RESUMO
Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity â¼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.
Assuntos
Células Clonais/metabolismo , Síndrome de Down/genética , Mutação , Doença Aguda , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Cromatografia Líquida de Alta Pressão/métodos , Células Clonais/patologia , Análise Mutacional de DNA/métodos , Síndrome de Down/sangue , Fator de Transcrição GATA1 , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Recém-Nascido , Leucemia Mieloide/sangue , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Mielopoese/genética , Triagem Neonatal/métodos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Pré-Leucemia/sangue , Pré-Leucemia/diagnóstico , Pré-Leucemia/genética , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Serum calcium, 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were measured in umbilical cord blood samples taken from 54 White and 22 South Asian babies born in the UK during the summer months. South Asians had lower serum calcium (p < 0.0027) and 25OHD (p < 0.0002) than Whites. Serum PTH was low in all subjects, but South Asians had relatively higher concentrations of serum PTH (p < 0.001) than Whites. The lower vitamin D and calcium in South Asian newborns is not associated with secondary hyperparathyroidism as previously reported but may still explain their increased prevalence of neonatal hypocalcaemia and rickets.