permissão concedida pela Elsevier para reprodução do material em português somente. Abreviações: 2D: bidimensional 3D: tridimensional Área A: área abaixo da curva da onda A da fluxo mitral Onda A: Fluxo mitral correspondente ao momento da contração atrial Onda a': Onda obtida no nível do anel mitral pelo Doppler tecidual durante a contração atrial Onda Ar: Velocidade de fluxo reverso pulmonar ou sistêmico durante a contração atrial VAo: Valva aórtica ASE: Sociedade Americana de Ecocardiografia AV: Atrioventricular SC: Superfície corpórea CC: Cardiopatia congênita Onda D: Componente diastólico do fluxo venoso pulmonar ou sistêmico dP/dt: Primeira derivado de pressão em relação ao tempo Área A: Área abaixo da curva da onda A do fluxo mitral (diástole precoce) Onda E: Fluxo mitral correspondente ao componente diastólico precoce Onda e': Onda obtida pelo Doppler tecidual no nível do anel valvar mitral durante a diástole precoce DDF: Diâmetro diastólico final VDF: Volume diastólico final FE: Fração de ejeção DSF: Diâmetro sistólico final VSF: Volume sistólico final VCI: Veia cava inferior TCIV': Tempo de contração isovolumétrica obtido ao Doppler tecidual TRIV: Tempo de relaxamento isovolumétrico obtido ao Doppler convencional TRIV': Tempo de relaxamento isovolumétrico obtido ao Doppler tecidual L: Comprimento AE: Átrio esquerdo VE: Ventrículo esquerdo RNM: Ressonância nuclear magnética VM: Valva mitral PFR SV : Taxa máxima de enchimento/volume ejetado VP: valva pulmonar AD: Átrio direito VD: Ventrículo direito Onda s': Onda obtida pelo Doppler tecidual no nível do anel valvar mitral durante a sístole Onda S: Componente sistólico do fluxo venoso pulmonar ou sistêmico ▲D: Fração de encurtamento TAPSE: Deslocamento do anel tricúspide durante a sístole VT: Valva tricúspide V: Volume ventricular VTI: Integral da velocidade x tempo

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To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

BackgroundElevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. Design and MethodsA prospective multicenter study of 310 patients aged 3-20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. ResultsElevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). ConclusionsAccording to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.Key words: sickle cell disease, pulmonary hypertension, hemolysis, oxygen saturation, tricuspid regurgitant jet velocity, children.Citation: Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, Onyekwere O, Nouraie M, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009; 94:340-347. doi:10.3324/haematol.13812 ©2009 Ferrata Storti Foundation.

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.