Carlo Baronci

Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation)

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.

Acute Lymphoblastic Leukemia and Down Syndrome Presenting Features and Treatment Outcome in the Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP)

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.

Effect of eradication of Helicobacter pylori in children with chronic immune thrombocytopenia: A prospective, controlled, multicenter study†

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.

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 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.

Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: Tailoring better vaccination strategies

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.

Management of Acute Childhood Idiopathic Thrombocytopenic Purpura according to AIEOP Consensus Guidelines: Assessment of Italian Experience

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.

Idiopathic thrombocytopenic purpura (ITP) in children

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/kg × 4 days), 63 with HDMP (7.5 mg/kg × 4 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 ≥10 × 109/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 ≥30 × 109/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. Pediatr Blood Cancer 2006;47:665–667.