Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Current assessment of newborn hearing screening protocols.

PURPOSE OF REVIEW: The objective of this article is to assess current newborn hearing screening protocols. We will focus on technologies or modalities used, protocol steps, training of screeners, timing of first screen, and loss to follow-up. A summary of program reports focusing on protocols from Greece, China, South Africa, France, Spain, South Korea, Denmark, Italy, Turkey, Taiwan, South Korea, Poland and Iran as they are recently reported will also be presented. RECENT FINDINGS: Community-based hearing screening programs in South Africa and efforts in the Asian region are being reported. The use of automated auditory brainstem response and staged procedures are gaining popularity because of low refer rates. However, follow-up issues remain a problem. The importance of having trained nonprofessional screeners and an efficient database is becoming more evident as the number of newborns screened for hearing loss increase each year. SUMMARY: There are many reported protocols using different technologies, involving several stages, implemented in different settings which should not confuse but rather guide stakeholders so that programs may attain certain benchmarks and ultimately help the hard-at-hearing child in achieving his or her full potential.

Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.

BACKGROUND: Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access. METHODS: Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing. RESULTS: Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear. CONCLUSIONS: These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.

Prevalence of sensorineural hearing loss and its association with glycemic control in Filipino patients with diabetes at the Philippine General Hospital / Journal of the ASEAN Federation of Endocrine Societies

@#<p style="text-align: justify;"><strong>BACKGROUND:</strong> Sensorineural hearing loss (SNHL) is a form of diabetic neuropathy. Its prevalence rate varies from 21.7-73.3% among different populations. The association of this complication with long-term glycemic control has not been described extensively.<br /><strong>OBJECTIVES:</strong> The study aims to determine the prevalence of SNHL in Filipino patients with diabetes consulting in a tertiary hospital; and to determine the association of SNHL with the degree of blood sugar control as measured by the mean hemoglobin bA1c (HbA1c) for the last five years.<br /><strong>METHODOLOGY</strong>: A cross-sectional study of 128 patients in a tertiary hospital was done. Patients were recruited via stratified random sampling with the different clinics as the stratifying variable. They underwent physical examination and pure tone audiometry (PTA) to detect presence of SNHL and presence of distal peripheral neuropathy. Chart review was done to gather the HbA1c levels for the last five years, as well as data on the presence of retinopathy and nephropathy. The average HbA1c levels, and other clinical and demographic factors and their association with SNHL were analyzed using logistic regression.<br /><strong>RESULTS:</strong> The prevalence of SNHL among patients with diabetes is 45.31%. Glycemic control does not seem to be associated with SNHL (p value 0.451, OR 1.447). Age was found to be significantly associated with SNHL (p value=0.046, OR=1.035). Among patients age 60 years old and below, retinopathy was significantly associated with SNHL (p value 0.023, OR=3.564). Multivariate analysis did not show any significant predictor for SNHL. There was no observed difference in the proportion of patients with SNHL among males (48.94%) compared to females (43.21%), p value of 0.530. A more advanced age is associated with SNHL among males (p value 0.024, OR=1.095) and a family history of hearing loss is an independent predictor of SNHL (p value 0.047, OR=1.088).<br /><strong>CONCLUSION:</strong> There is a high prevalence rate of SNHL among Filipino patients with diabetes. SNHL does not seem to be associated with glycemic control. Screening for SNHL maybe warranted for patients with diabetes due to its high prevalence rate regardless of glycemic control. Hearing care, focusing on prevention of hearing loss, should be advocated for patients with diabetes mellitus</p>

Granulation tissue mimicking a glomus tumor in a patient with chronic middle ear infection

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> To present an unusual cause of pulsatile tinnitus, presenting in a young adult suffering from chronic recurrent foul-smelling discharge from the same ear.<br /><strong>METHODS:</strong><br /><strong>Design:</strong> Case Report<br /><strong>Setting:</strong> Tertiary National University Hospital<br /><strong>Patient:</strong> One<br /><strong>RESULTS:</strong> A 24 year-old woman presented with pulsatile tinnitus on a background of chronic recurrent foul-smelling discharge. Clinico-radiologic findings seemed consistent with a glomus tympanicum coexisting with chronic suppurative otitis media with cholesteatoma. She underwent tympanomastoidectomy with excision of the mass. Histopathologic evaluation revealed the mass to be granulation tissue.<br /><strong>CONCLUSION:</strong> Pulsatile tinnitus is rarely associated with chronic middle ear infection. Granulation tissue arising at the promontory may mimic glomus tumors when accompanied with this symptom. Despite this revelation, it would still be prudent to prepare for a possible glomus tumor intraoperatively so that profuse bleeding and complications may be avoided.</p>

Rare A2ML1 variants confer susceptibility to otitis media.

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

Preliminary results of static tests of balance among asymptomatic normal Filipino adult volunteers

OBJECTIVES: To determine the effect of age, ex and body index on selected static tests of balance and to generate referance normtive data among the different population groups. METHODS: In this cross-sectional study, 100 asymptomatic normal adult Filipino volunteers, aged 20 to 69 years were tasked to perform selected static balance tests. These tests included classic Romberg (CR), Romberg with Jendrassik (RJ) maneuver, tandem Romberg (TR), standing on foam with feet apart (SOFFA), standing on foam with feet together (SOFFT) and standing on one leg (SOL). All tests were done with eyes opened (EO) followed by eyes closed (EC) for 30 seconds each. Volunteers were grouped into age groups by decades, normative values were obtained and effects of age, sex and body mass index, if any, on performance of the various tests were determined. RESULTS: All volunteers were able to do the CR and RJ maneuver for 30 seconds. All were able to perform for 30 seconds the TREO, SOFFA EO and SOFFT EO procedures. Some volunteers were unable to complete the TREC, SOFFA EC, SOFFT EC, SOL EO and SOL EC procedures. The mean performance duration values for TREC, SOFFA EC, SOFFT EC, SOL EO AND SOL EC were significantly negatively correlated with age. Although majority of tests were negatively correlated with body mass index, the correlations were not statistically significant. CONCLUSION: Age significantly affects selected static balance performance whereas sex and body mass index do not significantly affect selected static balance performance. The normative values generated in this study are inconclusive because of inadequate sample size, particularly in the older age group. The results, however, showed the potential value of the 5th percentile as a normative norm in systematically assessing the involvement of the vesticular, visual and proprioceptive organs i balance function.