MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate firstline treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (< 18 years, 36 of 42 ‫؍‬ 85.7%; > 18 years, 41 of 48 ‫؍‬ 85.4%, P ‫؍‬ not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P ‫؍‬ .018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial. (Blood.

BackgroundBernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbb, 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 MethodsOver 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. ResultsWe 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. ConclusionsOur 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.Key words: inherited thrombocytopenia, Bolzano mutation, monoallelic, Bernard-Soulier syndrome Citation: Noris P, Perrotta S, Bottega R, Pecci A, Melazzini F, Civaschi E, Russo S, Magrin S, Loffredo G, Di Salvo V, Russo G, Casale M, De Rocco D, Grignani C, Cattaneo M, Baronci C, Dragani A, Albano V, Jankovic M, Scianguetta S, Savoia A, and Balduini CL. Clinical and laboratory

Key Points ACTN1 mutations were identified in 10 of 239 families with inherited thrombocytopenia of unknown origin. ACTN1-related thrombocytopenia is characterized by mild thrombocytopenia with platelet macrocytosis and low risk for bleeding.

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. Keywords: Asplenia r Memory B cells r Serum anti-PnPS r Splenectomy r Streptococcus pneumoniaeAdditional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2013Immunol. . 43: 2659Immunol. -2670 Introduction Asplenic patients have an increased susceptibility to bacterial infections that can evolve into severe and often lethal overwhelming postsplenectomy infection (OPSI) [1,2]. Lifetime risk of developing an OPSI is nearly 1-5% and mortality rates range between 40 and 70% [3]. Streptococcus pneumoniae is the most common pathogen causing bacteremia in splenectomized patients, followed by Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Salmonella, Pseudomonas, and Klebsiella [3,4]. The red pulp of the spleen represents a very important defense from bacteremia. In the red pulp of the spleen, the blood flows slowly in a large net of sinusoids. Macrophages, located among endothelial cells, have the function of removing and destroying particulate antigens, such as bacteria [5][6][7]. In the absence of the spleen, bacteria can therefore accumulate and replicate in the blood causing septic shock.Over the last few years, the role of the spleen in the maintenance of a pool of memory B cells involved in the protection against encapsulated bacteria has been also demonstrated. In particular, we showed that splenectomized patients lack IgM memory B cells [8]. This cell population, also known as marginal zone B cells or effector memory B cells, is produced by a T-independent mechanism [9] and inhabits the marginal zone of the spleen. IgM memory B cells generate the response to pneumococcal polysaccharide (PnP...