RESUMO
BACKGROUND: Early-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension. METHODS: Whole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals. RESULTS: In one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop-gain variant in the NPR1 gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels. NPR1 gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant in NPR1 (NM_000906.4:c.175del (p.Val59TrpfsTer8)). CONCLUSION: We show for the first time that biallelic loss of function of NPR1 is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice. NPR1 gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.
Assuntos
Hipertensão , Doenças do Recém-Nascido , Animais , Humanos , Recém-Nascido , Camundongos , Consanguinidade , Mutação da Fase de Leitura , Homozigoto , Hipertensão/genética , Choque CardiogênicoAssuntos
Bacteriemia/microbiologia , Endocardite Bacteriana/microbiologia , Encefalite Infecciosa/microbiologia , Kingella kingae/isolamento & purificação , Infecções por Neisseriaceae/microbiologia , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Líquido Cefalorraquidiano/microbiologia , Ciprofloxacina/uso terapêutico , Combinação de Medicamentos , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/tratamento farmacológico , Feminino , Humanos , Lactente , Encefalite Infecciosa/diagnóstico , Encefalite Infecciosa/tratamento farmacológico , Imageamento por Ressonância Magnética , Infecções por Neisseriaceae/diagnóstico , Infecções por Neisseriaceae/tratamento farmacológico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects small and medium blood vessels. Intensified treatments for the most severely affected patients have been proposed recently, and the early identification of KD patients at high risk for coronary artery aneurysms (CAA) is crucial. However, the risk scoring systems developed in Japan have not been validated in European populations, and little data is available concerning the link between initial echocardiogram findings other than high z-scores and cardiac prognosis. METHODS: In order to investigate whether the presence of any abnormalities, other than high z-scores in first echocardiogram, are associated with resistance to IV immunoglobulins and/or subsequent development of CAA, we retrospectively analyzed data from children diagnosed with KD between 2006 and 2016 at a tertiary Hospital in Paris, France. RESULTS: A total of 157 children were included. The initial echocardiogram was performed after a median of 7 days of fever and was abnormal in 48 cases (31%). The initial presence of any echocardiographic abnormality (coronary artery dilatation, CAA, pericardial effusion, perivascular brightness of the coronary arteries, left-ventricular dysfunction and mitral insufficiency) was strongly associated with resistance to intravenous immunoglobulin (p = 0.005) and development of coronary artery lesions within the first 6 weeks of disease (p = 0.01). All patients (n = 7) with persistent coronary abnormalities at 1 year already had an abnormal initial echocardiogram. Severity scoring systems from Japan had low sensitivity (0-33%) and low specificity (71-82%) for predicting immunoglobulin resistance or cardiac involvement. CONCLUSIONS: In European populations with mixed ethnic backgrounds, the presence of any abnormalities at the initial echocardiogram may contribute to early identification of patients with severe disease.