Janet Lioy

Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA‐binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Effect of tracheostomy timing in premature infants

OBJECTIVE To examine if timing of tracheostomy placement in premature infants affects the rates of decannulation and length of time required for mechanical ventilatory support. MATERIALS AND METHODS Consecutive case series with chart review of premature patients born at a gestational age of 36 weeks or less at a tertiary-care, academic childrens hospital who underwent tracheostomy placement between July 1, 2007 and December 31, 2010 for failure to extubate and chronic lung disease of prematurity. Last follow-up data reviewed was January 1, 2013. RESULTS 43 patients were identified. 32 patients (74.4%) were able to be weaned from mechanical ventilation by the end of follow-up period, and the average time that elapsed between tracheostomy placement and weaning from mechanical ventilator support was 17.9 months. 19 patients (44.2%) were able to be decannulated, and of those patients, the amount of time between tracheostomy placement and decannulation was 27.9 months. No statistical significance was found in the relationship between tracheostomy timing placement and ability to wean from mechanical ventilator support or decannulate. For those patients able to wean from mechanical ventilator support and get decannulated, no difference in the amount of time and tracheostomy timing was found. Earlier premature patients tended to undergo tracheostomy later in life. CONCLUSIONS Decisions regarding tracheostomy placement should be individualized. We were unable to detect a relationship between tracheostomy timing and the ability or duration for premature infants with chronic lung disease of prematurity to wean from mechanical ventilator support or successfully decannulate.

Mandibular distraction osteogenesis for the treatment of neonatal tongue-based airway obstruction.

AbstractEarly postnatal tracheostomy for airway compromise is associated with high morbidity and cost. In certain patients with tongue-base airway obstruction (TBAO), mandibular distraction osteogenesis may be preferred. We present a comprehensive analysis of surgical, airway, and cephalometric outcomes in a large series of neonatal patients with TBAO. A retrospective review was performed of patients with laryngoscopically proven TBAO who underwent mandibular distraction osteogenesis before 1 year of age at our institution. Demographic, operative, postoperative, polysomnographic, and radiographic data were analyzed with the appropriate statistical test.Between 2010 and 2013, 28 patients younger than 1 year underwent mandibular distraction for TBAO. Distraction was performed for documented TBAO and failure to thrive at an average age of 58 days (range, 11–312) days with distractor removal after an average of 90 days. Preoperative polysomnograms were obtained on 20 patients with an average apnea-hypopnea index of 39.3 ± 22.0/h; the apnea-hypopnea index on postoperative polysomnograms obtained after distraction completion was significantly reduced in all 14 patients in whom it was measured (mean, 3.0 ± 1.5/h; P < 0.0001). Twenty patients transitioned to oral feeding, and cephalometric and airway diameters were improved (P < 0.0001). Distraction was successful in all but 4 patients including all patients with GILLS scores of 2 or less and 66% of patients with GILLS scores of 3 or greater. Neonatal mandibular distraction is a powerful tool to treat critical obstructive apnea in patients with TBAO. Appropriate patient selection remains a challenge; however, mandibular distraction represents a compelling treatment modality.

Airway disorders of the fetus and neonate: An overview.

Differences between neonatal, pediatric and adult airway anatomy, structure and function are important to understand. Size, surface area, proportion, resistance and compliance are all very different between age groups and infants are certainly not small adults. Knowledge of these airway differences is essential in rapid correction of an emergency situation. Unanticipated airway emergencies are the most serious of all and may be classified into profiles such as the unanticipated emergency in the non-intubated patient, the unanticipated emergency in the intubated patient, and patients with tracheostomy. A neonatal airway emergency can be effectively managed by a strategy for anticipation, identification, preparation, mobilization, and execution. Furthermore, neonatal airways may be classified by severity in being considered either difficult or critical. These neonatal specific clinical challenges have recently substantiated the need for a distinct neonatal airway algorithm. This strategy is strengthened by regular education of the team and frequent simulation of airway emergencies. Following a predetermined pathway for activating an airway emergency alert and having all necessary equipment readily available are essential components of a well-defined strategy. Finally, knowing the pediatric otolaryngologists perspective of what defines these airway disorders and current management is key to working collaboratively.

Evolution of Obstructive Sleep Apnea in Infants with Cleft Palate and Micrognathia

STUDY OBJECTIVES Children with craniofacial anomalies are a heterogeneous group at high risk for obstructive sleep apnea (OSA). However, the prevalence and structural predictors of OSA in this population are unknown. We hypothesized that infants with micrognathia would have more significant OSA than those with isolated cleft palate ± cleft lip (ICP), and those with ICP would have more significant OSA than controls. We postulated that OSA severity would correlate with reduced mandibular size, neurodevelopmental scores, and growth. METHODS Prospective cohort study. 15 infants with ICP, 19 with micrognathia, and 9 controls were recruited for polysomnograms, neurodevelopmental testing, cephalometrics (ICP and micrognathia groups) at baseline and a follow-up at 6 mo. RESULTS Baseline apnea-hypopnea index (AHI) [median (range)] of the micrognathia group [20.1 events/h (0.8, 54.7)] was greater than ICP [3.2 (0.3, 30.7)] or controls [3.1 (0.5, 23.3)] (p = 0.001). Polysomnographic findings were similar between ICP and controls. Controls had a greater AHI than previously reported in the literature. Cephalometric measures of both midface hypoplasia and micrognathia correlated with OSA severity. Neurodevelopment was similar among groups. OSA improved with growth in participants with ICP and postoperatively in infants with micrognathia. CONCLUSIONS Micrognathia, but not ICP, was associated with more significant OSA compared to controls. Both midface and mandibular hypoplasia contribute to OSA in these populations. OSA improved after surgical correction in most infants with micrognathia, and improved without intervention before palate repair in infants with ICP.

The Use of Early Lung Biopsy in Detection of Fatal Pulmonary Disease in the Neonate

We report a case of alveolar capillary dysplasia with misaligned pulmonary veins and review the literature to highlight the importance of lung biopsy, which can affect the decision to use invasive and likely ineffective therapy such as extracorporeal membrane oxygenation.

Challenges of the Neonatal Airway

Increasingly complex patients treated in neonatal intensive care units create a unique set of challenges in managing the neonate’s airway including both anatomical and physiological considerations that differentiate them from the general pediatric or adult populations. Potential airway emergencies can be classified into profiles such as the unanticipated emergency in the non-intubated patient, the unanticipated emergency in the intubated patient, and patients with tracheostomy. Furthermore, neonatal airways can be classified by severity in being considered either difficult or critical. These neonatal specific clinical challenges have recently substantiated the need for a distinct neonatal airway algorithm.

Creating an Effective Quality Improvement (QI) Process for Airway Emergencies

Airway emergencies are life-threatening situations that have little tolerance for errors and require immediate responses by qualified surgeons, neonatologists, and support staff. Therefore to ensure patients do not suffer harm from airway emergencies, an airway safety program must not only have rapid and effective response processes that are reliable, but also processes that can identify and mitigate high risk situations. Principles of high reliability organizations (HRO), which include sensitivity to operations, preoccupation with failure, deference to expertise, resilience, and reluctance to simplify [1], are applied to drive a higher state of mindfulness. The goal is to cultivate a workplace culture where all providers become stakeholders and engaged in HRO practices, and eliminate unnecessary variations in healthcare delivery that can lead to miscommunication and suboptimal care. By making practice more consistent amongst providers wherever possible, we are able to better practices for better outcomes. Numerous quality improvement collaboratives have embarked on such efforts and have contributed significantly to understanding factors that affect success [2–5].

A five year retrospective study of short term respiratory support outcomes for infants who received tracheostomy before one year of age.

OBJECTIVES This study aims to describe respiratory support requirements at the time of hospital discharge for infants who undergo tracheostomy, and to determine whether certain indications for tracheostomy are significantly associated with ventilator or oxygen dependence at the time of discharge. METHODS Retrospective chart review identified 150 patients who underwent tracheostomy before 1 year of age at a single center from 2007 to 2012 and were discharged alive. Patients were divided into groups based on primary indication for tracheostomy: chronic lung disease (CLD); cardiac; airway anomalies (e.g., tracheomalacia, subglottic stenosis); anatomic anomalies of head, neck and chest; neuro/muscular; mixed group (>1 primary indication). Chi-squared tests were used to compare respiratory support requirements at time of discharge, as well as need for supplemental oxygen. RESULTS Of the 150 patients included in the study, three were discharged on room air alone. Of those 147 who did require some form of support at discharge, significant differences were found between groups when comparing CPAP to ventilator support. For example, of the patients with CLD, 82% were discharged on ventilator support whereas of those with a primary airway indication nearly 54% were discharged on CPAP. Significant differences were also found among groups when comparing patients discharged on room air vs. supplemental oxygen. Patients with CLD were more likely to be discharged on supplemental oxygen (p=0.001) whereas of the patients with anatomic indication 77% required no supplemental oxygen at the time of discharge. CONCLUSION Respiratory support needs at the time of discharge for neonates who underwent tracheostomy varied significantly depending on the initial indication for tracheostomy. Information about respiratory requirements of infants who undergo tracheostomy can help clinicians counsel families and anticipate post-discharge needs.