Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss.

Understanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children's hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.

Survey of Pediatric Otolaryngology Frenotomy Practice Patterns.

OBJECTIVES: Assess current frenotomy practice patterns of pediatric otolaryngologists via a cross-sectional survey. STUDY DESIGN: Survey study. METHODS: A 31-question electronic survey assessing frenotomy practice patterns was distributed to all American Society of Pediatric Otolaryngology (ASPO) members. Descriptive statistics were used to summarize responses and demographics of respondents. RESULTS: Of all ASPO members, 41% (240/588) completed the survey. Most respondents, 185 (77%), reported increased frenotomy referrals over the last 5 years and 144 (60%) described the current number of referrals as "too many." The two primary lingual frenotomy indications identified in infants were: breastfeeding/nipple pain (92%) and inability to latch (83%). For older children, speech difficulty (87%) was the primary indication. Maxillary frenotomy indications in infants varied amongst respondents. For analgesia during in-office frenotomy procedures, respondents used glucose/sucrose drops (48%), topical lidocaine (29%), or no pain control measure (27%). For post-procedure care, respondents recommended continuing lactation support (45%), massaging/stretching the wound (38%), or none (40%). Most respondents, 143 (60%), reported having seen a complication from frenotomy, and the most reported frenotomy complications were frenulum re-attachment and excessive bleeding. CONCLUSIONS: In the last 5 years, otolaryngologists have seen an increase in referrals for frenotomy. Pediatric otolaryngologists have varying practice patterns with regards to ankyloglossia diagnosis and treatment. The reported indications for frenotomy varied amongst pediatric otolaryngologists especially with respect to maxillary frenotomy. Practice patterns also varied with respect to procedural pain control and frenotomy aftercare recommendations. More frenotomy research is needed to establish a standard of care for patients with ankyloglossia. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2505-2512, 2022.

Access Challenge Index: A Novel Disparity Measure Predictive of Language Outcomes in Children Who Are Deaf/Hard of Hearing.

OBJECTIVE: To evaluate the effect of demographic disparities on language outcomes in a diverse group of children who are deaf or hard of hearing. STUDY DESIGN: Retrospective cohort study. SETTING: UCSF Benioff Children's Hospital (a tertiary care center). METHODS: Forty-four patients aged <18 years were identified with sensorineural hearing loss managed with a behind-the-ear hearing aid or cochlear implant. Demographic and clinical data were extracted from the medical record. The primary outcome measure was the Preschool Language Scales-5 at least 6 months after intervention. Predictors of language outcome were assessed: hearing level at the time of hearing intervention, cochlear implant status, age of identification and intervention, travel time to site of hearing care, home language, race/ethnicity, insurance type, and Access Challenge Index-a novel measure of educational environment and family support based on the Child Cochlear Implant Profile. Multivariate and univariate analysis assessed predictors for association with intervention and receptive, expressive, and total language scores. RESULTS: Overall 82% of patients had cochlear implants. The median age at hearing intervention was 12 months. The sample was 59% female, 52% non-White, and 61% publicly insured, and 20% had a non-English primary home language. Accounting for multiple demographic and clinical predictors, a high Access Challenge Index score was independently associated with longer time to intervention (P = .01) and poorer language outcomes (P < .001). CONCLUSION: Access Challenge Index-a novel comprehensive measure of educational and family environment-is a strong independent predictor of language outcomes in children who are deaf or hard of hearing.

Extensive airway hemangiomas in two patients without beard hemangiomas.

Airway hemangiomas are most often seen in association with cutaneous hemangiomas involving the "beard area." We report two unusual cases of extensive airway hemangiomas developing in patients with facial hemangiomas predominantly involving the upper face, emphasizing the need to consider the possibility of airway hemangiomas even in the absence of "beard area" hemangiomas.

Genetic Testing Leading to Early Identification of Childhood Ocular Manifestations of Usher Syndrome.

OBJECTIVES: Hearing-loss gene panel testing (HLGPT) is increasingly accessible as a first-line test in determining the etiology of sensorineural hearing loss (SNHL) in children. A major advantage of HLGPT is early identification of syndromic forms of SNHL, especially Usher syndrome, prior to the development of overt syndromic phenotype, which may impact management and counseling. Here, we describe early ocular findings in children with clinically non-syndromic SNHL identified by HLGPT as having two variants associated with Usher Syndrome. METHODS: A total of 184 children, ages 1 month - 15 years of age, evaluated at one tertiary pediatric children's hospital for clinically non-syndromic SNHL, underwent next-generation sequencing of 150 genes involved in hearing loss. Children with two variants in genes associated with Usher syndrome were referred for evaluation by pediatric ophthalmology. RESULTS: A total of 18/184 tested children had two variants in Usher syndrome-associated genes, including MYO7A, GPR98 (ADGRV1), USH2A, and PDZD7. SNHL varied from moderate to profound. 29% of the children who underwent clinical ophthalmology evaluation were found to have previously unidentified retinal abnormalities on retinal imaging or electroretinography consistent with inherited retinal degeneration. CONCLUSION: Among this ethnically and racially diverse pediatric population with apparently non-syndromic SNHL, HLGPT yielded a high proportion (10%) of children with two variants in genes associated with Usher syndrome. Early genetic testing allows early identification of variants conferring a diagnosis of Usher syndrome at a stage prior to visual symptoms. This allows for more informed genetic counseling, reproductive planning, and sensory deficit interventions. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2053-E2059, 2021.

Primary Immunodeficiency in Children With Autoimmune Cytopenias: Retrospective 154-Patient Cohort.

Background: Primary immunodeficiency is common among patients with autoimmune cytopenia. Objective: The purpose of this study is to retrospectively identify key clinical features and biomarkers of primary immunodeficiency (PID) in pediatric patients with autoimmune cytopenias (AIC) so as to facilitate early diagnosis and targeted therapy. Methods: Electronic medical records at a pediatric tertiary care center were reviewed. We selected 154 patients with both AIC and PID (n=17), or AIC alone (n=137) for inclusion in two cohorts. Immunoglobulin levels, vaccine titers, lymphocyte subsets (T, B and NK cells), autoantibodies, clinical characteristics, and response to treatment were recorded. Results: Clinical features associated with AIC-PID included splenomegaly, short stature, and recurrent or chronic infections. PID patients were more likely to have autoimmune hemolytic anemia (AIHA) or Evans syndrome than AIC-only patients. The AIC-PID group was also distinguished by low T cells (CD3 and CD8), low immunoglobulins (IgG and IgA), and higher prevalence of autoantibodies to red blood cells, platelets or neutrophils. AIC diagnosis preceded PID diagnosis by 3 years on average, except among those with partial DiGeorge syndrome. AIC-PID patients were more likely to fail first-line treatment. Conclusions: AIC patients, especially those with Evans syndrome or AIHA, should be evaluated for PID. Lymphocyte subsets and immune globulins serve as a rapid screen for underlying PID. Early detection of patients with comorbid PID and AIC may improve treatment outcomes. Prospective studies are needed to confirm the diagnostic clues identified and to guide targeted therapy.

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

Clinical Consensus Statement: Ankyloglossia in Children.

OBJECTIVE: To identify and seek consensus on issues and controversies related to ankyloglossia and upper lip tie in children by using established methodology for American Academy of Otolaryngology-Head and Neck Surgery clinical consensus statements. METHODS: An expert panel of pediatric otolaryngologists was assembled with nominated representatives of otolaryngology organizations. The target population was children aged 0 to 18 years, including breastfeeding infants. A modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus, per established methodology published by the American Academy of Otolaryngology-Head and Neck Surgery. RESULTS: After 3 iterative Delphi method surveys of 89 total statements, 41 met the predefined criteria for consensus, 17 were near consensus, and 28 did not reach consensus. The clinical statements were grouped into several categories for the purposes of presentation and discussion: ankyloglossia (general), buccal tie, ankyloglossia and sleep apnea, ankyloglossia and breastfeeding, frenotomy indications and informed consent, frenotomy procedure, ankyloglossia in older children, and maxillary labial frenulum. CONCLUSION: This expert panel reached consensus on several statements that clarify the diagnosis, management, and treatment of ankyloglossia in children 0 to 18 years of age. Lack of consensus on other statements likely reflects knowledge gaps and lack of evidence regarding the diagnosis, management, and treatment of ankyloglossia. Expert panel consensus may provide helpful information for otolaryngologists treating patients with ankyloglossia.

Cryoprobe retrieval of an airway foreign body: A case report and literature review.

We report a case of a 7-year-old boy with clinical and radiographic evidence of foreign body (FB) aspiration with a 2-week delay in diagnosis. The retrieval of the pushpin with traditional bronchoscopic instrumentation was made difficult by granulation tissue formation. A cryoprobe through a flexible bronchoscope was used to successfully remove the FB. To our knowledge, this is the first report of interventional bronchoscopy with a cryoprobe to remove a pushpin in a child under suspension laryngoscopy and spontaneous ventilation. A high index of suspicion is crucial for identifying FBs early and minimizing granulation tissue development which complicates FB removal.

Vasculitis in a Child With the Hyper-IgM Variant of Ataxia-Telangiectasia.

A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a "hyper-IgM phenotype" (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.

Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening.

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene-based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5'and 3' untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.

Sleep-disordered breathing in pediatric head and neck vascular malformations.

OBJECTIVES: To determine the prevalence of sleep-disordered breathing (SDB) symptoms among children with head and neck vascular malformations and to compare obstructive sleep apnea (OSA)-18 scores between children with head and neck vascular malformations and children with non-head and neck vascular malformations. STUDY DESIGN: Retrospective cohort and prospective cross-sectional studies METHODS: Forty-three pediatric subjects with head and neck vascular malformations evaluated at a tertiary-care multidisciplinary vascular anomalies center were included in a retrospective cohort study. Eighty-three consecutive pediatric subjects with vascular malformations evaluated at the same center were included in the prospective cross-sectional study. RESULTS: In the retrospective cohort study, 20 (47%) subjects with head and neck malformations had documented SDB symptoms. Of those with SDB symptoms, five (25%) required long-term tracheotomy. The children with SDB symptoms had greater vascular malformation size, more extensive pharyngeal involvement, greater vascular malformation mass effect on airway, and closer proximity of malformation to airway when compared to children without SDB symptoms. For the prospective cross-sectional study, 23% of pediatric subjects had malformations of the head and neck. Those with head and neck malformations had a higher OSA-18 score and a lower overall quality of life (QOL) score when compared to subjects with non-head and neck malformations. CONCLUSION: Nearly half of children with head and neck vascular malformations have SDB symptoms. Children with head and neck vascular malformations have a higher OSA-18 score and lower overall QOL score when compared to children with non-head and neck vascular malformations. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2159-2164, 2017.

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.

Pregnancy outcomes among African-American patients with systemic lupus erythematosus compared with controls.

OBJECTIVE: In a study of Gullah African-Americans, we compared pregnancy outcomes before and after systemic lupus erythematosus (SLE) diagnosis to controls to test whether there is a predisease state that negativelyaffects pregnancy outcomes. DESIGN: Cases and controls reporting at least one pregnancy were included. Controls were all Gullah African-American females. We collected demographic, socioeconomic and pregnancy data. We modelled pregnancy outcome associations with case status using multiple logistic regression to calculate ORs. RESULTS: After adjustment for age, years of education, medical coverage and pregnancy number, compared with controls, cases were more likely to have any adverse outcome (OR 2.35, 95% CI 1.78 to 3.10), including stillbirth (OR 4.55, 95% CI 1.53 to 13.50), spontaneous abortion (OR 2.05, 95% CI 1.40 to 3.00), preterm birth (OR 2.58, 95% CI 1.58 to 4.20), low birth weight (OR 2.64, 95% CI 1.61 to 4.34) and preeclampsia (OR 1.80, 95% CI 1.08 to 3.01). The odds of adverse pregnancy outcomes all increased after SLE diagnosis compared with before diagnosis, even after adjustment for age, years of education, pregnancy number and medical coverage. CONCLUSION: From a large cohort of African-American women, our findings suggest there may be a predisease state that predisposes to adverse pregnancy outcomes.

Drug-induced sleep endoscopy in persistent pediatric sleep-disordered breathing after adenotonsillectomy.

OBJECTIVES: To demonstrate the feasibility of drug-induced sleep endoscopy (DISE) in the pediatric population and to examine DISE results in children with persistent sleep-disordered breathing (SDB) after tonsillectomy and adenoidectomy (T&A). DESIGN: Retrospective case series with medical chart review. SETTING: Tertiary pediatric medical center. PATIENTS: Thirteen pediatric subjects with persistent SDB after T&A are included in the study. INTERVENTION: Drug-induced sleep endoscopy was per-formed on all patients with documentation of all sites of persistent airway obstruction. RESULTS: Multilevel upper-airway obstruction was identified in the majority of patients, most commonly related to tongue base obstruction, adenoid regrowth, and/or inferior turbinate hypertrophy. There were no differences among the 4 subgroups. CONCLUSIONS: Findings from DISE suggest that multiple factors contribute to airway obstruction in persistent SDB after T&A. Further research can address the extent to which directed surgical treatment can improve outcomes in these patients.

Comparison of imaging modalities in pediatric thyroglossal duct cysts.

OBJECTIVES/HYPOTHESIS: To determine and compare the accuracy of different imaging modalities including ultrasound (US), magnetic resonance imaging (MRI), and computed tomography (CT) in the diagnosis of thyroglossal duct cysts (TGDC) in children. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was performed on patients under the age of 18 years who had undergone surgical excision of midline neck masses between January 2002 and June 2011. All patients had preoperative imaging. Data including age at surgery, preoperative imaging results, and postoperative pathology results were recorded. Preoperative imaging diagnoses were then compared to postoperative pathologic diagnoses. Diagnostic test statistics were performed. RESULTS: A total of 44 patients met the study criteria. There were 15 patients who underwent more than one modality of imaging study. US had a sensitivity of 75% in diagnosis of TGDC. MRI sensitivity was 60% and CT was 82%. None of the tests had high specificity for TGDC; US was the highest at 80%. All three modalities had positive predictive values higher than 90%. US had the highest positive likelihood ratio (3.8), although the 95% confidence interval was not statistically significant. CONCLUSIONS: In a comparison of the three most commonly used imaging modalities for pediatric TGDC, US was the preferred exam given its comparable accuracy, ease of administration, and lower cost. In addition, the added risks of general anesthesia with MRI and ionizing radiation with CT are not justified in this setting given their equivalent or inferior performance when compared to US in this cohort.

Airway hemangiomas in PHACE syndrome.

OBJECTIVES/HYPOTHESIS: To describe the clinical presentation and airway characteristics of infants with airway hemangiomas and concomitant PHACE syndrome and to determine the prevalence of airway hemangiomas in PHACE subjects at our institution. STUDY DESIGN: Case series. METHODS: Retrospective review including clinical presentation, airway findings, treatment measures, and outcomes. RESULTS: A total of 23 subjects were diagnosed with definite PHACE at our institution between September 1, 2005 and September 1, 2011. Twelve (52%) of these subjects had documented airway hemangiomas, six of whom were diagnosed and treated at our institution. All six subjects underwent direct laryngoscopy and bronchoscopy by a pediatric otolaryngologist. Five (83%) subjects had subglottic hemangioma. Three subjects (50%) had additional hemangioma within the airway located on the epiglottis, vocal folds, posterior pharyngeal wall, and tracheal wall. Five subjects (83%) were treated with propranolol, five (83%) were treated with systemic steroids, and one subject received vincristine. One subject required laser ablation of subglottic hemangioma and tracheotomy. All subjects were airway symptom free at last follow-up (average, 35 months; range, 13-76 months). CONCLUSIONS: Airway hemangiomas can be a life-threatening complication of PHACE syndrome. At our institution, 52% of all PHACE subjects were diagnosed with airway hemangiomas. Early detection of airway involvement is paramount. Given the high rates of airway hemangiomas, we recommend performing direct laryngoscopy and bronchoscopy in all PHACE patients with respiratory symptoms. We recommend having a low threshold for airway evaluation in asymptomatic PHACE patients, especially those who will not be otherwise started on propranolol.

Propranolol in the management of airway infantile hemangiomas.

OBJECTIVE: To report our experience with propranolol in managing airway infantile hemangiomas. DESIGN: Case series of 3 consecutive patients who had extensive, symptomatic airway infantile hemangiomas treated with propranolol. SETTING: Tertiary academic medical center. PATIENTS: Three infants with facial cutaneous hemangiomas who developed stridor that progressed to respiratory distress, which according to laryngoscopic examination results was confirmed to be caused by extensive subglottic hemangiomas. These patients underwent follow-up during their course of therapy, ranging from 3 weeks to 15 months. RESULTS: Patient 1 failed to respond to systemic corticosteroids, laser ablation, and intravenous vincristine for her airway hemangioma and had to undergo tracheotomy. She was given propranolol after her tracheotomy and had a significant reduction in her subglottic airway obstruction. Patient 2 developed progressive stridor secondary to airway hemangioma at age 6 1/2 months following tapering of systemic corticosteroids prescribed for her periorbital hemangioma. Systemic corticosteroids were restarted with the addition of propranolol. The stridor improved within 24 hours, and she was able to be weaned off corticosteroids. Patient 3 was also treated with initial combined therapy of systemic corticosteroids and propranolol. He had a significant reduction in stridor within 24 hours and was weaned off corticosteroids. CONCLUSIONS: Our 3 patients had severe respiratory symptoms related to their airway infantile hemangiomas. In the first patient, propranolol was used when other treatments were ineffective or associated with intolerable adverse effects. In the second and third patients, propranolol was part of a dual regimen that resulted in rapid resolution of airway symptoms and allowed for quicker weaning of corticosteroids.