Esophageal Atresia With or Without Tracheoesophageal Fistula: Comorbidities, Genetic Evaluations, and Neonatal Outcomes.

Objective Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) has a reported incidence of 1 in 3500 live births and requires intensive care and surgery. To evaluate the prevalence of a molecularly confirmed genetic etiology of EA/TEF in a level IV neonatal intensive care unit (NICU), focusing on genetic evaluation, diagnostic yield, and clinical outcomes of these neonates. Study design A retrospective cohort study over a period of seven years was performed for all patients admitted with a diagnosis of EA/TEF. Automated data was extracted for demographic information and manual extraction was done to evaluate the frequency of associated anomalies, type of genetic evaluations and diagnoses, and outcomes at NICU discharge. Results Sixty-eight infants met the inclusion criteria. The majority were male (n=42; 62%), born at >37 weeks' gestation (n=36; 53%), and had EA with distal TEF (n=54; 79%). Most (n=53; 78%) had additional associated congenital anomalies, but only 47 (69%) patients had a genetics evaluation performed and genetic testing was sent for 44 (65%) of those patients. The most common genetic testing performed was chromosomal microarray analysis (n=40; 59%), followed by chromosome analysis (n=11; 16%), and whole exome/genome sequencing (n=7; 10%). Five unique genetic diagnoses including CHARGE Syndrome, Fanconi Syndrome, EFTUD2-related mandibulofacial dysostosis, and two different chromosomal deletion syndromes were made for a total of nine (13%) patients in our cohort. The cohort suffered a high rate of morbidity and mortality during their NICU stay with important differences noted in isolated vs non-isolated EA/TEF. Twelve infants (18%) died prior to NICU discharge. Of those surviving, 40 (71%) infants had a primary repair, 37 (66%) infants required G or GJ feedings at NICU discharge, and eight (14%) patients were discharged on some type of respiratory support. Conclusion In this high-risk cohort of EA/TEF patients cared for at a quaternary NICU, a majority were non-isolated and had some form of a genetic evaluation, but a minority underwent exome or genome sequencing. Given the high prevalence of associated anomalies, high mortality, and genetic disease prevalence in this cohort, we recommend standardization of phenotyping and genetic evaluation to allow for precision care and appropriate risk stratification.

Sleep Apnea in Children With Down Syndrome.

OBJECTIVE: The authors of this study aimed to evaluate the use of polysomnography (PSG) in children with Down syndrome (DS) between ages 0 and 7 years, to assess the prevalence and severity of obstructive sleep apnea (OSA) and associated comorbidities, and to describe interventions used for OSA. METHODS: A retrospective cohort study was performed at Cincinnati Children's Hospital Medical Center for children with DS born between 2013 and 2019. Data were extracted from the electronic medical record, including demographics, age at PSG, PSG results, and interventions after an abnormal PSG. Statistical analysis included unadjusted bivariate association testing and multivariable logistic regression modeling to investigate associations with OSA severity. RESULTS: Among 397 patients in the cohort, 59% (n = 235) had a documented PSG and 94% (n = 221) had an abnormal study with 60% (n = 141) demonstrating moderate or severe OSA. There was an inverse relationship between age and OSA severity (P < .001). In a multiple regression model, OSA severity was associated with increased rates of failure to thrive (P < .01), aspiration (P = .02), and laryngomalacia (P < .01). After medical or surgical intervention, 73% of patients experienced the resolution of OSA or an improvement in OSA severity. CONCLUSION: In this study of pediatric patients with DS, OSA was identified most frequently in the first year of life. In addition, to prompt evaluation of symptomatic infants, our data support earlier PSG screening for patients requiring neonatal ICU care and those with feeding difficulties, airway abnormalities, and/or pulmonary hypertension given their increased risk for severe OSA.

Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III.

Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.

Neonatal complications of Down syndrome and factors necessitating intensive care.

Limited knowledge exists about how frequently newborns with Down syndrome receive a prenatal diagnosis, require intensive care, and what surgical and medical factors are contributory. A retrospective cohort study was performed for patients with a diagnosis of Down syndrome born in 2013 and 2014 who sought care at Cincinnati Children's Hospital Medical Center during the first year of life. Data were extracted from the electronic medical record through the first year of life including need for intensive care as a newborn, prenatal diagnosis, and medical and surgical complications. Of the 129 patients in the study, 65% required intensive care as newborns. The presence of a structural abnormality that required surgical correction in the neonatal period and certain types of congenital heart disease not requiring surgical intervention in the neonatal period were positively associated with the need for intensive care. A minority of infants, 8%, had a confirmed prenatal diagnosis. A majority of newborns with Down syndrome required intensive care following birth while a minority had any concern for the diagnosis prenatally. Improving prenatal diagnostic rates would allow for better prenatal counseling and delivery planning, while targeting therapeutic interventions for this population is needed to improve outcomes.

Making a Genetic Diagnosis in a Level IV Neonatal Intensive Care Unit Population: Who, When, How, and at What Cost?

OBJECTIVE: To investigate the prevalence of genetic disease and its economic impact in a level IV neonatal intensive care unit (NICU) by identifying and describing diseases diagnosed, genetic testing methodologies used, timing of diagnosis, length of NICU stay, and charges for NICU care. STUDY DESIGN: A retrospective chart review of patients admitted to a level IV NICU from 2013 to 2014 (n = 1327) was undertaken and data collected up to 2 years of age from the electronic medical record. RESULTS: In total, 117 patients (9%) received 120 genetic diagnoses using a variety of methodologies. A significant minority of diagnoses, 36%, were made after NICU discharge and 41% were made after 28 days of age. Patients receiving a genetic diagnosis had significantly longer mean lengths of stay (46 days vs 29.1 days; P < .01) and costlier mean charges ($598 712 vs $352 102; P < .01) for their NICU care. The NICU stay charge difference to care for a newborn with a genetic condition was on average $246 610 in excess of that for a patient without a genetic diagnosis, resulting in more than $28 000 000 in excess charges to care for all patients with genetic conditions in a single NICU over a 2-year period. CONCLUSIONS: Given the high prevalence of genetic disease in this population and the documented higher cost of care, shortening the time to diagnosis and targeting therapeutic interventions for this population could make a significant impact on neonatal care in level IV NICUs.

Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction.

Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial fatty acid oxidation enzyme whose expression in humans is low or absent in organs known to utilize fatty acids for energy such as heart, muscle, and liver. This study demonstrates localization of LCAD to human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. The physiological role of LCAD and the fatty acid oxidation pathway in lung was subsequently studied using LCAD knock-out mice. Lung fatty acid oxidation was reduced in LCAD(-/-) mice. LCAD(-/-) mice demonstrated reduced pulmonary compliance, but histological examination of lung tissue revealed no obvious signs of inflammation or pathology. The changes in lung mechanics were found to be due to pulmonary surfactant dysfunction. Large aggregate surfactant isolated from LCAD(-/-) mouse lavage fluid had significantly reduced phospholipid content as well as alterations in the acyl chain composition of phosphatidylcholine and phosphatidylglycerol. LCAD(-/-) surfactant demonstrated functional abnormalities when subjected to dynamic compression-expansion cycling on a constrained drop surfactometer. Serum albumin, which has been shown to degrade and inactivate pulmonary surfactant, was significantly increased in LCAD(-/-) lavage fluid, suggesting increased epithelial permeability. Finally, we identified two cases of sudden unexplained infant death where no lung LCAD antigen was detectable. Both infants were homozygous for an amino acid changing polymorphism (K333Q). These findings for the first time identify the fatty acid oxidation pathway and LCAD in particular as factors contributing to the pathophysiology of pulmonary disease.