immunophenotype (P < or = .001). TEL/AML1 molecular fusion transcript was found in only 1 of 44 (2.2%) tested patients. Induction death occurred more often in DS patients (4.2%, P = .009), but not failure to achieve remission. Leukemia relapse occurred in 31.6% of DS patients (vs 23.5%; P = .003), usually in the marrow. Remission death was more frequent in DS patients (4.2%, P = .03). Ten-year event-free survival and survival were significantly worse compared with non-DS patients (P < 0.001). DS patients diagnosed since 1995 had a better outcome (P = .06) than those diagnosed in previous years, but still had worse outcomes than non-DS patients (P = .04). Event-free survival of DS patients at NCI standard risk was lower than that of non-DS patients (P = .006). CONCLUSIONS: Presenting features of childhood ALL in DS differ from those in non-DS patients. They are almost invariably characterized by BCP phenotype, and are often TEL/AML1 negative. Treatment results, although not as good as for non-DS patients, improved progressively, with modern therapy and support allowing 75% to survive.
Assuntos
Síndrome de Down/diagnóstico , Síndrome de Down/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Síndrome de Down/complicações , Síndrome de Down/mortalidade , Feminino , Humanos , Lactente , Itália/epidemiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Consensus guidelines for diagnosis and treatment of acute childhood idiopathic thrombocytopenic purpura (ITP) were published in 2000 by the Italian Association of Pediatric Haematology and Oncology (AIEOP). The assessment of guideline implementation was the primary objective of the present study. PATIENTS AND METHODS: Information on each newly diagnosed case of ITP referring to centres conforming with the guidelines was obtained by a questionnaire. RESULTS: Data concerning 609 new cases of acute childhood ITP were collected including 346 (56.8%) asymptomatic-paucisymptomatic forms (type A), 262 (43%) intermediate clinical forms (type B), and 1 (0.2%) severe form (type C). At diagnosis, 82% of cases were hospitalized. Age, platelet count and duration of hospitalization were significantly different in type A and type B cases. Of the total number of cases, 25% were kept under observation, 38.6% received intravenous immunoglobulins, 23.9% oral or parenteral steroids, and 12.7% other treatments. The initial treatment turned out to be appropriate for 428 cases (72.2%), of uncertain appropriateness in 71 (11.9%), and inappropriate in 95 cases (15.9%). The total level of implementation was 84.1%. CONCLUSIONS: A high rate of guideline implementation was observed during the study period. The guidelines should be reviewed taking into account more recent evidence.
Assuntos
Púrpura Trombocitopênica Idiopática/terapia , Doença Aguda , Adolescente , Corticosteroides/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Tempo de Internação , Masculino , Contagem de Plaquetas , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Idiopathic thrombocytopenic purpura in children remits spontaneously in the majority of cases but most children require treatment. Between 1995 and 2005, 265 children (0-15 years old) have been consecutively observed and treated: 28 children with high doses of methylprednisolone (HDMP) (15 mg/kgx4 days), 63 with HDMP (7.5 mg/kgx4 days), 37 with HD dexamethasone (DXM) pulses, 29 with low doses of MP, and 51 with different doses of intravenous immunoglobulins (IVIG) (0.4 or 0.8 g/kg). Fifty-seven children have not been treated because of a platelet count>or=10x10(9)/L and no significant bleeding. Two hundred forty-four (92.1%) children reached a persistent CR, 237 (89.4%) after a first-line treatment or the wait and see strategy. No statistically significant differences in CR related to different treatments have been observed. IVIG and HDMP (7.5 mg/kg for 4 days) are the best treatments to reach quickly safe platelet levels>or=30x10(9)/L (3-6 days) and CR (7-11 days). Among non-responding (NR) patients, seven have been splenectomized and three reached stable CR. These results emphasize differences with adult ITP.