The role of CDHR3 in susceptibility to otitis media.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes (n = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes CR1 and SAA1 overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be used as reference for identification of genes or pathways that are relevant to upper and lower airways, whether common across sites, or unique to each disease.

Generation of consensus in the application of a rating scale to nasendoscopic assessment of velopharyngeal function.

OBJECTIVE: To generate consensus ratings of velopharyngeal function on nasendoscopy (NE) with the goal of creating a video instruction tool. METHODS: The American Society of Pediatric Otolaryngology Velopharyngeal Insufficiency Study Group convened to identify NE segments to be included in an instructional video. Of 24 segments reviewed, 11 were selected based on the quality of the examinations and spectrum of closure patterns. Participating otolaryngologists independently rated NE segments using the Golding-Kushner scale. The participants then convened and rated each of the NE segments as a group. Thirty-nine members of the American Society of Pediatric Otolaryngology met and agreed with the group ratings, creating a consensus standard. RESULTS: Individual scores for palate and lateral wall motion showed high variability, ranging from 0 to 6 points difference from the consensus. Variability was also seen for the following qualitative findings: the Passavant ridge, aberrant pulsations, and dorsal palatal notch. The individual ratings are presented graphically to demonstrate the range of individual responses as well as to compare responses to the consensus ratings. No further changes were made to the proposed consensus ratings when reviewed by the larger group. CONCLUSIONS: Rating of NE evaluations of velopharyngeal function was variable among a group of pediatric otolaryngologists experienced in treating velopharyngeal insufficiency. These results highlight the need to develop a standardized method of reporting NE findings for velopharyngeal insufficiency. Despite this, consensus ratings were achieved that will facilitate development of a video instruction tool.

Clinicopathological characteristics of extramedullary acute megakaryoblastic leukemia (AMKL): report of a case with initial mastoid presentation and review of literature to compare extramedullary AMKL and non-AMKL cases.

Extramedullary acute megakaryoblastic leukemia (AMKL) is a rare neoplasm with a varied clinical presentation. AMKL with initial mastoid presentation has never been reported. The extreme rarity of mastoid AMKL, together with the tendency of extramedullary AMKL to mimic other small blue cell tumors, can create a diagnostic challenge. We report a case of AMKL that initially presented as a mastoid lesion and provide a comprehensive review and analysis that compares the characteristics of extramedullary AMKL and nonmegakaryoblastic acute myeloid leukemia (AML) in reported pediatric cases over the past 30 years. We found that patients with extramedullary AMKL were not only younger than patients without megakaryocytic differentiation but were also limited to those ≤ 2 years of age. In addition, girls predominated in both AMKL and AML MLL(+) groups compared with other types of AML (P  =  0.0366 and P  =  0.0082). Furthermore, we found that extramedullary AMKL was more likely to involve bone than AML MLL(+) (P < 0.0001) or other types of AML (P  =  0.0002). These findings suggest that extramedullary AMKL should be considered in the differential diagnosis of SBCT in children, especially in patients with mastoid or other bony lesions, those ≤ 2 years of age, and female patients.

Pediatric vocal fold paralysis after cardiac surgery: rate of recovery and sequelae.

OBJECTIVE: To determine the rate of recovery of pediatric vocal fold paralysis (VFP) after cardiac surgery. STUDY DESIGN AND SETTING: Retrospective case series from January 2000 to 2005 at 4 tertiary care pediatric hospitals. RESULTS: A total of 109 children with VFP were identified. Of 80 patients with follow-up >3 months, 28 (35%) recovered vocal fold function with a median time to diagnosis of recovery of 6.6 months. Fifty-two (65%) patients had persistent vocal fold paralysis with a median follow-up time of 16.4 months. Twenty-five (45%) of 55 patients demonstrated aspiration or laryngeal penetration with modified barium swallow. Twenty-nine (27%) of the 109 patients underwent surgical intervention for their airway, feeding, or voice. CONCLUSIONS: Pediatric VFP is not an uncommon complication after cardiac surgery and can result in serious sequelae. This study demonstrates a 35% rate of recovery, 45% rate of aspiration, and 27% rate of complications that require surgical intervention.

Interrater and intrarater reliability in the evaluation of velopharyngeal insufficiency within a single institution.

OBJECTIVE: To explore the interrater and intrarater reliability in nasoendoscopic assessment of velopharyngeal (VP) function using the standardized reporting method described by Golding-Kushner within a single institution. DESIGN: Prospective blinded study. SETTING: Academic, tertiary care, pediatric hospital. PARTICIPANTS: Six health care providers (2 pediatric otolaryngology faculty members, 2 pediatric otolaryngology fellows, and 2 speech pathologists) independently rated 50 videotaped nasoendoscopy segments twice. The segments on the videotape were obtained in a clinical setting. MAIN OUTCOME MEASURES: The Golding-Kushner rating system was used to rate VP function. Raters described VP closure quantitatively by rating palatal and lateral pharyngeal wall movement for each segment. They also qualitatively described characteristics of the VP gap, rated gap size as none, small, medium, or large, and estimated the percentage gap size relative to the resting position. Reliability coefficients were calculated for the data sets. RESULTS: Fairly good interrater and intrarater reliability was seen in the quantitative measures. Faculty otolaryngologists rated segments more similarly to each other than did pediatric otolaryngology fellows, but intrarater reliability was similar for both the experienced and less experienced otolaryngologists. Less consistency was seen in the ratings of the speech pathologists. Raters tended to rate with less consistency when describing qualitative characteristics of the VP gap than when making quantitative measurements. CONCLUSIONS: The Golding-Kushner scale is a reasonably reliable tool for reporting nasoendoscopic findings at our institution. However, these data also indicate that there exists room for improvement and that rater training may increase reliability.

Partial promontory technique in stapedotomy cases with narrow niche.

OBJECTIVE: The objective of this study was to examine clinical and audiometric outcomes of a laser partial promontory technique in stapedotomy cases with a narrow oval window niche. STUDY DESIGN: We conducted a retrospective chart review. SETTING: This study was conducted at a tertiary referral center. PATIENTS: We studied 59 patients who underwent a partial promontory technique with stapedotomy between 1994 and 2000. Seventy-two patients who underwent primary stapedotomy without promontory technique served as a control group. METHODS: Preoperative and postoperative audiometric results were obtained for 59 patients undergoing laser stapedotomy with a narrow oval window niche. The partial promontory removal was performed with a KTP laser. Results were compared with 72 primary laser stapedotomy cases without the promontory technique within the same time period and analyzed using paired Student t test. RESULTS: Ninety percent of the partial promontory cases were successful (air-bone gap [ABG] <10 dB). The mean postoperative ABG was 5.1 dB, which was comparable to the non-promontory cases (p = 0.7). The mean change in postoperative bone conduction was also comparable (p = 0.98). There were no cases of sensorineural hearing loss. An overhanging facial nerve was present in 32% of the narrow niche cases and a dehiscent facial nerve was encountered in 17% of these cases. CONCLUSIONS: Partial laser removal of the promontory as an adjunct to laser stapedotomy cases with a narrow oval window niche is a safe, effective technique with comparable results to primary laser stapedotomy.

Prevention and correction of nasal tip bossae in rhinoplasty.

OBJECTIVE: To describe our experiences with nasal tip bossae, suggest a standard nomenclature, discuss causative factors, and provide a comprehensive, analytic approach to the prevention and correction of bossae. BACKGROUND: Nasal tip bossae are knoblike protuberances of the alar cartilages that can arise after rhinoplasty. Early bossae are due to uncorrected or inadvertently created asymmetries, while late bossae are due to fibrosis and scar contracture acting on a weakened or unreconstituted cartilaginous framework. Numerous techniques may be used to prevent and treat bossae; however, we found no article in the existing literature that presents an in-depth, analytic description of management techniques. METHODS: We analyzed the predisposing factors and techniques leading to bossa formation and studied principles of prevention and correction. All rhinoplasty cases that presented for revision from 1985 through 2000 were reviewed for bossae formation via internal computer search. Previous operative records for rhinoplasty cases were examined when available. Intraoperative notes and photgraphs of the revision surgery were examined. RESULTS: Etiologies for bossae were consistently found, and successful treatment modalities were noted. CONCLUSIONS: Nasal tip bossae are most often due to dynamic forces acting on iatrogenic changes and/or weakness in the alar cartilages. By minimizing cartilage excision, reinforcing areas of weakness, avoiding asymmetry and irregularity, and maintaining alar integrity, formation of bossae may be prevented. The treatment of bossae must be individualized and can range from simple suture stabilization techniques to complex domal cartilage replacement grafts, depending on the observed defect.