Genomic Contributors to Esophageal Atresia and Tracheoesophageal Fistula: A 12 Year Retrospective Review.

OBJECTIVE: To evaluate genetic testing utilization and diagnostic yield in infants with esophageal atresia (EA)/tracheoesophageal fistula (TEF) over the past 12 years to inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed for all infants with EA or EA/TEF hospitalized between January 2011 and January 2023 at a quaternary children's hospital. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: There were 212 infants who were classified as follows: 1) complex/syndromic with EA/TEF plus an additional major anatomic anomaly (n = 114, of which 74 met VACTERL criteria); 2) isolated/nonsyndromic EA/TEF (n = 88) and 3) isolated/nonsyndromic EA (n = 10). A range of genetic tests were sent with varying diagnostic rates including karyotype analysis in 12 (all with complex/syndromic phenotypes and all positive), chromosomal microarray analysis in 189 (114 of whom were complex/syndromic with an overall diagnostic rate of 3/189), single gene testing for CHD7 in 18 (4 positive), and exome analysis in 37 complex/syndromic patients (8 positive). CONCLUSIONS: EA/TEF with and without additional anomalies is genetically heterogeneous with a broad range of associated phenotypes. While the genetic etiology of EA/TEF with or without VACTERL remains largely unknown, genome wide testing (exome or genome) including copy number analysis is recommended over chromosomal microarray testing. We anticipate that expanded genetic/genomic testing modalities such as RNA sequencing and tissue specific molecular testing are needed in this cohort to improve our understanding of the genomic contributors to EA/TEF.

Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia: Lessons Learned through Video Review.

INTRODUCTION: Delivery room (DR) interventions for infants with congenital diaphragmatic hernia (CDH) are not well described. This study sought to describe timing and order of DR interventions and identify system factors impacting CDH DR resuscitations using a human factors framework. METHODS: Single center observational study of video recorded CDH DR resuscitations documenting timing and order of interventions. The team used the Systems Engineering Initiative for Patient Safety (SEIPS) model to identify system factors impacting DR resuscitations and time to invasive ventilation. RESULTS: We analyzed 31 video recorded CDH resuscitations. We observed variability in timing and order of resuscitation tasks. The 'Internal Environment' and 'Tasks' components of the SEIPS model were prominent factors affecting resuscitation efficiency; significant room and bed spatial constraints exist, and nurses have a significant task burden. Additionally, endotracheal tube preparation was a prominent barrier to timely invasive ventilation. CONCLUSION: Video review revealed variation in event timing and order during CDH resuscitations. Standardization of room set-up, equipment, and event order and reallocation of tasks facilitate more efficient intubation and ventilation, representing targets for CDH DR improvement initiatives. This work emphasizes the utility of rigorous human factors review to identify areas for improvement during DR resuscitation.

Randomized Controlled Trials of Pulmonary Vasodilator Therapy Adjunctive to Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: A Systematic Review.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator considered standard of care to treat persistent pulmonary hypertension of the newborn. However, not all infants respond to iNO. The authors performed a systematic review to examine methodology, outcomes, and challenges of randomized controlled trials testing pulmonary vasodilator medications adjunctive to iNO. The 5 trials identified showed heterogeneity in eligibility criteria and outcomes assessed. No trial achieved recruitment goals, limiting conclusions regarding efficacy, safety, and pharmacology. Trial design consensus and alternative methodologic strategies such as deferred consent, real-world controls, nonrandomized database assessments, and Bayesian statistical approaches are needed.

The Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia Treated with Fetoscopic Endoluminal Tracheal Occlusion: Beyond the Balloon.

INTRODUCTION: Randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and improved survival for infants with isolated, severe left-sided congenital diaphragmatic hernia (CDH). The delivery room resuscitation of these infants is particularly unique, and the specific delivery room events are largely unknown. The objective of this study was to compare the delivery room resuscitation of infants treated with FETO to standard of care (SOC) and describe lessons learned. METHODS: Retrospective single-center cohort study of infants treated with FETO compared to infants who met FETO criteria during the same period but who received SOC. RESULTS: FETO infants were more likely to be born prematurely with 8/12 infants born <35 weeks gestational age compared to 3/35 SOC infants. There were 5 infants who required emergent balloon removal (2 ex utero intrapartum treatment and 3 tracheoscopic removal on placental bypass with delayed cord clamping) and 7 with prenatal balloon removal. Surfactant was administered in 6/12 FETO (50%) infants compared to 2/35 (6%) in the SOC group. Extracorporeal membrane oxygenation use was lower at 25% and survival was higher at 92% compared to 60% and 71% in the SOC infants, respectively. CONCLUSION: The delivery room resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered <48 h after balloon removal.

Spectrum of Disease in Hospitalized Newborns with Congenital Micrognathia: A Cohort of 3,236 Infants at North American Tertiary-Care Intensive Care Units.

OBJECTIVE: To describe the spectrum of disease and burden of care in infants with congenital micrognathia from a multicenter cohort hospitalized at tertiary care centers. STUDY DESIGN: The Children's Hospitals Neonatal Database was queried from 2010 through 2020 for infants diagnosed with micrognathia. Demographics, presence of genetic syndromes, and cleft status were summarized. Outcomes included death, length of hospitalization, neonatal surgery, and feeding and respiratory support at discharge. RESULTS: Analysis included 3,236 infants with congenital micrognathia. Cleft palate was identified in 1266 (39.1%). A genetic syndrome associated with micrognathia was diagnosed during the neonatal hospitalization in 256 (7.9%). Median (IQR) length of hospitalization was 35 (16, 63) days. Death during the hospitalization (n = 228, 6.8%) was associated with absence of cleft palate (4.4%, P < .001) and maternal Black race (11.6%, P < .001). During the neonatal hospitalization, 1289 (39.7%) underwent surgery to correct airway obstruction and 1059 (32.7%) underwent gastrostomy tube placement. At the time of discharge, 1035 (40.3%) were exclusively feeding orally. There was significant variability between centers related to length of stay and presence of a feeding tube at discharge (P < .001 for both). CONCLUSIONS: Infants hospitalized with congenital micrognathia have a significant burden of disease, commonly receive surgical intervention, and most often require tube feedings at hospital discharge. We identified disparities based on race and among centers. Development of evidence-based guidelines could improve neonatal care.

Update on Management and Outcomes of Congenital Diaphragmatic Hernia.

Infants with congenital diaphragmatic hernia (CDH) benefit from comprehensive multidisciplinary teams that have experience in caring for the unique and complex issues associated with CDH. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies and pulmonary hypertension management, and extracorporeal membrane oxygenation, mortality and morbidity remain high. These infants have unique and complex issues that begin in fetal and infant life, but persist through adulthood. Here we will review the literature and share our clinical care pathway for neonatal care and follow up. While many advances have occurred in the past few decades, our work is just beginning to continue to improve the mortality, but also importantly the morbidity of CDH.

Neonatal Thrombocytopenia as a Presenting Finding in de novo Pyruvate Kinase Deficiency.

Thrombocytopenia is a common laboratory abnormality encountered in critically ill neonates. The broad differential for thrombocytopenia, and its association with potentially severe neonatal pathology, often presents a diagnostic dilemma prompting extensive evaluation. Hemolysis due to red cell enzymopathies is a rare cause of neonatal thrombocytopenia that is typically brief and self-limiting. Here, we present a case of thrombocytopenia, refractory to transfusion, associated with anemia and hyperbilirubinemia in a neonate with pyruvate kinase deficiency (PKD) arising from compound heterozygous PKLR mutations. The nature of the thrombocytopenia in this patient created considerable diagnostic uncertainty, which was ultimately resolved by whole-exome sequencing. This case emphasizes that inherited red cell defects, such as PKD, are important to consider in cases of neonatal thrombocytopenia.

Respiratory function after birth in infants with congenital diaphragmatic hernia.

OBJECTIVE: To characterise the transitional pulmonary physiology of infants with congenital diaphragmatic hernia (CDH) using measures of expiratory tidal volume (TV) and end-tidal carbon dioxide (ETCO2). DESIGN: Prospective single-centre observational study. SETTING: Quaternary neonatal intensive care unit. PATIENTS: Infants with an antenatal diagnosis of CDH born at the Children's Hospital of Philadelphia. INTERVENTIONS: TV and ETCO2 were simultaneously recorded using a respiratory function monitor (RFM) during invasive positive pressure ventilation immediately after birth. MAIN OUTCOME MEASURES: TV per birth weight and ETCO2 values were summarised for each minute after birth. Subgroups of interest were defined by liver position (thoracic vs abdominal) and extracorporeal membrane oxygenation (ECMO) treatment. RESULTS: RFM data were available for 50 infants from intubation until a median (IQR) of 9 (7-14) min after birth. TV and ETCO2 values increased for the first 10 min after birth, but intersubject values were heterogeneous. TVs were overall lower and ETCO2 values higher in infants with an intrathoracic liver and infants who were ultimately treated with ECMO. On hospital discharge, survival was 88% (n=43) and 34% (n=17) of infants were treated with ECMO. CONCLUSION: Respiratory function immediately after birth is heterogeneous for infants with CDH. Lung aeration, as evidenced by expired TV and ETCO2, appears to be ongoing throughout the first 10 min after birth during invasive positive pressure ventilation. Close attention to expired TV and ETCO2 levels by 10 min after birth may provide an opportunity to optimise and individualise ventilatory support for this high-risk population.

Expanding neonatal ECMO criteria: When is the premature neonate too premature.

Extracorporeal membrane oxygenation (ECMO) is a universally accepted and life-saving therapy for neonates with respiratory or cardiac failure that is refractory to maximal medical management. Early studies found unacceptable risks of mortality and morbidities such as intracranial hemorrhage among premature and low birthweight neonates, leading to widely accepted ECMO inclusion criteria of gestational age ≥34 weeks and birthweight >2 kg. Although contemporary data is lacking, the most recent literature demonstrates increased survival and decreased rates of intracranial hemorrhage in premature neonates who are supported with ECMO. As such, it seems like the right time to push the boundaries of ECMO on a case-by-case basis beginning with neonates 32-34 weeks GA in large volume centers with careful neurodevelopmental follow-up to better inform practices changes on this select population.

Current Practices for Genetic Testing in Neonatal Extracorporeal Membrane Oxygenation: Findings from a National survey.

Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO.Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children's Hospitals Neonatal Consortium (CHNC).Results: Common indications for WES and WGS included concerning phenotype, severity of disease, unexpected postnatal clinical course, and inability to wean from ECMO support. Unexpected severity of disease on ECMO was the most common indication for rapid genetic testing. Cost of utilization was the primary barrier to testing. If rapid WES or WGS were readily available, 63% of centers would consider incorporating universal screening for neonates upon ECMO cannulation.Conclusion: Despite variation in the use of WES and WGS, universal testing may offer earlier diagnosis and influence the treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening on ECMO if readily available.

The Genomics of Congenital Diaphragmatic Hernia: A 10-Year Retrospective Review.

OBJECTIVE: To evaluate genetic testing use in infants with congenital diaphragmatic hernia (CDH) over the past decade to better inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed of all infants with CDH enrolled in the Pulmonary Hypoplasia Program at Children's Hospital of Philadelphia, born between January 2011 and February 2021. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: The charts of 411 infants were analyzed. Overall, 22% (n = 89) were complex/syndromic and 78% (n = 322) were isolated/nonsyndromic. Mortality was significantly higher in complex/syndromic infants (P < .001) and in infants with diagnostic genetic testing (P < .001). Microarray was diagnostic in 9% (n = 34/399) and exome sequencing was diagnostic in 38% (n = 15/39). Genetic testing was diagnostic in 57% (n = 51/89) of complex/syndromic infants, but in only 2% of isolated/nonsyndromic infants (n = 8/322). Overall, genetic testing was diagnostic in 14% (n = 56). CONCLUSIONS: The high diagnostic rate in this cohort highlights the utility of comprehensive genetic testing in infants with CDH. However, 43% of complex/syndromic and 98% of isolated/nonsyndromic infants do not have a genetic etiology identified. This finding underscores the need for additional genetic and genomic studies (eg, whole genome, RNA sequencing) to identify novel genes and mutational mechanisms (single genes, regulatory elements, complex traits) that will allow for improved diagnostic rates and ultimately individualized management of infants with CDH.

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Achieving adequate growth in infants with congenital diaphragmatic hernia prior to discharge.

BACKGROUND/PURPOSE: To evaluate the enteral feeding requirements, including caloric provisions, of infants with CDH in relation to growth patterns. METHODS: A retrospective observational study was conducted on infants with CDH between August 2012 and March 2017. Electronic medical records were reviewed to extract detailed infant feeding data and anthropometric measurements at monthly intervals until discharge. Statistical methods of analysis included generalized linear models, Pearson correlation coefficient, Analysis of variance (ANOVA), Kruskal-Wallis, Wilcoxon rank sum, and Fisher's Exact tests. RESULTS: Among 149 infants with CDH, 45% (n = 67) met criteria for malnutrition at discharge. Maternal human milk (HM) was initiated in 95% of infants (n = 142) and continued in 79% of infants (n = 118) at discharge. Overall, 50% received fortification of feeds, including 60% (n = 89) of formula fed infants compared to only 21% (n = 31) of HM fed infants (p<0.001). Infants fed formula had lower weight-for-length z-scores at discharge compared to those fed HM. CONCLUSIONS: Infants receiving HM demonstrated improved growth compared to formula fed infants. However, higher calorie feeding regimens need to be initiated earlier to improve growth velocity. Prompt recognition of malnutrition and growth failure with aggressive supplementation may improve the overall growth of infants with CDH and has the potential to improve long term neurodevelopmental outcomes.

Hyperinsulinism in an individual with an EP300 variant of Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic syndrome characterized by distinct facial features, broad thumbs, growth restriction, microcephaly, intellectual disability, and developmental delay. Pathogenic variants in both CREBBP and EP300 have been associated with RSTS. Here we present a case of a female with hyperinsulinism and features consistent with RSTS, found to have a pathogenic variant in EP300. While there have been a few rare case reports of hyperinsulinism in RSTS, we suggest that hyperinsulinism might be a more prominent feature in EP300 variant RSTS than previously recognized.

Reconsidering ECMO in Premature Neonates.

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for neonates with respiratory failure or congenital cardiac disease refractory to maximal medical management. Early studies showed high rates of mortality and morbidities among preterm and low birthweight (BW) neonates, leading to widely accepted ECMO inclusion criteria of gestational age (GA) ≥34 weeks and BW >2 kg. In recent years, publications involving neonates of 32-34 weeks GA have reported improved survival and decreased intracranial hemorrhage. As such, ECMO should be considered on a case-by-case basis in premature neonates as long as the risks are understood.

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome.

Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X-linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L-related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L-related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus.

Broadening the phenotypic spectrum of Pearson syndrome: Five new cases and a review of the literature.

Pearson syndrome (PS) is a multisystem mitochondrial respiratory chain disorder typically characterized by sideroblastic anemia and exocrine pancreatic insufficiency. PS is caused by a single large-scale mitochondrial DNA (mtDNA) deletion. PS classically presents in the first year of life and may be fatal in infancy. Children who survive PS may progress to develop Kearns-Sayre syndrome later in life. The full phenotypic spectrum and prognosis of the condition continue to evolve. Here we report five new patients with PS with unique clinical presentations, including four patients with onset later than previously reported in the literature, and one patient with prenatal onset of symptoms. The timing and unique features of these presentations support an expanded phenotypic spectrum of single large-scale mtDNA deletion syndromes (SLSMDS) and reinforce the importance of including SLSMDS in the differential for children with complex multisystem presentations.