The management of pediatric Graves' disease.

PURPOSE OF REVIEW: Graves' disease (GD) constitutes a significant proportion of thyroid disorders seen during childhood. Several specialties may be closely involved in the management of pediatric patients with GD and emerging research in each field contributes to variations in the approach over time. Here we review the recent literature on the management of the disease, with the hope that this can be a valuable resource for treating specialists who need to be continuously updated on new data obtained in relevant fields. RECENT FINDINGS: Genetic, postinfectious and environmental factors may play a role in the immunological pathophysiology of GD. Research performed during the COVID-19 pandemic supports that viral-induced immune dysregulation may be a possible trigger for the disease. The various current treatment options all have positive and negative factors to consider. Antithyroidal drug therapy (ATD) is generally recommended as the initial treatment, although remission rates are only 20-30% at 2 years and 75% at 9 years. Unfortunately, about half of patients will relapse within 1 year of discontinuing therapy. Radioactive iodine therapy (RAI) is an effective treatment option and can be considered in certain pediatric patients. There continues to be no definitive evidence that the doses used for GD lead to a higher risk of cancer. Surgical treatment via thyroidectomy is effective and safe when performed by a high-volume surgeon. Recent studies show improvement in quality-of-life after surgery in adolescents and young adults. Future medical treatment options for GD currently being studied include antigen-specific immunotherapy and monoclonal antibodies. SUMMARY: Although the future holds promising new therapeutic options for autoimmune diseases including GD, the current choices continue to be ATD, usually first-line, and definitive treatments including RAI and surgery. While all three offer the possibility of remission or cure, drug therapy and RAI have a possibility of relapse. Risks of each approach should be broached in detail with patients and their families, and the nuances of treating this disease specifically in children should be familiar to all treating providers.

Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations.

Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell­derived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

Pediatric intraoperative nerve monitoring during thyroid surgery: A review from the American Head and Neck Society Endocrine Surgery Section and the International Neural Monitoring Study Group.

Children are more likely to experience recurrent laryngeal nerve (RLN) injury during thyroid surgery. Intraoperative nerve monitoring (IONM) may assist in nerve identification and surgical decision making. A literature review of pediatric IONM was performed and used to inform a monitoring technique guide and expert opinion statements. Pediatric IONM is achieved using a variety of methods. When age-appropriate endotracheal tubes with integrated surface electrodes are not available, an alternative method should be used. Patient age and surgeon experience with laryngoscopy influence technique selection; four techniques are described in detail. Surgeons must be familiar with the nuances of monitoring technique and interpretation; opinion statements address optimizing this technology in children. Adult IONM guidelines may offer strategies for surgical decision making in children. In some cases, delay of second-sided surgery may reduce bilateral RLN injury risk.

Prevalence and Risk Factors for Multifocality in Pediatric Thyroid Cancer.

Importance: Current guidelines recommend total thyroidectomy for the majority of pediatric thyroid cancer owing to an increased prevalence of multifocality. However, there is a paucity of information on the exact prevalence and risk factors for multifocal disease-knowledge that is critical to improving pediatric thyroid cancer management and outcomes. Objective: To determine the prevalence and risk factors for multifocal disease in pediatric patients with papillary thyroid carcinoma (PTC). Design, Setting, and Participants: This multicenter retrospective cohort study included patients 18 years or younger who underwent thyroidectomy for PTC from 2010 to 2020 at 3 tertiary pediatric hospitals and 2 tertiary adult and pediatric hospitals in the US. Main Outcomes and Measures: Demographic and clinical variables, including age, family history of thyroid cancer, autoimmune thyroiditis, prior radiation exposure, cancer predisposition syndrome, tumor size, tumor and nodal stage, PTC pathologic variant, and preoperative imaging, were assessed for association with presence of any multifocal, unilateral multifocal, and bilateral multifocal disease using multiple logistic regression analyses. Least absolute shrinkage and selection operator analysis was performed to develop a model of variables that may predict multifocal disease. Results: Of 212 patients, the mean age was 14.1 years, with 23 patients 10 years or younger; 173 (82%) patients were female. Any multifocal disease was present in 98 (46%) patients, with bilateral multifocal disease in 73 (34%). Bilateral multifocal disease was more accurately predicted on preoperative imaging than unilateral multifocal disease (48 of 73 [66%] patients vs 9 of 25 [36%] patients). Being 10 years or younger, T3 tumor stage, and N1b nodal stage were identified as predictors for multifocal and bilateral multifocal disease. Conclusions and Relevance: This large, multicenter cohort study demonstrated a high prevalence of multifocal disease in pediatric patients with PTC. Additionally, several potential predictors of multifocal disease, including age and advanced T and N stages, were identified. These risk factors and the high prevalence of multifocal disease should be considered when weighing the risks and benefits of surgical management options in pediatric patients with PTC.

Management of Pediatric Graves Disease: A Review.

Importance: The incidence of Graves disease (GD) is rising in children, and adequate care of these patients requires a multidisciplinary approach. Whether patients are seen in the context of endocrinology, nuclear medicine, or surgery, it is important to know the nuances of the therapeutic options in children. Observations: Given the rarity of GD in children, it is important to recognize its various clinical presenting signs and symptoms, as well as the tests that may be important for diagnosis. The diagnosis is typically suspected clinically and then confirmed biochemically. Imaging tests, including thyroid ultrasonography and/or nuclear scintigraphy, may also be used as indicated during care. It is important to understand the indications for and interpretation of laboratory and imaging tools so that a diagnosis is made efficiently and unnecessary tests are not ordered. Clinicians should be well-versed in treatment options to appropriately counsel families. There are specific scenarios in which medical therapy, radioactive iodine therapy, or surgery should be offered. Conclusions and Relevance: The diagnosis and treatment of pediatric patients with GD requires a multidisciplinary approach, involving pediatric specialists in the fields of endocrinology, ophthalmology, radiology, nuclear medicine, and surgery/otolaryngology. Antithyroid drugs are typically the first-line treatment, but sustained remission rates with medical management are low in the pediatric population. Consequently, definitive treatment is often necessary, either with radioactive iodine or with surgery, ideally performed by experienced, high-volume pediatric experts. Specific clinical characteristics, such as patients younger than 5 years or the presence of a thyroid nodule, may make surgery the optimal treatment for certain patients.

Drug-Induced Sleep Endoscopy Findings in Children With Obstructive Sleep Apnea With vs Without Obesity or Down Syndrome.

Importance: Persistent obstructive sleep apnea after adenotonsillectomy is common in children with Down syndrome or obesity. Drug-induced sleep endoscopy could help to identify anatomic differences in these patients that might affect surgical decision-making. Objective: To assess drug-induced sleep endoscopy findings in surgically naive children with obstructive sleep apnea with obesity or Down syndrome and compare these findings with children without obesity or Down syndrome. Design, Setting, and Participants: This cross-sectional analysis of data from a prospective cohort study of patients enrolled between May 1, 2015, and December 31, 2019, was conducted at an academic tertiary care children's hospital and included a consecutive sample of surgically naive children (age 2-18 years) who underwent drug-induced sleep endoscopy at the time of adenotonsillectomy for sleep-disordered breathing. Indications for sleep endoscopy included severe sleep apnea, age older than 7 years, obesity, African American race, and Down syndrome. Exposures: Drug-induced sleep endoscopy. Main Outcomes and Measures: Sleep endoscopy findings were scored according to the Sleep Endoscopy Rating Scale. Ratings at 6 anatomic levels for children with obesity and those with Down syndrome were compared with controls without obesity or Down syndrome using several measures of effect size (Cohen d, Cramer V, and η2). Results: A total of 317 children (158 girls [50%]; 219 [69%] White, 20 [6%] Black, and 103 [34%] Hispanic; mean [95% CI] age, 9.6 [9.2-10.0] years) were included, of whom 115 (36%) were controls without obesity or Down syndrome, 179 (56%) had obesity without Down syndrome, and 23 (7%) had Down syndrome. The mean apnea-hypopnea index was 16 (95% CI, 13-19), and the mean minimum O2 saturation was 83% (95% CI, 81%-85%). Compared with controls without obesity or Down syndrome, children with Down syndrome demonstrated greater overall obstruction (mean sleep endoscopy rating scale total score of 5.6 vs 4.8; Cohen d, 0.46), and greater tonsillar (percentage of complete obstruction: 65% vs 54%), tongue base (percentage of complete obstruction: 26% vs 12%), and arytenoid obstruction (percentage of at least partial obstruction, 35% vs 6%). Children with obesity had greater tonsillar (percentage of complete obstruction, 74% vs 54%) and less base of tongue obstruction (percentage of complete obstruction, 2% vs 12%) compared with controls. Conclusions and Relevance: In this cohort study, surgically naive children with obesity with obstructive sleep apnea had predominantly tonsillar obstruction, whereas children with Down syndrome demonstrated greater obstruction of the tonsils, tongue base, and arytenoids compared with controls. Routine drug-induced sleep endoscopy should be considered in surgically naive children with Down syndrome to help inform the surgical plan.

Needlestick Injury in Otolaryngology-Head and Neck Surgery Resident Programs.

OBJECTIVES/HYPOTHESIS: Up to 800,000 percutaneous injuries involving healthcare workers occur each year. The morbidity of needlestick injuries (NSIs) ranges from nothing to death. The incidence of NSI in otolaryngology residency is deemed to be high based on prior studies. This study aimed at defining the trends in otolaryngology residents regarding sharps exposure. STUDY DESIGN: Cross-sectional study using survey/questionnaire. METHODS: Otolaryngology accredited residency programs in North America were surveyed in 2013 and 2017 regarding their experience with NSI and perceived risk of acquiring a blood-borne infection. RESULTS: Surveys were received from 314 residents (31 programs). There was a total of 509 needlesticks, primarily occurring during junior years (post-graduate year 1-3, 81%). Sixty-eight percent of residents had experienced an NSI. Of the residents that had an injury, the mean number of sticks was 2.37 sticks/resident. Junior residents were less likely to report their injury compared to senior residents (50% vs. 30%). The primary reason for not reporting was the time commitment. Residents underestimated their risk of acquiring human immunodeficiency virus (51% of residents) and overestimated their risk of acquiring hepatitis C virus (90% of residents). CONCLUSIONS: Occupational exposure is high in healthcare and particularly high in surgical trainees. The majority of otolaryngology trainees undergo a needlestick injury in their junior years. There continues to be underreporting of these injuries by residents, who report that the process is too time-consuming. Most residents do not have an accurate understanding of their actual risk of acquiring a blood-borne disease. These findings emphasize the need for education regarding risks and development of strategies to encourage reporting of injuries. LEVEL OF EVIDENCE: VI Laryngoscope, 131:E1076-E1080, 2021.

Immediate and partial neural dysfunction after thyroid and parathyroid surgery: Need for recognition, laryngeal exam, and early treatment.

BACKGROUND: Laryngeal dysfunction after thyroid and parathyroid surgery requires early recognition and a standardized approach for patients that present with voice, swallowing, and breathing issues. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to define the terms "immediate vocal fold paralysis" and "partial neural dysfunction" and to provide clinical consensus statements based on review of the literature, integrated with expert opinion of the group. METHODS: A multidisciplinary expert panel constructed the manuscript and recommendations for laryngeal dysfunction after thyroid and parathyroid surgery. A meta-analysis was performed using the literature and published guidelines. Consensus was achieved using polling and a modified Delphi approach. RESULTS: Twenty-two panelists achieved consensus on five statements regarding the role of early identification and standardization of evaluation for patients with "immediate vocal fold paralysis" and "partial neural dysfunction" after thyroid and parathyroid surgery. CONCLUSION: After endorsement by the AHNS Endocrine Section and Quality of Care Committee, it received final approval from the AHNS Council.

Congenital Neck Masses.

Congenital neck masses can be a developmental anomaly of cystic, solid, or vascular origin. They can also constitute neoplasms, including malignancies, although this is rare in the pediatric population. The history and examination can help quickly narrow the differential diagnosis. Imaging also plays an essential role in defining the characteristics and likely cause of neck masses. The most common neck masses in young children are thyroglossal duct cysts, branchial cleft anomalies, and dermoid cysts. Also important to consider in the differential diagnosis are solid tumors, such as teratomas, or vascular lesions, such as hemangiomas.

Opioid Prescribing Practice and Needs in Thyroid and Parathyroid Surgery.

Importance: In recent years, the medical community's inadvertent contribution to opioid addiction has been recognized. Objective: To determine the opioid prescribing practices and opioid needs for patients undergoing thyroid and parathyroid surgery to help reduce postoperative opioid administration. Design, Setting, and Participants: This retrospective cohort study included 1788 opioid-naive patients who underwent thyroid and parathyroid surgery from January 1, 2012, through December 31, 2017, at the high-volume academic endocrine surgery center at Oregon Health and Sciences University. Patients with long-term opioid treatment and those who underwent other head and neck procedures or robotic thyroidectomy were excluded. For analysis, 1765 procedures were available (723 parathyroidectomy, 400 hemithyroidectomy, and 642 total thyroidectomy). Main Outcomes and Measures: The quantity of prescribed opioids was determined in morphine milligram equivalents (MME). Opioid refill data after discharge were also analyzed. Patients were then divided into past (1336 in group 1 [January 1, 2012, to September 30, 2016]) and current (429 in group 2 [October 31, 2016, to December 31, 2017]) prescribing practices. For each procedure, the mean quantity prescribed for each group, difference between the means, 95% CI for the difference, and effect size were calculated. Results: A total of 1702 patients (80.0% female [n = 1361]; mean age, 51.2 years [range, 7-97 years]) undergoing 1765 procedures were included in the analysis. For parathyroidectomy, the mean (SD) opioid quantity prescribed was 176.20 (86.66) MME in group 1 vs 80.08 (74.43) MME in group 2 (effect size, 1.139); for hemithyroidectomy, 204.65 (112.24) MME in group 1 vs 112.24 (102.31) MME in group 2 (effect size, 0.842); and for total thyroidectomy, 214.87 (161.09) MME for group 1 vs 102.29 (87.72) MME for group 2 (effect size, 0.754). In the last quarter of 2017, the numbers of patients discharged without any opioid prescription were 15 of 26 (57.5%) for parathyroidectomy, 12 of 32 (37.5%) for hemithyroidectomy, and 9 of 27 (33.3%) for total thyroidectomy. Patient calls requesting pain medications for group 2 were similar or fewer, depending on the procedure. Those who were prescribed less than 75.0 MME postoperatively did not call for additional opioid prescriptions. Conclusions and Relevance: Our study suggests that patients undergoing thyroid and parathyroid surgery need little, if any, postoperative opioids.

Chronic Rhinosinusitis in Children.

PURPOSE OF REVIEW: Pediatric chronic rhinosinusitis (CRS) is a common condition that is often misdiagnosed and can be challenging to treat. This review aims to 1) Review definitions, presentation, complications, and management of CRS in children. 2) Highlight the paucity of evidence in the management of pediatric CRS. RECENT FINDINGS: There are few studies supporting the usual recommended medical therapy for pediatric CRS (antibiotics, nasal saline irrigations, intranasal steroid). Adenoidectomy remains a mainstay of surgical treatment, but recent evidence demonstrates the utility of balloon sinuplasty and functional endoscopic sinus surgery (FESS) for patients who fail adenoidectomy alone. SUMMARY: Pediatric CRS is distinct from ARS and adult CRS. It is a common problem that is poorly studied, in part because of significant symptomatic overlap with related conditions. Recent evidence supports the use of surgical treatment in children who fail medical management. However, further outcome studies are needed to better evaluate the effectiveness of current medical and surgical management protocols.

Pediatric post-tonsillectomy hemorrhage in the setting of post-transplantation immunosuppression.

INTRODUCTION: Long-term immunosuppressants form an integral part of therapy for post-transplantation patients. Immunosuppressants may also have an anticoagulant effect, and little is known about their effects on bleeding risk after adenotonsillectomy. Our objective was to investigate whether there is an increased observed rate of post-tonsillectomy hemorrhage in a population of pediatric patients on long-term immunosuppressants after solid organ transplantation, compared to healthy controls. METHODS: This was a retrospective chart review of pediatric patients with a history of renal or heart transplant undergoing adenotonsillectomy at our institution between 2000 and 2014. All patients underwent tonsillectomy with monopolar electrocautery. Retrieved data included perioperative medications, occurrence of post-operative bleeding and associated treatment. For comparison, we obtained a population of age-matched controls with no history of immunosuppression who underwent the same procedure. RESULTS: A total of 34 patients meeting criteria were identified, of which 3 (8.82%) suffered a postoperative bleed. Forty-seven controls were obtained, with a total of 2 (4.26%) postoperative hemorrhages (p = 0.65). Two of the post-transplantation patients who bled postoperatively required cauterization in the operating room. None of the controls required surgical treatment. The incidences of postoperative bleeding requiring surgical treatment were 5.88% and 0%, respectively (p = 0.17). CONCLUSION: We failed to demonstrate an increased risk of bleeding after undergoing adenotonsillectomy in our cohort of post-transplantation pediatric patients on chronic immunosuppression. Future research, likely requiring a multi-institutional effort, could stratify by immunosuppressive agent to elucidate bleeding risk with specific medications.

Characteristics of superior orbital subperiosteal abscesses in children.

OBJECTIVES/HYPOTHESIS: Superior pediatric orbital subperiosteal abscesses (SPAs) are less common than medial ones, and clinical features specific to patients with superior SPAs have not been well defined. Clinical characteristics between patients with superior and medial SPAs are compared to determine whether superior location is a risk factor for surgical intervention. STUDY DESIGN: Retrospective cohort study. METHODS: The target population consisted of patients diagnosed with an SPA and seen by the pediatric otolaryngology service at a tertiary children's hospital between January 2010 and October 2014. Imaging characteristics including proptosis, hypoglobus, intraorbital air, and abscess volume as well as treatment interventions were reviewed. RESULTS: Forty patients between 5 and 17 years of age treated for an orbital SPA were identified. Thirteen patients were identified as having superior SPAs; 27 had medial SPAs. The average ages in the two groups were 10.92 and 9.26 years, respectively. The odds ratio for surgical treatment per each increasing year of age was 1.5 (P = .004). The proportion of patients requiring surgery was significantly different between the groups (12/13 superior vs. 13/27 medial, P = .01). The predominant organism group cultured in surgical patients was Streptococcus anginosus (8/24, 29.17%). Superior SPA patients had significantly more proptosis, hypoglobus, and abscess volume on computed tomography scan. CONCLUSIONS: Patients with superior SPAs may present with more advanced disease, leading to a higher rate of characteristics such as proptosis, hypoglobus, and intraorbital air, factors that would predispose to surgical drainage. We found that abscess volume was the most predictive of surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:735-740, 2017.

Surgical Approaches to First Branchial Cleft Anomaly Excision: A Case Series.

Objectives. First branchial cleft anomalies (BCAs) constitute a rare entity with variable clinical presentations and anatomic findings. Given the high rate of recurrence with incomplete excision, identification of the entire tract during surgical treatment is of paramount importance. The objectives of this paper were to present five anatomic variations of first BCAs and describe the presentation, evaluation, and surgical approach to each one. Methods. A retrospective case review and literature review were performed. We describe patient characteristics, presentation, evaluation, and surgical approach of five patients with first BCAs. Results. Age at definitive surgical treatment ranged from 8 months to 7 years. Various clinical presentations were encountered, some of which were atypical for first BCAs. All had preoperative imaging demonstrating the tract. Four surgical approaches required a superficial parotidectomy with identification of the facial nerve, one of which revealed an aberrant facial nerve. In one case the tract was found to travel into the angle of the mandible, terminating as a mandibular cyst. This required en bloc excision that included the lateral cortex of the mandible. Conclusions. First BCAs have variable presentations. Complete surgical excision can be challenging. Therefore, careful preoperative planning and the recognition of atypical variants during surgery are essential.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity.

The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB) or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study.

The objective was to detect changes in cytokine expression within cochleae in a murine model of systemic inflammation, with or without aminoglycoside exposure. Four groups of mice received 1 of the following: saline only, systemic bacterial lipopolysaccharides (LPS) for 6 hours to induce endotoxemia and inflammatory responses, systemic gentamicin for 3 hours, or both treatments. After exsanguination, pooled cochleae (4/group) were processed for enzyme-linked immunosorbent assay (ELISA) for 16 cytokines. Gentamicin alone did not change cochlear cytokine levels, while LPS (± gentamicin) substantially elevated cochlear expression of several cytokines, particularly interleukin-1α, interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and RANTES. Since cytokines increase blood-brain barrier permeability, we hypothesize that cytokine-enhanced permeability of the blood-labyrinth barrier (BLB) could potentiate aminoglycoside-induced ototoxicity. This pilot study demonstrated the feasibility of detecting cytokine expression in murine cochleae using ELISA and facilitates future studies investigating BLB permeability in animal models of systemic inflammation.

HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

Comparison of disease-specific quality-of-life instruments in the assessment of chronic rhinosinusitis.

BACKGROUND: Many disease-specific, quality-of-life (QOL) instruments exist for chronic rhinosinusitis (CRS), resulting in confusion about the best application and use of each instrument. We hypothesized that the most prevalently utilized instruments do not strongly correlate in all domains, but rather act in complementary fashion for QOL assessment. METHODS: A systematic literature review (MEDLINE) was performed to identify the type and frequency of available CRS-specific QOL instruments. Univariate analyses of the 3 most common instruments (Rhinosinusitis Disability Index [RSDI], Chronic Sinusitis Survey [CSS] and 22-item Sinonasal Outcomes Test [SNOT-22]) were performed using a multi-institutional prospective cohort of sinusitis patients. RESULTS: Systematic literature review found that the SNOT-20 (and its derivatives), RSDI, and CSS are the most commonly utilized CRS-specific QOL instruments. The majority of RSDI domains were weakly or not correlated with the CSS domains (r = 0.097-0.501; p < 0.001). In contrast, the RSDI was highly correlated with the SNOT-22 (r ≥ 0.666; p < 0.001). Patients with asthma and/or allergies reported significantly worse CSS scores (p < 0.001). Comorbidities had no significant impact on RSDI or SNOT-22 responses. CONCLUSION: Different disease-specific CRS QOL instruments measure different aspects of the patient's experience. The RSDI and SNOT-22 are more sensitive to measuring the emotional impact of CRS, whereas the CSS examines medication use and symptoms. These instruments play complementary roles in the evaluation of CRS treatment outcomes.