Diagnostic and service impact of genomic testing technologies in a neonatal intensive care unit.

AIM: To investigate the diagnostic and service impact of chromosomal microarray and whole exome sequencing (WES) in a neonatal intensive care unit (NICU). METHODS: This was a retrospective medical record review of NICU patients referred for genetics consultation at three time points over a 9-year period at a single centre to determine referral indications, genetic consultation outcomes and time to diagnosis. RESULTS: The number of NICU patients referred for genetics consultation increased from 44 in 2007 to 95 in 2015. The proportion of NICU patients suspected of having a genetic condition following clinical geneticist assessment remained stable, averaging 5.3% of all admissions. The proportion of patients receiving a confirmed diagnosis rose from 21% in 2007 to 53% in 2015, with a shift from primarily chromosomal abnormalities to a broad range of monogenic disorders, increasingly diagnosed by WES as a first-tier test. The average age at diagnosis in 2015 was 19 days (range 12-38 days) for chromosomal abnormalities and 138 days (range 10-309 days) for monogenic conditions. CONCLUSIONS: The adoption of new genetic technologies at our centre has increased the proportion of patients receiving a confirmed genetic diagnosis. This study provides important benchmark data to measure further improvements as turn-around times for genomic testing decrease.

Neonatal oesophageal perforation: The role for non-operative management.

AIM: Isolated oesophageal perforation in neonates is a rare but potentially life-threatening condition. Although management has historically been operative, conservative management (antibiotics, bowel rest, parenteral nutrition) is now more routinely used. The aim of this study was to evaluate the management of this condition in two large neonatal surgical centres. METHODS: A retrospective cohort study was conducted for neonates admitted to The Hospital for Sick Children (Toronto, Canada) or The Royal Children's Hospital (Melbourne, Australia) with a diagnosis of oesophageal perforation, from 2006 to 2016. Patients with oesophageal atresia or tracheo-oesophageal fistula were excluded. Data were collected from chart review regarding demographics, clinical course, management and outcomes. RESULTS: Eleven neonates with oesophageal perforation were identified over a 10-year period at the two centres. Median gestational age at birth was 25.3 weeks (interquartile range 24.2-28.8) and the majority (7/11, 64%) of neonates were extremely low birthweight. Diagnosis was made on day 1 of life for 9 of 11 (81%) neonates and was secondary to nasogastric tube insertion in 10 of 11 (91%) neonates. Only four (36%) neonates had symptomatic complications. All neonates were managed with bowel rest and intravenous antibiotics for a median of 7 days (interquartile range 7-10); two patients required operative intervention. Three neonates (27%) developed chronic lung disease and two (19%) died prior to discharge. CONCLUSIONS: Oesophageal perforation is severe complication secondary to instrumentation of the upper gastrointestinal tract in neonates. Prompt and accurate diagnosis is crucial. Non-operative management is effective for the majority, though morbidity is common.

Development and validation of self-reported line drawings for assessment of knee malalignment and foot rotation: a cross-sectional comparative study.

BACKGROUND: For large scale epidemiological studies clinical assessments and radiographs can be impractical and expensive to apply to more than just a sample of the population examined. The study objectives were to develop and validate two novel instruments for self-reported knee malalignment and foot rotation suitable for use in questionnaire studies of knee pain and osteoarthritis. METHODS: Two sets of line drawings were developed using similar methodology. Each instrument consisted of an explanatory question followed by a set of drawings showing straight alignment, then two each at 7.5 degrees angulation and 15 degrees angulation in the varus/valgus (knee) and inward/outward (foot) directions. Forty one participants undertaking a community study completed the instruments on two occasions. Participants were assessed once by a blinded expert clinical observer with demonstrated excellent reproducibility. Validity was assessed by sensitivity, specificity and likelihood ratio (LR) using the observer as the reference standard. Reliability was assessed using weighted kappa (kappa). Knee malalignment was measured on 400 knee radiographs. General linear model was used to assess for the presence of a linear increase in knee alignment angle (measured medially) from self-reported severe varus to mild varus, straight, mild valgus and severe valgus deformity. RESULTS: Observer reproducibility (kappa) was 0.89 and 0.81 for the knee malalignment and foot rotation instruments respectively. Self-reported participant reproducibility was also good for the knee (kappa 0.73) and foot (kappa 0.87) instruments. Validity was excellent for the knee malalignment instrument, with a sensitivity of 0.74 (95%CI 0.54, 0.93) and specificity of 0.97 (95%CI 0.94, 1.00). Similarly the foot rotation instrument was also found to have high sensitivity (0.92, 95%CI 0.83, 1.01) and specificity (0.96, 95%CI 0.93, 1.00). The knee alignment angle increased progressively from self reported severe varus to mild varus, straight, mild valgus and severe valgus knee malalignment (ptrend <0.001). CONCLUSIONS: The two novel instruments appear to provide a valid and reliable assessment of self-reported knee malalignment and foot rotation, and may have a practical use in epidemiological studies.

Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure.

Heterozygous pathogenic variants in SPTB cause autosomal dominant hereditary spherocytosis, an important cause of neonatal nonimmune hemolytic anemia. Biallelic mutations are rarely reported, all with severe neonatal presentation. We describe rapid (68 h) genomic diagnosis of homozygous ß-spectrin deficiency in a newborn with severe transfusion-dependent hemolytic anemia, conjugated hyperbilirubinemia, and progressive liver failure. Trio whole-exome sequencing identified a novel biallelic SPTB variant (c.6119C>T; p.Thr2040Ile) located in the critical spectrin repeat region. Pretransfusion blood film showed marked spherocytosis including microspherocytes and nucleated erythrocytes, and eosin-5-maleimide (E5M) staining was markedly reduced, supporting pathogenicity. Both asymptomatic heterozygous parents demonstrated mildly reduced E5M staining, with occasional spherocytes and elliptocytes. Early molecular diagnosis facilitated hypertransfusion to suppress ineffective erythropoiesis and reverse hepatic dysfunction. This report broadens the genotypic and phenotypic spectrum of spectrin deficiency and highlights the utility of rapid genomic testing in facilitating early diagnosis and informing targeted therapy in critically ill patients.

What influences children's conceptualizations of language input?

PURPOSE: Children learning language conceptualize the nature of input they receive in ways that allow them to understand and construct utterances they have never heard before. This study was designed to illuminate the types of information children with and without specific language impairment (SLI) focus on to develop their conceptualizations and whether they can rapidly shift their initial conceptualizations if provided with additional input. METHOD: In 2 studies, preschool children with and without SLI were exposed to an artificial language, the characteristics of which allowed for various types of conceptualizations about its fundamental properties. After being familiarized with the language, children were asked to judge test strings that conformed to the input in 1 of 4 different ways. RESULTS: All children preferred test items that reflected a narrow conceptualization of the input (i.e., items most like those heard during familiarization). Children showed a strong preference for phonology as a defining property of the artificial language. Restructuring the input to the child could induce them to track word order information as well. CONCLUSION: Children tend toward narrow conceptualizations of language input, but the nature of their conceptualizations can be influenced by the nature of the input they receive.

Triad of tracheoesophageal fistula-esophageal atresia, pulmonary hypoplasia, and duodenal atresia.

We describe 3 cases of tracheoesophageal fistula with esophageal atresia who also had right pulmonary hypoplasia-aplasia and duodenal atresia. We review the current literature and propose that this may be a distinct association.