Hb Alesha [β67(E11)Val→Met, GTG→ATG] in an Argentinean girl

Hb Alesha is caused by a GTG>ATG mutation at codon 67 of the b-globin gene, resulting in abnormal beta-globin chains in which the normal beta67(E11) valine is changed to methionine. This hemoglobin (Hb) is also known as Hb Bristol, the first unstable Hb described, since in a fraction of the variant the methionine is modified into an aspartic acid by a posttranslational modification. This replacement disrupts the apolar bonds between the valine and the heme group, producing an unstable Hb and severe hemolysis. We have identified this rare hemoglobinopathy in an Argentinean girl with severe hemolytic anemia, splenomegaly and frequent requirement for red blood cell transfusions.Fil: Eberle, Silvia Eandi. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Noguera, Nelida Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Sciuccati, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Bonduel, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Díaz, Lilian. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Staciuk, Raquel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Feliu Torres, Aurora. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Haemophilia B, severe childhood obesity and other extra-haematological features associated with similar 4Mb-deletions on Xq27: Clinical findings, molecular insights and literature update

Introduction: Haemophilia B (HB) is associated with pathogenic variants in F9. Hemizygous deletions encompassing the entire F9 and proximate genes may express extra-haematological clinical phenotypes. Aim: To analyse the genotype/phenotype correlations in two unrelated boys with severe early childhood obesity (SCO), global developmental delay (GDD) and similar bleeding phenotype associated with comparable Xq27 deletions spanning the entire F9 and proximate genes, and characterise the pathogenic events estimating the most likely mutational mechanism involved. Methods: Entire F9-deletions were detected in three hemizygous unrelated probands with HB: two cases, C#1/C#2, presented SCO and GDD and a control patient (Co), who only had severe bleeding symptoms. Dense SNP-array and case-specific STS walking scan allowed characterisation of the deletion breakpoints. Extensive use of bioinformatics, statistics and clinical databases allowed the investigation of genotype-phenotype associations. Results: Patients C#1/C#2 and Co resulted in a complete F9 and additional gene deletions of variable extensions on Xq26.3-Xq27.2 (C#1/C#2/Co: 4.3Mb/3.9Mb/160Kb). C#1/C#2 common deleted gene SOX3 is directly associated with SCO, GDD and pituitary hypothyroidism (PH) whilst C#2 extra-deleted gene MAGEC2 indirectly relates to anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanisms of Alu/Alu recombination for the first time in HB and non-homologous or alternative end-joining. Conclusion: Our results represent the first report of unrelated patients with HB, SCO and GDD. This study and the literature update expand the spectrum of clinical findings and molecular insights observed in patients with HB caused by complete F9 and nearby SOX3 and MAGEC2 gene deletions, which may configure a contiguous gene syndrome.Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ziegler, Betiana Michelle. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Marchione, Vanina Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Nevado, Julián. Instituto de Investigacion del Hospital de la Paz.; España. Centro de Investigación Biomédica en Red de Enfermedades Raras; EspañaFil: Lapunzina, Pablo. Centro de Investigación Biomédica en Red de Enfermedades Raras; España. Instituto de Investigacion del Hospital de la Paz.; EspañaFil: Sciuccati, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Neme, Daniela. Fundación de la Hemofilia Alfredo Pavlovsky; ArgentinaFil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bonduel, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentin

Consensus‐based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID‐19–related illness

Background: Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness has recently been initiated in the United States. To date, there remains a paucity of high-quality evidence to inform clinical practice world-wide. Therefore, the objective of this scientific statement is to provide consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses, and to identify priorities for future research. Methods: We surveyed 20 pediatric hematologists and pediatric critical care physicians from several continents who were identified by Pediatric/Neonatal Hemostasis and Thrombosis Subcommittee leadership as having experience and expertise in the use of anticoagulant thromboprophylaxis and/or the management of COVID-19-related illness in children. A comprehensive review of the literature on COVID-19 in children was also performed. Results: Response rate was 90%. Based on consensus of expert opinions, we suggest the administration of low-dose low molecular weight heparin subcutaneously twice-daily as anticoagulant thromboprophylaxis (in the absence of contraindications, and in combination with mechanical thromboprophylaxis with sequential compression devices, where feasible) in children hospitalized for COVID-19-related illness (including the multisystem inflammatory syndrome in children [MIS-C]) who have markedly elevated D-dimer levels or superimposed clinical risk factors for hospitalassociated VTE. For children who are clinically unstable or have severe renal impairment, we suggest the use of unfractionated heparin by continuous intravenous infusion as anticoagulant thromboprophylaxis. In addition, continued efforts to characterize VTE risk and risk factors in children with COVID-19, as well as to evaluate the safety and efficacy of anticoagulant thromboprophylaxis strategies in children hospitalized with COVID-19-related illness (including MIS-C) via cooperative multicenter trials, were identified among several key priorities for future research. Conclusion: These consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses and priorities for future research will be updated as high-quality evidence emerges

Severe hemotytic anemia due to hemoglobin Hammersmith

Las variantes estructurales de la hemoglobina resultan, en su mayoría, de sustituciones concretas de aminoácidos en una de las cadenas de globina. En muchos casos, estas hemoglobinopatías son inocuas, pero en otros determinan alteraciones de las propiedades físicas y químicas, cuyas manifestaciones clínicas son de gravedad variable. En el caso de las hemoglobinas inestables, las alteraciones disminuyen la solubilidad y facilitan la formación de complejos de hemoglobina precipitada y desnaturalizada (cuerpos de Heinz), que ocasionan el daño de la membrana y, finalmente, la destrucción prematura de los eritrocitos. Hasta la actualidad se han descrito más de 150 hemoglobinas inestables diferentes, la mayoría ocasionan hemolisis crónica, exacerbada por infecciones o la ingesta de medicamentos. Presentamos un caso clínico de hemoglobina inestable (hemoglobina Hammersmith) en una niña con anemia hemolítica grave, esplenomegalia y requerimiento transfusional.Most of the hemoglobin variants are the result of single amino acid replacement in one of the globin chains. In many cases, these hemoglobinopathies are harmless, while in others they determine alterations in the physical and chemical properties, raising clínical manifestations of variable severity. In the unstable hemoglobinopathies, the changes reduce solubility, inducing the formation of precipítales of denaturated hemoglobin (Heinz bodies), which damage the membrane and finally destroy the red blood cells prematurely. Up to now, more than 150 different unstable hemoglobins have been described; most of them cause chronic hemolysis, increa-sed by infections or drugs. We report the clinical presentation of an unstable hemoglobin (hemoglobin Hammersmith) in a girl with severe hemolytic anemia, splenomegaly and red blood cell requirement.Fil: Eberle Eandi, Silvia J.. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Centro Regional de Hemoterapia; ArgentinaFil: Noguera, Nelida Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Calvo, Karina Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Ojeda, Mara Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Bragós, Irma Margarita. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Pratti, Arianna Flavia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Milani, Angela Cristina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Bioquímica Clínica; ArgentinaFil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Sciuccati, Gabriela. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Centro Regional de Hemoterapia; ArgentinaFil: Díaz, Lilian. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Centro Regional de Hemoterapia; ArgentinaFil: Bonduel, Mariana. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Centro Regional de Hemoterapia; ArgentinaFil: Feliu Torres, Aurora. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Centro Regional de Hemoterapia; Argentin

Impact of persistent antiphospholipid antibodies on risk of incident symptomatic thromboembolism in children: a systematic review and meta-analysis.

none20noneKenet G;Aronis S;Berkun Y;Bonduel M;Chan A;Goldenberg NA;Holzhauer S;Iorio A;Journeycake J;Junker R;Male C;Manco-Johnson M;Massicotte P;Mesters R;Monagle P;van Ommen H;Rafini L;Simioni P;Young G;Nowak-Göttl UKenet, G; Aronis, S; Berkun, Y; Bonduel, M; Chan, A; Goldenberg, Na; Holzhauer, S; Iorio, A; Journeycake, J; Junker, R; Male, C; Manco Johnson, M; Massicotte, P; Mesters, R; Monagle, P; van Ommen, H; Rafini, L; Simioni, Paolo; Young, G; Nowak Göttl, U

Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies

The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigate