Dylan K. Chan

GJB2‐associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype

To perform a systematic review of GJB2‐associated hearing loss to describe genotype distributions and auditory phenotype.

Supraglottoplasty for Occult Laryngomalacia to Improve Obstructive Sleep Apnea Syndrome

OBJECTIVE To evaluate the polysomnographic outcomes after supraglottoplasty (SGP) performed for obstructive sleep apnea syndrome (OSAS) associated with occult laryngomalacia. DESIGN Retrospective case series with medical chart review. SETTING Tertiary pediatric medical center. PATIENTS Twenty-two patients aged 2 to 17 years met the inclusion criteria of polysomnography-proven OSAS and occult laryngomalacia seen on flexible fiber-optic sleep endoscopy. Infants with congenital laryngomalacia were excluded. INTERVENTION Carbon dioxide laser SGP was performed either alone or in conjunction with other operations for OSAS. MAIN OUTCOME MEASURE Preoperative and postoperative nocturnal polysomnographic data were paired and analyzed statistically. RESULTS Supraglottoplasty for occult laryngomalacia resulted in statistically significant reduction in the apnea-hypopnea index (AHI) (from 15.4 to 5.4) (P <.001). Subgroup analysis of children who underwent either SGP alone or in combination with other interventions showed comparable reductions in AHI. Medical comorbidities were associated with worsened postoperative outcomes, although still significantly improved compared with baseline. Overall, 91% of children had an improvement in AHI, and 64% had only mild or no residual OSAS after SGP. CONCLUSION Supraglottoplasty is an effective technique for the treatment of OSAS associated with occult laryngomalacia.

AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity.

Hypothesis: Delivery of the gene encoding X-linked inhibitor of apoptosis (XIAP) using an adeno-associated viral (AAV) vector can protect against cisplatin-mediated ototoxicity. Background: Cisplatin is a widely used chemotherapeutic agent with significant ototoxic side effects. One possible mechanism of toxicity is apoptotic death of many cochlear cell types. Acute treatment with inhibitors of caspases- enzymes critical for apoptosis- has been shown to prevent hearing loss in vivo, but is too short-acting for therapeutic use. Gene therapy provides a specific and chronic means of delivering potential therapeutic gents. Introducing an anti-apoptotic gene into the cochlea could provide long-term prophylaxis against the ototoxic effects of cisplatin. Method: Two groups of rats were treated with unilateral injection into the round window of AAV harboring a gene encoding either XIAP or green fluorescent protein (GFP). After at least two months of gene expression, auditory-brainstem-response (ABR) threshold shifts and outer-hair-cell (OHC) number were measured in these two groups of animals after 72-hour treatment with cisplatin. Results: Consistent with previous reports, uninjected and AAV.GFP-injected ears displayed profound ABR threshold elevations and OHC loss after cisplatin treatment. Ears that had been injected with AAV encoding XIAP, however, were significantly protected from these effects: cisplatin-induced ABR-threshold shift and hair-cell loss were attenuated by as much as 78% and 45%, respectively, when compared with contralateral (untreated) ears. Conclusion: XIAP delivery to the cochlea can protect against the audiometric changes and hair-cell loss associated with cisplatin ototoxicity. The efficacy, specificity, and duration of the protective effects make this a potentially attractive therapeutic paradigm.

Connexin-26–associated deafness: Phenotypic variability and progression of hearing loss

Purpose: To evaluate genotype-phenotype correlation over time for a cohort of children with connexin-26 (GJB2)–associated autosomal recessive hearing loss.Methods: Fifty-two children were identified from a database of individuals with homozygous or compound heterozygous mutations in GJB2 and subjected to chart review of their otolaryngologic and serial audiometric evaluations. Genotype-phenotype correlations were identified among the members of this group by appropriate statistical analyses.Results: Hearing loss was most severe in individuals with two truncating mutations in GJB2 and mildest in those with two nontruncating mutations. Progressive hearing loss was seen directly by serial audiometry in 24% of all subjects, and suggested in a total of 28% when those with normal newborn hearing screens and subsequent hearing loss were included. Progression was particularly common among carriers of the p.V37I allele either in homozygosity or in compound heterozygosity with a truncating allele; these children are primarily of Asian descent and demonstrate mild, slowly progressive hearing loss.Conclusions: Phenotype in GJB2-associated hearing loss is correlated with genotype, with truncating mutations giving rise to more severe hearing loss. Progression of hearing loss is not uncommon, especially in association with the p.V37I allele. These results suggest that close audiometric follow-up is warranted for patients with GJB2-associated recessive hearing loss.

Protection against cisplatin-induced ototoxicity by adeno-associated virus-mediated delivery of the X-linked inhibitor of apoptosis protein is not dependent on caspase inhibition.

Hypothesis: Gene therapy with an adeno-associated viral (AAV) vector encoding the X-linked inhibitor of apoptosis protein (XIAP) in an animal model of cisplatin-induced ototoxicity can elucidate apoptotic pathways in the inner ear. Background: Cisplatin is limited clinically by ototoxicity associated with apoptosis in the inner ear. The relevant intracellular apoptotic pathways, however, are unknown. XIAP is an antiapoptotic protein that both inhibits caspases and reciprocally regulates the proapoptotic Smac/Omi proteins. AAV-mediated delivery of various XIAP mutants could distinguish between these antiapoptotic pathways in the ear and further the development of specific reagents for gene therapy- mediated prevention of cisplatin-induced ototoxicity. Methods: We administered unilaterally through the round-window AAV-harboring genes encoding wild-type dXIAP, yellow fluorescent protein, or either of two dXIAP point mutants-one deficient in caspase inhibition (dXIAP-d) and the other additionally deficient in the binding of Smac/Omi (dXIAP-t). All rats received a 3-day systemic course of cisplatin. Functional hearing loss was measured by shifts in auditory brainstem response (ABR) thresholds after cisplatin treatment, and hair-cell loss was assessed by whole-mount phalloidin staining of cochlear turns. Results: Uninjected ears universally displayed high-frequency-specific hair-cell loss and ABR threshold shifts upon cisplatin treatment. Although yellow fluorescent protein had no effect, ears injected with dXIAP exhibited 68% less ABR threshold shift at 32 kHz and 50% less basal-turn outer-hair-cell loss compared with contralateral untreated ears. This protection was maintained in ears injected with dXIAP-d but was abolished in those expressing dXIAP-t, which is incapable of blocking Smac/Omi. Conclusion: Hair-cell apoptosis induced by cisplatin involves the Smac/Omi pathway. Thus, gene therapy with either wild-type dXIAP or Smac/Omi-selective dXIAP-d may be effective to protect against cisplatin-mediated ototoxicity.

Effect of Obesity and Medical Comorbidities on Outcomes After Adjunct Surgery for Obstructive Sleep Apnea in Cases of Adenotonsillectomy Failure

OBJECTIVE To evaluate the effect of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and medical comorbidities on outcomes after lingual tonsillectomy and supraglottoplasty performed for obstructive sleep apnea syndrome (OSAS) caused by lingual tonsillar hypertrophy and occult laryngomalacia. DESIGN Retrospective case review series SETTING Academic tertiary referral center PATIENTS Children with persistent OSAS after adenotonsillectomy who underwent surgery to correct obstruction at the level of the lingual tonsils and/or supraglottis identified on sleep endoscopy. INTERVENTIONS All children underwent lingual tonsillectomy, supraglottoplasty, or both. MAIN OUTCOME MEASURES Change in polysomnographic parameters, including apnea-hypopnea index (AHI), number of nighttime apneas, and lowest oxygen saturation level. RESULTS We analyzed the medical records of 84 children with persistent OSAS after adenotonsillectomy who underwent either lingual tonsillectomy (n = 68), supraglottoplasty (n = 24) or both (n = 8). Compared with children with lingual tonsillar hypertrophy, children with occult laryngomalacia were younger, had lower BMI, and were more likely to have a medical comorbidity. Overall, both operations significantly improved the AHI; however, children with comorbidities had significantly higher postoperative AHIs after supraglottoplasty than those without, and overweight children had significantly higher postoperative AHIs after lingual tonsillectomy than those of normal weight. The BMI z-score and age had direct, though weak, correlations with postoperative AHI among all children undergoing either technique of adjunct airway surgery. CONCLUSIONS Lingual tonsillar hypertrophy and occult laryngomalacia are 2 important causes of residual OSAS after adenotonsillectomy. However, they tend to affect distinct populations of children, and though appropriate surgical correction can improve AHI, cure rates are significantly worse for overweight children undergoing lingual tonsillectomy and for children with medical comorbidities undergoing supraglottoplasty.

A New Scoring System for Upper Airway Pediatric Sleep Endoscopy

IMPORTANCE Sleep-associated upper-airway obstruction in children is a significant cause of morbidity. Development of a simple, standardized, quantitative technique to assess anatomic causes of sleep-related breathing disorder is important for surgical planning, clinical communication, and research. OBJECTIVE To design, implement, and evaluate a scoring system to quantify airway obstruction in pediatric drug-induced sleep endoscopy. DESIGN, SETTING, AND PARTICIPANTS This study was a retrospective case series conducted at a tertiary pediatric hospital. The patients were children with sleep-related breathing disorder who underwent polysomnography and drug-induced sleep endoscopy. INTERVENTIONS Flexible fiber-optic laryngoscopy was performed. Endoscopic examinations were recorded on video and assessed by 4 independent raters based on a scoring template. MAIN OUTCOMES AND MEASURES Five locations in the upper aerodigestive tract (adenoid, velum, lateral pharyngeal wall, tongue base, and supraglottis) were evaluated on a 4-point scale for minimum and maximum obstruction. Internal reliability was assessed by calculating interrater and intrarater intraclass correlation coefficients (ICCs). For external validation, aggregate and site-specific scores were correlated with preoperative polysomnographic indices. RESULTS Videos recorded of sleep endoscopies from 23 children (mean age, 2.2 years) were reviewed and rated. Children had an average apnea-hypopnea index of 24.8. Seventy percent of interrater and intrarater ICC values (7 of 10 for each set) were above 0.6, demonstrating substantial agreement. Higher total obstructive scores were associated with lower oxygen saturation nadir (P = .04). The scoring system was also used to quantitatively identify children with multilevel airway obstruction, who were found to have significantly worse polysomnographic indices compared with children with single-level obstruction (P = .02). CONCLUSIONS AND RELEVANCE The proposed scoring system, which is designed to be easy to use and allow for subjectivity in evaluating obstruction at multiple levels, nonetheless achieves good internal reliability and external validity. Implementing this system will allow for standardization of reporting for sleep endoscopy outcomes, as well as aid the practicing clinician in the interpretation of sleep endoscopy findings to inform site-directed surgical intervention in cases of complicated obstructive sleep apnea.

Perioperative ketorolac increases post-tonsillectomy hemorrhage in adults but not children.

To evaluate the risk of post‐tonsillectomy hemorrhage associated with perioperative ketorolac use.

Diagnostic yield in the workup of congenital sensorineural hearing loss is dependent on patient ethnicity.

Hypothesis: Diagnostic yield on GJB2 sequencing and computed tomography in the workup for idiopathic congenital sensorineural hearing loss is related to patient ethnicity. Background: GJB2 sequencing and computed tomography of the temporal bones are important initial diagnostic tests in the workup of idiopathic congenital sensorineural hearing loss. Previous studies showed an association between mild or unilateral hearing loss and positive imaging findings and between severe or bilateral deafness and GJB2 mutations. Recent studies on connexin 26-associated deafness demonstrate a wide range of phenotypes that vary with ethnicity. Methods: We present a retrospective case series of 271 consecutive ethnically diverse patients evaluated for idiopathic congenital sensorineural hearing loss. Results of genetic testing and imaging were correlated with audiologic findings and ethnicity. Results: All patients with asymmetric hearing loss had more positive findings on imaging. With respect to the severity of hearing loss, however, differences were noted between ethnic groups. Whereas white patients conformed to previous findings, Hispanics with severe hearing loss had similar rates of positive imaging and genetic testing results. Asians with mild hearing loss had significantly greater yield on genetic testing rather than on imaging. This reflects the high prevalence of the p.V37I mutation in GJB2 among Asians, which gives rise to a mild, frequently progressive phenotype. Conclusion: Ethnicity should be considered when determining the optimal sequence of diagnostic testing for idiopathic congenital sensorineural hearing loss. Asian patients, in particular, should all be screened for mutations in GJB2, especially in the case of mild hearing loss.

Airway response to sirolimus therapy for the treatment of complex pediatric lymphatic malformations.

Head and neck lymphatic malformations can create airway management challenges requiring tracheotomy. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), may inhibit growth of lymphatic malformations. We describe two patients born with large lymphatic malformations with improved airway symptoms following sirolimus therapy. Patient #1 underwent tracheotomy and multi-modal therapy including sirolimus with reduction in airway involvement but regrowth after discontinuation of sirolimus. Patient #2 also experienced a significant response to sirolimus allowing for extubation and discharge without tracheotomy. Early initiation of sirolimus therapy should be considered as a means to avoid tracheotomy in complex head and neck lymphatic malformations.