Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Spontaneous tracheal and subglottic tears in neonates.

OBJECTIVES/HYPOTHESIS: Spontaneous rupture of the trachea or subglottis as a complication of difficult delivery has not been reported in the United States literature. There have been a few cases reported in the European literature. The present report describes a series of newborns with this complication and discusses the signs and treatment options of this difficult, life-threatening problem. STUDY DESIGN: Retrospective review. METHODS: Newborns born between 1996 and 2001 who were treated for spontaneous subglottic or tracheal rupture at a tertiary care children's hospital neonatal intensive care unit were reviewed. RESULTS: Four cases of spontaneous subglottic rupture were seen at the hospital. In three of the four cases the tracheas were intubated on an emergency basis after subcutaneous air was noted in the anterior aspect of the neck. In the fourth patient the trachea was not intubated until the subglottic tear was visualized intraoperatively. Two of the four patients died. One died without securing of an airway; the other died of complications of prolonged hypoxia. Eight cases from European literature of spontaneous neonatal subglottic and tracheal tears are reviewed and are compared with the cases presented in the current report. CONCLUSIONS: Early detection of airway rupture by flexible endoscopy is essential for timely diagnosis and appropriate treatment. Standard endotracheal intubation can exacerbate the problem and should be deferred if possible until direct airway visualization can be accomplished. Signs associated with tracheal tears include subcutaneous emphysema, respiratory distress, pneumothorax, and pneumomediastinum. These should lead to emergent consultation with otolaryngologists for examination and securing of the airway.

Protocolized management of infants with congenital diaphragmatic hernia: effect on survival.

BACKGROUND/PURPOSE: In 2006, we introduced a new protocol for congenital diaphragmatic hernia (CDH) management featuring nitric oxide in the delivery room, gentle ventilation, lower criteria for extracorporeal membrane oxygenation (ECMO), and appropriately timed operative repair on ECMO. Our goals were to assess outcomes after institution of this protocol and to compare results with historical controls. METHODS: Charts were reviewed of all newborns admitted to a large metropolitan children's hospital from 2002 to 2009 with a diagnosis of CDH. Data were recorded regarding delivery, ECMO, operative repair, length of stay, comorbidities/anomalies, complications, and survival. Postprotocol outcomes were compared to those from the preprotocol era and to data from the international CDH Registry. RESULTS: Comparison of the protocolized group (n = 43) to the historical group (n = 51) revealed no significant differences in gestational age, birth weight, Apgar scores, or comorbidities. New treatment strategies substantially improved survival to discharge (67% preprotocol, 88% postprotocol; P = .015). Among ECMO patients, survival increased to 82% (20% preprotocol; P = .002). CONCLUSIONS: Our new protocol significantly improved survival to discharge for newborns with CDH. Institution of such a protocol is valuable in improving outcomes for patients with CDH and merits consideration for widespread adoption.