Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test.

The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.

[Stroke in neonates and children]. / Les accidents vasculaires cérébraux du nouveau-né et de l'enfant.

The clinical presentation, risk factors, causes, vital or functional prognosis, and acute management options for stroke occurring in neonates and children are specific, differing from those observed in young adults. Compared with the adult population, less is known about the epidemiology of stroke in the under-18 population where the disease could become more frequent because of advances in both neonatal resuscitation techniques for cerebral disorders and neuroimaging techniques enabling the diagnosis of small lesions. Clinical features are often delayed, especially in neonates, and unlike epilepsy or dystonia of the affected limb, which are frequent complications, aphasia is rather rare. The most frequent causes of stroke at the beginning of life are cardiac embolism, for ischemic stroke, and arteriovenous malformations, for intracerebral hemorrhage. Acute management at this age is specific. This article reviews the literature on the epidemiological and clinical features, the main causes, and the acute management guidelines of stroke occurring in newborn infants and children and highlights the need for neurologists to have comprehensive knowledge of this disease.

[Prospective epidemiological study of rotavirus gastroenteritis in Europe (REVEAL study). Results in the French area of the study]. / Etude épidémiologique prospective de la gastroentérite à rotavirus en Europe (étude REVEAL). Résultats de la zone d'étude française.

PRIMARY OBJECTIVE: To estimate the incidence of acute gastroenteritis (AGE) and rotavirus acute gastroenteritis (RVAGE) in children less than 5 years of age seeking medical care in primary care, emergency department, and hospital settings. SECONDARY OBJECTIVES: To compare the clinical profile of RVAGE and non-RVAGE and to describe the distribution of RV serotypes among RVAGE cases. METHODS: A prospective primary care, emergency ward and hospital-based observational study was conducted during 1 year in a selected city of France with 250,000 inhabitants. Children less than 5 years of age presenting with symptoms of AGE were included. Rotavirus was identified using an Elisa test in stools. RESULTS: The estimated annual incidence of RVAGE was 1.56% for AGE and 0.87% for RVAGE in hospital, 5.87% for AGE and 2.65% for RVAGE in emergency-wards, 7.39% for AGE and 1.45% for RVAGE in primary care. Total incidence was 14.82% for AGE and 4.96% for RVAGE among children less than 5 years of age. RVAGE were more clinically severe than the AGE: dehydration (26.8% vs. 14.7%, p<0.0001), vomiting 84.9% vs. 60.9%, p<0.0001), fever (74.3% vs. 44.4%, p<0.0001), lethargy (84.9% vs. 70.2%, p<0.0001). G9 serotype was the most frequent serotype encountered (54.7%) during the study period followed by G3 serotype (33.6%) and G2 serotype (7.9%). CONCLUSION: In this study, RVAGE, caused by serotypes G9 and G3, represented about 1/3 of AGE and were more severe than non-RV AGE with twice as high dehydration rate. These results underline the need for continued promotion on the use of oral rehydration fluids and provide some arguments on the benefits of vaccination against rotavirus and also permanent virological monitoring of circulating serotypes.

Clinical severity and molecular characteristics of circulating and emerging rotaviruses in young children attending hospital emergency departments in France.

Group A rotavirus (RVA) is the leading cause of acute gastroenteritis in young children worldwide. A prospective surveillance network has been set up to investigate the virological and clinical features of RVA infections and to detect the emergence of potentially epidemic strains in France. From 2009 to 2014, RVA-positive stool samples were collected from 4800 children <5 years old attending the paediatric emergency units of 16 large hospitals. Rotaviruses were then genotyped by RT-PCR with regard to their outer capsid proteins VP4 and VP7. Genotyping of 4708 RVA showed that G1P[8] strains (62.2%) were predominant. The incidence of G9P[8] (11.5%), G3P[8] (10.4%) and G2P[4] (6.6%) strains varied considerably, whereas G4P[8] (2.7%) strains were circulating mostly locally. Of note, G12P[8] (1.6%) strains emerged during the seasons 2011-12 and 2012-13 with 4.1% and 3.0% prevalence, respectively. Overall, 40 possible zoonotic reassortants, such as G6 (33.3%) and G8 (15.4%) strains, were detected, and were mostly associated with P[6] (67.5%). Analysis of clinical records of 624 hospitalized children and severity scores from 282 of them showed no difference in clinical manifestations or severity in relation to the genotype. The relative stability of RVA genotypes currently co-circulating and the large predominance of P[8] type strains may ensure vaccine effectiveness in France. The surveillance will continue to monitor the emergence of new reassortants that might not respond to current vaccines, all the more so as all genotypes can cause severe infections in infants.

[Renal effects of prolonged indomethacin therapy in premature infants]. / Effets rénaux d'un traitement prolongé par indométacine chez le prématuré.

BACKGROUND: Indomethacin therapy for large patent ductus arterious would be more effective when it is prescribed for 5 or 6 days vs 2 or 3 days. Effects on renal function of such prolonged therapy is still debated. PATIENTS AND METHODS: Seven preterm infants (gestational age: 28.6 +/- 0.9 weeks; birth-weight: 1,169 +/- 267 g) with symptomatic patent ductus arterious were given indomethacin, 0.1 mg/kg/day for 6 days (four patients) and 5 days (three patients). Urinary water excretion, water output/input ratio, creatinine clearance and body weight were measured before and every day during therapy. RESULTS: Urinary water excretion, water output/input ratio and creatinine clearance were significantly decreased after 5 days of treatment, -40 +/- 30%, -42 +/- 27% and -48 +/- 31%, respectively. Creatinemia and body weight were significantly increased, + 34 +/- 36% and + 9 +/- 7%, respectively. Mean sodium plasma level and fractional excretion of sodium, potassium and chloride remained stable. CONCLUSION: Prolonged therapy with indomethacin does not avoid the renal side effects seen with shorter administration.

[Agenesis of the corpus callosum: etiological and clinical aspects, diagnostic methods and prognosis]. / Les agénésies du corps calleux: aspects étiologiques, cliniques, moyens de diagnostic et pronostic.

Agenesis of the corpus callosum is a frequent congenital malformation with many etiologies and clinical features. It can occur as an isolated defect which is usually sporadic, it is frequently associated with other malformations, genetic syndromes and metabolic disorders. Ante- or postnatal diagnosis must be followed by a careful search for etiology, and it raises uncertain and difficult question with regard to pregnancy continuation and infant development.

[Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 9 treated pregnancies]. / Traitement prénatal de l'hyperplasie surrénale congénitale par déficit en 21-hydroxylase. A propos de neuf grossesses traitées.

Prenatal treatment based on administration of dexamethasone to the mother during pregnancy was initiated early during nine pregnancies with a high risk of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The purpose of this treatment was to prevent fetal virilization by reducing production of androgens by the adrenal glands. Prenatal diagnosis was achieved by comparing amniotic fluid cell HLA genotypes and more recently by subjecting trophoblasts to molecular genetic studies. Together with prenatal determination of fetal sex, this allowed to determine that only two female fetuses were affected. Efficacy of continued prenatal treatment in these two cases was good in one case and mediocre in the other. The treatment was well tolerated by the mothers and fetuses.