Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis.

Rationale: Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly.Objectives: To test the hypothesis that CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.Methods: CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents ("trio analysis") to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice.Measurements and Main Results: The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in SHH (Sonic Hedgehog), and inherited variants were identified in HSPG2 (perlecan), ROR2 (receptor tyrosine kinase-like orphan receptor 2), and WLS (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice.Conclusions: The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.

Congenital salivary gland anlage tumor - in utero and postnatal imaging.

We present a case of an infant with congenital salivary gland anlage tumor, with fetal and postnatal imaging. To the best of our knowledge, this is the first case describing the in utero imaging findings of salivary gland anlage tumor. A fetal MRI was performed secondary to the clinical finding of polyhydramnios, which identified a nasopharyngeal mass. Because findings were concerning for airway obstruction, the fetus was delivered by ex utero intrapartum treatment (EXIT) to airway procedure. A postnatal CT confirmed the findings of the fetal MRI. The lesion was resected when the baby was 4 days old and recovery was uneventful.

Tracheal agenesis with tracheoesophageal fistulae: fetal MRI diagnosis with confirmation by ultrasound during an ex utero intrapartum therapy (EXIT) delivery and postdelivery MRI.

Tracheal agenesis is a rare and essentially lethal anomaly with divergent prenatal imaging findings depending on the presence or absence of a tracheoesophageal fistula. All prenatally diagnosed cases of tracheal agenesis reported to date have not had a tracheoesophageal fistula and presented with thoracoabdominal findings similar to congenital high airway obstruction syndrome. We present the case of a 32-week gestation fetus with rapid onset of polyhydramnios and no persistent findings of congenital high airway obstruction syndrome that was ultimately diagnosed with tracheal agenesis plus tracheoesophageal fistula by fetal MRI. Additionally, we present the novel uses of intraoperative US during a staged ex utero intrapartum therapy delivery and postdelivery MRI, facilitated by proximity within the neonatal ICU, to confirm diagnosis and direct patient management while minimizing unnecessary investigations.

Upper airway complications of junctional epidermolysis bullosa.

OBJECTIVE: To assess the incidence of upper airway pathology in patients with junctional epidermolysis bullosa (JEB). STUDY DESIGN: We conducted a retrospective chart review of all patients with JEB who came to an interdisciplinary epidermolysis bullosa center at a tertiary care institution between 2004 and 2010. RESULTS: Twenty-five patients with JEB were identified, and 12 patients were seen in the otolaryngology clinic (age range, 2 months-15 years; 8 male, 4 female). Of the 12 patients, 8 underwent rigid laryngoscopy and bronchoscopy for upper respiratory tract symptoms; 7 of these patients displayed laryngeal pathology, and 5 of them underwent surgical intervention with successful resolution of symptoms. Furthermore, none of these patients had any short- or long-term complications from their surgery. A strict protocol and a precise problem-focused cold surgical technique were used in these cases to protect skin and mucus membranes. CONCLUSION: With appropriate precautions, endoscopic laryngeal surgery can be safe and effective in patients with JEB and larygnotracheal disease. Endoscopic laryngeal surgery is feasible when indicated for these patients.

Use of sentinel node biopsy for staging parameningeal rhabdomyosarcoma.

Identification of nodal involvement is important for treatment planning in patients with rhabdomyosarcoma, and is facilitated by sentinel node biopsy. Although it is employed primarily for extremity tumors, we report using sentinel node biopsy in a patient with parameningeal rhabdomyosarcoma arising in the ethmoid sinus. Lymphoscintigraphy with single photon emission computed tomography following injection of tracer at the tumor site helped identify contralateral cervical node involvement not previously recognized by physical exam, cross sectional imaging, or other functional imaging. This case demonstrates how information from sentinel node identification and biopsy can change therapy recommendations in patients with parameningeal rhabdomyosarcoma.

Advanced practice providers and children's hospital-based pediatric otolarynology practices.

INTRODUCTION: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting. METHODS: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice. RESULTS: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale. DISCUSSION: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.

Severe micrognathia: indications for EXIT-to-Airway.

The ex utero intrapartum treatment (EXIT) procedure has become an important management option in cases of fetal airway obstruction. Select cases of severe micrognathia may be candidates for EXIT-to-Airway due to high-risk of airway obstruction at birth. Here we present three successful EXIT-to-Airway procedures for the management of congenital micrognathia in its most severe manifestations. CASE 1: A 23-year-old G3P1011 with a pregnancy complicated by severe micorgnathia, jaw index <5th percentile, as well as polyhydramnios. At 36 weeks EXIT-to-Airway was performed utilizing a bronchoscopically positioned laryngeal mask airway (LMA) during 23 min of uteroplacental support followed by tracheostomy. CASE 2: A 26-year-old G4P0120 with a pregnancy complicated by severe micrognathia, jaw index <5th percentile, and an obstructed oropharynx associated with polyhydramnios. At 37 weeks EXIT-to-Airway was performed with placement of tracheostomy. CASE 3: A 36-year-old G6P3023 with fetal magnetic resonance imaging (MRI) revealing esophageal atresia, polyhydramnios, and severe micrognathia with a jaw index <5th percentile. At 35 weeks the patient underwent EXIT-to-Airway with formal tracheostomy during 35 min of uteroplacental bypass. In the most severe cases of fetal micrognathia, EXIT-to-Airway provides time to evaluate and secure the fetal airway prior to delivery. We propose indications for EXIT-to-Airway in micrognathia to include a jaw index <5%, with indirect evidence of aerodigestive tract obstruction such as polyhydramnios, glossoptosis or an absent stomach bubble.

Reflux symptom index versus reflux finding score.

OBJECTIVES: We examined the correlation between the Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS) to determine the laryngeal signs and symptoms that were most significantly correlated. METHODS: Forty randomly selected patients were included in the study. A retrospective chart review was performed for patients who fit the inclusion criteria. Videostroboscopic samples for the study group were reviewed and RFS-rated by 6 experienced raters on 2 different occasions to evaluate the interrater and intrarater reliability. The RSI and the RFS were statistically compared regarding both the total scores and the individual parameters. RESULTS: The RFS ranged from 0 to 20, and the RSI varied from 14 to 38. There was a high agreement between the raters' scores, demonstrating high interrater and intrarater reliability for RFS. Additionally, the RSI and RFS were highly correlated (p < .0001). Hoarseness was highly correlated with vocal fold edema and thick laryngeal mucus (p < .01), and excessive throat clearing correlated significantly with thick endolaryngeal mucus (p < .01). CONCLUSIONS: The study demonstrates a highly significant correlation between the RFS and the RSI.

Cervicofacial vascular anomalies. II. Vascular malformations.

Vascular malformations are the second major category of vascular anomalies. In contrast to vascular tumors, they are present at birth and grow commensurately with the child. Although the molecular mechanisms underlying the formation of these lesions remain unclear, lesions are known to result from abnormal development and morphogenesis. Histologic examination of vascular malformations shows no evidence of cellular proliferation, but rather progressive dilation of abnormal channels. Vascular malformations are designated according to their predominant channel type; they may be capillary, venous, lymphatic, arterial, and combined malformations. Malformations with an arterial component are rheologically fast-flow, whereas capillary, lymphatic, and venous malformations are slow-flow in nature. The morbidity of vascular malformations varies greatly both within and among the clinical subgroups cited above. This article describes the clinical presentation, diagnosis, and management of vascular malformations. The more frequently encountered clinical presentations involving the head and neck are highlighted.

Changes in the cricoarytenoid joint induced by intubation in neonates.

OBJECTIVE: To characterize the histopathologic characteristics of the cricoarytenoid joint (CAJ) as a means to understand the mechanisms of vocal cord fixation in children after prolonged intubation. DESIGN: Histologic analysis of laryngeal specimens obtained from infants who had died secondary to various causes and who had been intubated from 1 to 30 days. MAIN OUTCOME MEASURE: Histopathologic characteristics of CAJ. RESULTS: Laryngeal specimens from infants who had been intubated for prolonged periods of time demonstrated evidence of hemorrhage, infection, inflammation, and fibrosis within the CAJ. Furthermore, a statistical correlation was found between the length of intubation and the presence of these histologic abnormalities. CONCLUSIONS: To our knowledge, this is the first study to demonstrate histologic changes in the CAJ in laryngeal specimens of children who have been intubated for prolonged periods of time. Such histological changes in the CAJ could explain the mechanism of vocal cord immobility in children after intubation.

Adenotonsillectomy for obstructive sleep apnea syndrome in young children: prevalence of pulmonary complications.

OBJECTIVE: To determine, in a series of children younger than 6 years undergoing adenotonsillectomy for treatment of clinical obstructive sleep apnea syndrome (OSAS), the effect of age on prevalence of postoperative respiratory complications. The primary objective was to define a practice standard for postoperative hospital admission. DESIGN: Retrospective analysis. SETTING: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. PATIENTS: All children younger than 6 years who underwent adenotonsillectomy to treat OSAS from June 1, 1999, to May 31, 2001. MAIN OUTCOME MEASURES: The percentage of children younger than 3 years undergoing adenotonsillectomy to treat OSAS who experience a postoperative respiratory complication. RESULTS: Of 2315 patients younger than 6 years undergoing an adenotonsillectomy for treatment of OSAS, 149 (6.4%) developed a postoperative respiratory complication. Even though there was a lower incidence of comorbid medical conditions in this cohort, children younger than 3 years were at a greater risk for developing a postoperative respiratory complication compared with those aged 3 to 5 years (9.8% vs 4.9%, P<.001). Logistic regression analysis revealed that children younger than 3 years had a nearly 2-fold increased risk for respiratory complications postoperatively (odds ratio, 1.98; 95% confidence interval, 1.41-2.77) when controlling for race and sex. CONCLUSIONS: Adenotonsillectomy to treat OSAS is associated with a significantly higher rate of postoperative respiratory complication in children younger than 3 years compared with children aged 3 to 5 years. Our results support hospital admission for all patients younger than 3 years undergoing adenotonsillectomy for treatment of OSAS.

Open excision of subglottic hemangiomas to avoid tracheostomy.

OBJECTIVE: To assess the efficacy of open excision as an alternative to tracheostomy in the management of subglottic hemangioma. DESIGN: A retrospective review of patients undergoing open surgical excision of subglottic hemangiomas over a 10-year period. SETTING: A tertiary pediatric center. PATIENTS: The study included 22 children ranging in age from 2 to 42 months (median age, 5 months) who underwent open excision of subglottic hemangioma over a 10-year period. RESULTS: Twenty-one patients were treated with single-stage procedures, with postoperative endotracheal intubation for an average of 5 days. One patient who had a preexisting tracheostomy was treated with a 2-stage procedure and underwent decannulation 2 months after excision. Seven other patients were tracheostomy dependent at the time of excision and underwent decannulation at the time of the procedure. Cartilage grafts were inserted in 10 patients. There were no problems with subglottic stenosis. Twenty-one patients reported good voice and no airway symptoms after a mean follow-up period of 42 months. Five patients had significant postoperative problems. Three patients required further endoscopic procedures for removal of granulation tissue, and 1 patient, who remains minimally symptomatic, developed an anterior glottic web. One patient required a 6-month course of steroids after surgery to treat residual glottic hemangioma. CONCLUSIONS: Open surgical excision of subglottic hemangiomas can be performed as a single procedure, avoiding a tracheostomy, when modern surgical techniques developed for laryngotracheal reconstruction are incorporated. This approach can avoid repeated endoscopic procedures, prolonged treatment with corticosteroids, and years spent with a tracheostomy waiting for spontaneous involution of the hemangioma.

Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m(2) per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Pediatric postcricoid vascular malformation: a diagnostic and treatment challenge.

Hemangioma of the upper aerodigestive tract is a rarely reported occurrence in the pediatric literature. To date, there have been three published case reports of postcricoid hemangiomas contributing to unexplained dysphagia and respiratory distress. We present three children with a history of swallowing difficulty and stridor who were found to have an occult postcricoid mass. Valsalva maneuvers confirmed the suspicion of a vascular malformation in both patients. Transoral laser therapy (KTP and CO2) was used to ablate the lesions. The patients are symptom-free at 5 months, 5 years, and 2 weeks, respectively. The diagnostic challenge in evaluating these children and the therapeutic choices are described.

Lingual cyst lined by squamous epithelium.

Lingual choristomas or foregut duplication cysts are infrequently reported congenital anomalies that typically present in the perinatal period, and can cause respiratory or feeding problems. These cysts are lined by epithelial cells characteristic of the upper aerodigestive tract. We describe two children who presented shortly after birth with lingual cysts lined with squamous epithelium and foci of respiratory epithelium. Unlike previously reported lingual choristomas, these cysts did not contain gastrointestinal epithelium. In both these cases, the lingual cysts were successfully excised via a transoral approach. This article will discuss the histological findings in these two cases, the differential diagnosis and attempt to classify these lesions in the context of existing terminology.

Multicenter Evaluation of the Effectiveness of Systemic Propranolol in the Treatment of Airway Hemangiomas.

OBJECTIVE: To evaluate the effectiveness of systemic propranolol in airway infantile hemangioma (AIH) treatment. DESIGN: Case series with chart review. PARTICIPANTS: Patients with AIH treated with propranolol between 2009 and 2012 with at least a 1-year follow-up. OUTCOMES: Presenting age, treating institution, syndrome presence, presenting AIH stage, endoscopy status, propranolol initiation location/dose/duration, time to stridor resolution, adjunctive medical and surgical therapy, and treatment-associated complications. RESULTS: Twenty-seven patients met inclusion criteria. Average age of diagnosis was 2.3 months (range, 1-5 months). The AIHs were stage 1 in 7 of 27 (26%), stage 2 in 12 of 27 (44%), and stage 3 in 8 of 27 (30%). Propranolol initiation was inpatient in 25 of 27 (93%) and outpatient in 2 of 27 (7%). Propranolol dose was maintained at 2 mg/kg/d in all patients for a minimum of 7 months (range, 7-34 months; median, 15 months). Stridor was eliminated within 24 hours or less of propranolol initiation in 23 of 27 (85%). At diagnosis, staging and propranolol initiation in 11 of 27 (41%) were managed with propranolol alone; the remaining 16 of 27 (59%) also had a steroid injection. The use of adjuvant therapy at the time of propranolol initiation and the size of the AIH were not statistically correlated. Twelve patients had additional treatments after the initiation of propranolol due to recurrence of respiratory symptoms, 1 of 27 (4%) of whom was considered a nonresponder. No complications related to propranolol use were noted. CONCLUSIONS: This multisite study of AIH treatment with propranolol demonstrates similar effectiveness to surgical treatment modalities. Propranolol therapy for AIH had no complications, had potentially lower resource utilization, and should be considered a first-line AIH treatment.

Standardized outcome and reporting measures in pediatric head and neck lymphatic malformations.

OBJECTIVE: To develop general and site-specific treatment effect and outcome measures to standardize the reporting of head and neck lymphatic malformation (HNLM) treatments. STUDY DESIGN: Consensus statement/expert opinion. SETTING: Multiple tertiary academic institutions. SUBJECTS AND METHODS: The modified Delphi method is an iterative process of collecting expert opinions, refining opinions through discussion and feedback, statistically aggregating opinions, and using these aggregates to generate consensus opinion in the absence of other data. The modified Delphi method was used by a multi-institutional group of otolaryngology and interventional radiology experts in the field of vascular anomalies to formulate a list of recommended reporting outcomes for the study and treatment of head and neck lymphatic malformations. RESULTS: Through 3 rounds of iteration, 10 expert panelists refined 98 proposed outcome measures and 9 outcome categories to a final consensus set of 50 recommended outcome measures in 3 global categories (general, demographics, and treatment complications) and 5 site-specific categories (orbit, oral cavity, pharynx, larynx, and neck). CONCLUSIONS: We propose the first consensus set of standardized reporting measures for clinical and treatment outcomes in studies of HNLMs. Consistent outcome measures across future studies will facilitate comparison of treatment options and allow systematic review. We hope that these guidelines facilitate the design and reporting of subsequent HNLM studies.

Electrocautery adenoidectomy compared with curettage and power-assisted methods.

OBJECTIVE: To compare electrocautery adenoidectomy with conventional (curettage) and power-assisted (endoscopic shaver) methods. STUDY DESIGN: Comparative review. METHODS: Prospective and retrospective studies comparing electrocautery adenoidectomy and conventional curettage or power-assisted methods were reviewed to provide direct comparisons regarding specific outcome variables. RESULTS: Electrocautery adenoidectomy is a precise, effective technique for removing adenoid tissue. Compared with curettage techniques, electrocautery involves less blood loss and shorter operating times. Power-assisted adenoidectomy also offers shorter operating times and less blood loss, but the necessary equipment is more expensive and more experience is required to attain proficiency with the technique. CONCLUSION: Electrocautery adenoidectomy provides the benefits of minimization of operating time and blood loss at a lower cost than power-assisted adenoidectomy.

Complications of adenotonsillectomy.

OBJECTIVE: To review the immediate, short-term, and long-term complications of adenotonsillectomy. STUDY DESIGN: Review. METHODS: Complications of adenotonsillectomy and methods for preventing and treating them were reviewed. RESULTS: The most common complications of adenotonsillectomy, such as bleeding, generally occur in the immediate perioperative period but can develop up to 2 weeks postoperatively. Long-term complications, such as nasopharyngeal stenosis, may appear months to years after surgery. These more unusual sequelae result from scar contracture and maturation. CONCLUSION: Although rare, complications associated with adenotonsillectomy can be taxing for patients and health care resources. The most common complications, namely, anesthesia risks, pain, otalgia, and bleeding, should be discussed with patients' caregivers.

Potential role of Sox9 in patterning tracheal cartilage ring formation in an embryonic mouse model.

OBJECTIVE: To identify genes expressed early in the formation of the mouse trachea that control patterning of tracheal cartilaginous rings. DESIGN: The mouse larynx and trachea begin as an outpouching from the ventral foregut endoderm at embryonic day (E) 9. Digoxigenin-labeled RNA probes to putative tracheal patterning genes were generated by in vitro transcription. Embryos ranging in age from E9 to E16 were then subjected to whole-mount in situ hybridization using these labeled RNA probes. The RNA probes were then localized using antidigoxigenin antibodies tagged with a reporter molecule. In this manner, the 3-dimensional spatial and temporal expression of putative tracheal patterning genes was examined. Subjects F/VBN mice. RESULTS: In the developing mouse trachea, the expression of Sox9 messenger RNA preceded cartilage ring formation. Sox9 was expressed as 2 distinct longitudinal stripes along the posterolateral aspect of the trachea as early as E9, when the developing trachea is first identified. Collagen 2A1, a cartilage-specific protein, was subsequently expressed in the same longitudinal pattern as Sox9, consistent with the early commitment of Sox9-expressing cells to the cartilage program. As cartilage rings formed, Sox9 and collagen 2A1 was expressed over the lateral and anterior aspects of the trachea. CONCLUSIONS: We have developed a system to study the early expression of genes that may pattern the formation of the trachea. We have identified a gene (Sox9) with a known role in chondrocyte differentiation that is expressed in a highly specific temporal and spatial pattern in the developing upper respiratory tract.