The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

Introduction: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders.

Methods: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.

Genetic testing for diffuse lung diseases in children.

Newly developing genomic technologies are an increasingly important part of clinical care and thus, it is not only important to understand the technologies and their limitations, but to also interpret the findings in an actionable fashion. Clinical geneticists and genetic counselors are now an integral part of the clinical team and are able to bridge the complexities of this rapidly changing science between the bedside clinicians and patients. This manuscript reviews the terminology, the current technology, some of the known genetic disorders that result in lung disease, and indications for genetic testing with associated caveats.

Child Interstitial Lung Disease in an Infant with Surfactant Protein C Dysfunction due to c.202G>T Variant (p.V68F).

For newborns suspected having childhood interstitial lung disease (ChILD), the sequencing of genes encoding surfactant proteins is recommended. However, it is still difficult to interpret the clinical significance of those variants found. We report a full-term born female infant who presented with respiratory distress and failure to thrive at 2 months of age and both imaging and lung biopsy were consistent with ChILD.

Accurate assignment of disease liability to genetic variants using only population data.

Purpose: The growing size of public variant repositories prompted us to test the accuracy of pathogenicity prediction of DNA variants using population data alone.

Methods: Under the a priori assumption that the ratio of the prevalence of variants in healthy population vs that in affected populations form 2 distinct distributions (pathogenic and benign), we used a Bayesian method to assign probability to a variant belonging to either distribution.

Results: The approach, termed Bayesian prevalence ratio (BayPR), accurately parsed 300 of 313 expertly curated CFTR variants: 284 of 296 pathogenic/likely pathogenic variants in 1 distribution and 16 of 17 benign/likely benign variants in another.

Biallelic variants of cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

Background: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the gene were recently identified as a new cause of adult-onset PAH. However, the contribution of risk alleles to child-onset PAH remains largely unexplored.

Coronavirus Disease 2019 in Pregnancy and Outcomes Among Pregnant Women and Neonates: A Literature Review.

Limited data are available about the outcomes of coronavirus disease 2019 (COVID-19) during pregnancy and risk of vertical transmission in exposed neonates. We reviewed studies published February 1, 2020, through August 15, 2020, on outcomes in pregnant women with COVID-19 and neonates with perinatal exposure. Among pregnant women with COVID-19, 181 (11%) required intensive care unit admission and 123 (8%) required mechanical ventilation.

Genetic Testing for Neonatal Respiratory Disease.

Genetic mechanisms are now recognized as rare causes of neonatal lung disease. Genes potentially responsible for neonatal lung disease include those encoding proteins important in surfactant function and metabolism, transcription factors important in lung development, proteins involved in ciliary assembly and function, and various other structural and immune regulation genes. The phenotypes of infants with genetic causes of neonatal lung disease may have some features that are difficult to distinguish clinically from more common, reversible causes of lung disease, and from each other.

Community-Onset Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Young Infants: A Systematic Review.

Objective: To summarize and evaluate current reports on community-onset severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young infants.

Study Design: We performed a systematic review to identify reports published from November 1, 2019, until June 15, 2020, on laboratory-confirmed community-onset SARS-CoV-2 infection in infants younger than 3 months of age. We excluded studies reporting neonates with perinatal coronavirus disease 2019 (COVID-19) exposure and diagnosis before hospital discharge and hospital-onset disease, as well as clinically diagnosed cases without confirmation.

A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency.

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis.

Neonatal respiratory failure due to novel compound heterozygous mutations in the ABCA3 lipid transporter.

The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant.

The common K333Q polymorphism in long-chain acyl-CoA dehydrogenase (LCAD) reduces enzyme stability and function.

The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed at high levels in human alveolar type II (ATII) cells in the lung. A common polymorphism causing an amino acid substitution (K333Q) was previously linked to a loss of LCAD antigen in the lung tissue in sudden infant death syndrome. However, the effects of the polymorphism on LCAD function has not been tested.

Single-Center Outcome of Fetoscopic Tracheal Balloon Occlusion for Severe Congenital Diaphragmatic Hernia.

Objective: To assess feasibility and maternal and infant outcome after fetoscopic tracheal balloon occlusion in patients with severe congenital diaphragmatic hernia.

Methods: We conducted a prospective cohort study of fetuses with congenital diaphragmatic hernia and observed/expected lung/head ratio less than 30%. Eligible women had planned fetoscopic tracheal balloon occlusion at 26 0/7-29 6/7 weeks of gestation and balloon removal 4-6 weeks later.

Genetic causes of surfactant protein abnormalities.

Purpose Of Review: Mutations in genes encoding proteins critical for the production and function of pulmonary surfactant cause diffuse lung disease. Timely recognition and diagnosis of affected individuals is important for proper counseling concerning prognosis and recurrence risk.

Recent Findings: Involved genes include those encoding for surfactant proteins A, B, and C, member A3 of the ATP-binding cassette family, and for thyroid transcription factor 1.

Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline.

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD).

Target Audience: Clinicians investigating adult and pediatric patients for possible PCD.

Methods: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions.

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction.