Roland D. Eavey

De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5–15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

Change in Prevalence of Hearing Loss in US Adolescents

CONTEXT Hearing loss is common and, in young persons, can compromise social development, communication skills, and educational achievement. OBJECTIVE To examine the current prevalence of hearing loss in US adolescents and determine whether it has changed over time. DESIGN Cross-sectional analyses of US representative demographic and audiometric data from the 1988 through 1994 and 2005 through 2006 time periods. SETTING The Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994, and NHANES 2005-2006. PARTICIPANTS NHANES III examined 2928 participants and NHANES 2005-2006 examined 1771 participants, aged 12 to 19 years. MAIN OUTCOME MEASURES We calculated the prevalence of hearing loss in participants aged 12 to 19 years after accounting for the complex survey design. Audiometrically determined hearing loss was categorized as either unilateral or bilateral for low frequency (0.5, 1, and 2 kHz) or high frequency (3, 4, 6, and 8 kHz), and as slight loss (> 15 to < 25 dB) or mild or greater loss (> or = 25 dB) according to hearing sensitivity in the worse ear. The prevalence of hearing loss from NHANES 2005-2006 was compared with the prevalence from NHANES III (1988-1994). We also examined the cross-sectional relations between several potential risk factors and hearing loss. Logistic regression was used to calculate multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS The prevalence of any hearing loss increased significantly from 14.9% (95% CI, 13.0%-16.9%) in 1988-1994 to 19.5% (95% CI, 15.2%-23.8%) in 2005-2006 (P = .02). In 2005-2006, hearing loss was more commonly unilateral (prevalence, 14.0%; 95% CI, 10.4%-17.6%, vs 11.1%; 95% CI, 9.5%-12.8% in 1988-1994; P = .005) and involved the high frequencies (prevalence, 16.4%; 95% CI, 13.2%-19.7%, vs 12.8%; 95% CI, 11.1%-14.5% in 1988-1994; P = .02). Individuals from families below the federal poverty threshold (prevalence, 23.6%; 95% CI, 18.5%-28.7%) had significantly higher odds of hearing loss (multivariate adjusted OR, 1.60; 95% CI, 1.10-2.32) than those above the threshold (prevalence, 18.4%; 95% CI, 13.6%-23.2%). CONCLUSION The prevalence of hearing loss among a sample of US adolescents aged 12 to 19 years was greater in 2005-2006 compared with 1988-1994.

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Evaluation of Noise-Induced Hearing Loss in Young People Using a Web-Based Survey Technique

Objective. Many adolescents and young adults consciously expose themselves to loud music for entertainment. We hypothesized that these individuals might not be aware that exposure to loud music could result in hearing loss. Furthermore, we wished to assess the feasibility of a web-based survey to collect health information from this group. Methods. A 28-question survey was designed to target adolescents and young adults. The survey contained questions about views toward general health issues, including hearing loss, and was presented to random visitors at the MTV web site. Results. In 3 days, 9693 web surveys were completed. Hearing loss was defined on a Likert scale as “a very big problem” by 8% of respondents compared with other health issues: sexually transmitted diseases, 50%; alcohol/drug use, 47%; depression, 44%; smoking, 45%; nutrition and weight issues, 31%; and acne, 18%. Notably, most respondents had experienced tinnitus or hearing impairment attending concerts (61%) and clubs (43%). Only 14% of respondents had used earplugs; however, many could be motivated to try ear protection if they were aware of the potential for permanent hearing loss (66%) or were advised by a medical professional (59%). Conclusions. A majority of young adults have experienced tinnitus and hearing impairment after exposure to loud music. Fortunately, many of these individuals could be motivated to wear ear protection. This novel web-based survey technique rapidly generated a large database and is a feasible method to obtain health data from this group.

Engineering Autogenous Cartilage in the Shape of a Helix Using an Injectable Hydrogel Scaffold

Objective Previous successful efforts to tissue engineer cartilage for an auricle have used an immunocompromised nude mouse xenograft model. Subsequent efforts in an immunocompetent autogenous animal model have been less successful because of an inflammatory response directed against the foreign scaffold polymer used to provide an auricular shape. We studied an alternative polymer material and surgical technique to engineer autogenous cartilage in the shape of a human ear helix using injectable hydrogel scaffolding, Pluronic F‐127 (polyethylene oxide and polypropylene oxide).

The epidemiology of hearing impairment in the United States: Newborns, children, and adolescents

Objective: Hearing loss ranks high among disabilities in the United States. The epidemiologic parameters of hearing impairment in the United States have not been systematically studied and important historic data have not diffused to relevant stakeholders; even otolaryngologists are unfamiliar with epidemiologic data. We wished to compile known studies to establish an epidemiologic baseline beginning with pediatric data. Data Sources: Relevant literature was retrieved from medical databases and Centers for Disease Control and Prevention reports. Methods: Candidate articles and national data sets encompassing pediatric hearing loss were analyzed and compared. Whenever possible, group analyses were performed. Results: The average incidence of neonatal hearing loss in the United States is 1.1 per 1000 infants, with variation among states (0.22 to 3.61 per 1000). Childhood and adolescent prevalence rates demonstrate variability. The prevalence of mild hearing impairment or worse (>20 dB) is 3.1 percent based on the average of comparable audiometric screening studies; self-reporting prevalence is 1.9 percent. Hispanic Americans demonstrate a higher prevalence of hearing impairment than other children. Low-income households demonstrate a higher prevalence of hearing loss compared to households with higher income levels. Genetic causes were attributed to 23 percent across studies. Conclusions: Analysis of the data reveals gaps in our knowledge of the epidemiology of hearing loss and stresses the importance of consistent definitions of hearing impairment for systematic assessment of changes over time. Hearing loss in childhood deserves further epidemiologic investigation and elevated awareness among health care professionals and the public. Genetic etiologies are likely underestimated in this review.

characteristics of Cartilage Engineered from Human Pediatric Auricular Cartilage

In the repair of cartilage defects, autologous tissue offers the advantage of lasting biocompatibility. The ability of bovine chondrocytes isolated from hyaline cartilage to generate tissue-engineered cartilage in a predetermined shape, such as a human ear, has been demonstrated; however, the potential of chondrocytes isolated from human elastic cartilage remains unknown. In this study, the authors examined the multiplication characteristics of human auricular chondrocytes and the ability of these cells to generate new elastic cartilage as a function of the length of time they are maintained in vitro. Human auricular cartilage, harvested from patients 5 to 17 years of age, was digested in collagenase, and the chondrocytes were isolated and cultured in vitro for up to 12 weeks. Cells were trypsinized, counted, and passaged every 2 weeks. Chondrocyte-polymer (polyglycolic acid) constructs were created at each passage and then implanted into athymic mice for 8 weeks. The ability of the cells to multiply in vitro and their ability to generate new cartilage as a function of the time they had been maintained in vitro were studied. A total of 31 experimental constructs from 12 patients were implanted and compared with a control group of constructs without chondrocytes. In parallel, a representative sample of cells was evaluated to determine the presence of collagen. The doubling rate of human auricular chondrocytes in vitro remained constant within the population studied. New tissue developed in 22 of 31 experimental implants. This tissue demonstrated the physical characteristics of auricular cartilage on gross inspection. Histologically, specimens exhibited dense cellularity and lacunae-containing cells embedded in a basophilic matrix. The specimens resembled immature cartilage and were partially devoid of the synthetic material of which the construct had been composed. Analyses for collagen, proteoglycans, and elastin were consistent with elastic cartilage. No cartilage was detected in the control implants. Human auricular chondrocytes multiply well in vitro and possess the ability to form new cartilage when seeded onto a three-dimensional scaffold. These growth characteristics might some day enable chondrocytes isolated from a small auricular biopsy to be expanded in vitro to generate a large, custom-shaped, autologous graft for clinical reconstruction of a cartilage defect, such as for congenital microtia.

Inlay Tympanoplasty: Cartilage Butterfly Technique

For closure of a nonmarginal tympanic membrane perforation, currently popular techniques utilize either an underlay or an onlay approach. However, both procedures require incising canal skin. A transcanal inlay procedure could provide theoretical advantages of ease, speed, and comfort. Specifically designed cartilage that could facilitate the transcanal approach similar to placement of a solid tube was employed and evaluated. A transcanal cartilage butterfly inlay technique was found to be efficient and effective to close a subgroup of small‐to‐medium‐sized tympanic membrane perforations including cases in which the condition of the tympanic membrane was somewhat hostile. Postoperative patient comfort was an additional benefit.

Comparison of computed tomography and surgical findings in deep neck infections.

Computed tomography is routinely used in the evaluation of patients suspected to have deep neck Infections. This 10-year retrospective study compares preoperative computed tomography scan reports with intraoperative findings in 38 patients who underwent surgical exploration of the parapharyngeal or retropharyngeal space within 48 hours of their radiographic assessment. Overall, intraoperative findings confirmed computed tomography scan interpretation in 76.3% of the patients. The false-positive rate was 13.2%, and the false-negative rate was 10.5%. The sensitivity of computed tomography scan for detection of parapharyngeal space or retropharyngeal space abscess was 87.9%. This studys documentation of false-positive computed tomography scans in the evaluation of deep neck infections emphasizes the importance of correlating radiologic interpretation with clinical examination before surgical intervention.

Dilated Cardiomyopathy and Sensorineural Hearing Loss A Heritable Syndrome That Maps to 6q23–24

BACKGROUND Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized. METHODS AND RESULTS Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified. CONCLUSIONS A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.