Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.

Peri- and neonatal factors influencing mortality and morbidity 2 years after esophageal atresia primary repair: a single center retrospective study.

Long-term digestive, respiratory, and neurological morbidity is significant in children who have undergone surgery for esophageal atresia (EA), especially after staged repair for long-gap EA. Risk factors for morbidity after primary repair (non-long-gap populations) have been less documented. We investigated peri- and neonatal factors associated with unfavorable outcomes in children 2 years after primary esophageal anastomosis. This was a single-center retrospective study, based on neonatal, surgical, and pediatric records of children born between December 1, 2002, and December 31, 2018, and followed up to age 2 years. The primary endpoint was unfavorable outcome at 2 years of age, defined by death or survival with severe respiratory, digestive, or neurologic morbidity. Univariate analyses followed by logistic regression analyses were performed to identify the peri- and neonatal risk factors of unfavorable outcomes among survivors at discharge. A total of 150 neonates were included (mean birth weight 2520 ± 718 g, associated malformations 61%); at age 2, 45 (30%) had one or more severe morbidities and 11 had died during the neonatal stay and 2 after discharge (8.7% deaths). In multivariate analyses of the 139 survivors at discharge, duration of ventilatory support (invasive and non-invasive) for more than 8 days (OR 3.74; CI95% [1.68-8.60]; p = 0.001) and achievement of full oral feeding before hospital discharge (OR 0.20; CI95% [0.06-0.56]; p = 0.003) were independently associated with adverse outcome after adjustment for sex, preterm birth, associated heart defect, any surgical complication, and the occurrence of more than one nosocomial infections during the neonatal stay. CONCLUSIONS: Post-operative ventilation and feeding management strategies may represent an opportunity for quality-of-care improvement to positively impact long-term outcomes after primary esophageal atresia repair. WHAT IS KNOWN: • Children operated on for esophageal atresia experience long-term digestive, respiratory, and neurologic morbidity, especially after multiple-stage esophageal repair. • Exclusive oral feeding at discharge is associated with a decreased risk of medical complications in the first years of life, in studies including all types of esophageal atresia repair. Outcomes of children after primary repair (non-long gap populations) have been less documented. WHAT IS NEW: • In our retrospective cohort of children with one-stage esophageal atresia repair, ventilatory support for more than 8 days and inability to achieve full oral feeding before hospital discharge in the neonatal period were independently associated with adverse digestive, respiratory, and neurologic outcomes at 2 years in survivors. • Both these factors are potentially modifiable, representing an opportunity for quality-of-care improvement to positively impact long-term outcomes. These results might also help identify children at risk of unfavorable evolution, to customize a multi-disciplinary follow-up program.

Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects.

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns-cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency-in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans.

A Program for Weaning Children from Enteral Feeding in a General Pediatric Unit: How, for Whom, and with What Results?

OBJECTIVE: To describe a series of children who were hospitalized for a tube-weaning program in the general pediatric ward of a pediatric tertiary university hospital: describe our method, to determine the success rate of our inpatient pediatric tube weaning program, and search for relevant factors linked to its success or failure. METHOD: We analyzed the medical files of consecutive children who were hospitalized for gastric-tube weaning over an 8-year period. We analyzed outcomes in terms of feeding and growth with at least 2 years of data. Success (weaning within 3 months) and failure were compared by characteristics of children. RESULTS: We included 37 children (29 females) with mean (SD) age 31.4 (21) months. Most had a severe medical history (30% prematurity; 50% intrauterine growth restriction, 50% neurological and genetic anomalies). The weaning program was successful for half of the children. Factors linked to success of the program were female sex (p = 0.0188), normal neurodevelopment (p = 0.0016), nasogastric tube (p = 0.0098), and with <24 months on EF before the stay (p = 0.0309). DISCUSSION: Comparing the efficiency of various methods and results among teams was difficult, which indicates the need to establish consensus about the outcome criteria. We confirm the need for these types of stays and programs.

Salvage Strategy for Long-Term Central Venous Catheter-Associated Staphylococcus aureus Infections in Children.

Introduction: Current international guidelines strongly recommend catheter removal in case of S. aureus central line-associated bloodstream infection (CLASBI), but a catheter salvage strategy may be considered in children given age-related specificities. No data is available regarding the outcome of this strategy in children. This study aims to evaluate catheter salvage strategy in children with S. aureus CLABSI, and to determine treatment failure rates and associated risk factors. Methods: We retrospectively analyzed data for all children <18 years having S. aureus CLABSI on a long-term central venous catheter in a tertiary hospital from 2010 to 2014. We defined catheter salvage strategy as a central venous catheter left in place ≥3 days after initiation of empiric treatment for suspected bacteremia, and catheter salvage strategy failure as the persistence or relapse of bacteremia with a S. aureus strain harboring the same antibiotic susceptibility pattern, or the occurrence or the worsening of local or systemic infectious complication between 72 h and 28 days after the first positive blood culture. Results: During the study period, 49 cases of S. aureus CLABSI on long-term central venous catheters were observed in 41 children (including 59% with long-term parenteral nutrition) and 6 (15%) isolates were resistant to methicillin. A catheter salvage strategy was chosen in 37/49 (76%) cases and failed in 12/37 (32%) cases. Initial presence of bloodstream co-infection, serum concentration of vancomycin under the targeted value and inadequate empiric treatment were significantly associated with catheter salvage therapy failure. Conclusions: The catheter salvage strategy of S. aureus CLABSI on a long-term central venous catheter was frequent in the studied hospital and failed only in one third of cases.

Posttraumatic Stress Reactions in Parents of Children Esophageal Atresia.

OBJECTIVE: The aim of this study was to investigate psychological stress in parents of children with esophageal atresia and to explore factors associated with the development of Posttraumatic Stress disorder (PTSD). DESIGN: Self-report questionnaires were administered to parents of children with EA. Domains included: (1) sociodemographic data, current personal difficulties, assessment scales for the quality of life and for the global health status of the child (2) French-validated versions of the Perinatal Posttraumatic Stress disorder Questionnaire and of the State-Trait Anxiety Inventory. Associations between PTSD and severity of the neonatal course, presence of severe sequelae at 2 years of age, and quality of life and global health status of children according to their parents' perception were studied. SETTING: A Tertiary care University Hospital. RESULTS: Among 64 eligible families, 54 parents of 38 children (59%) participated to the study. PTSD was present in 32 (59%) parents; mothers were more frequently affected than fathers (69 vs 46%, p = 0.03). Four mothers (8%) had severe anxiety. PTSD was neither associated with neonatal severity nor with severe sequelae at 2 years. Parents with PTSD rated their child's quality of life and global health status significantly lower (7.5 vs 8.6; p = 0.01 and 7.4 vs 8.3; p = 0.02 respectively). CONCLUSIONS: PTSD is frequent in parents of children with esophageal atresia, independently of neonatal severity and presence of severe sequelae at 2 years of age. Our results highlight the need for a long-term psychological support of families.