The genetics of Cholesteatoma

Introduction A cholesteatoma is a mass of keratinizing epithelium in the middle ear. It is a rare disorder, associated with significant morbidity, especially deafness. There is little evidence for Mendelian inheritance, but an original observation by the author of affected families in Norfolk, including individuals with bilateral disease, suggests a genetic component for its aetiology. Methods A systematic literature review to identify studies about the genetics of cholesteatoma has been performed and a biobank for subsequent whole exome sequencing studies of familial disease has been established. A pilot sequencing study to identify candidate variants that segregate with the disease phenotype, using NimbleGen library construction and exome capture and the Illumina HiSeq4000 platform, has been completed. Results The literature review identified several case-series with multiply-affected families and associations with congenital malformation syndromes. DNA and clinical data has been collected from 66 participants from 13 multiply affected Norfolk families. The pilot whole exome sequencing [WES] study of 16 participants from four families identified 95,437 variants. In one family all five recruited individuals have been sequenced. Variant filtering, using pedigree analysis, has identified several mutations of potential significance. Conclusion A systematic review has been completed and a unique biobank to explore the genetics of cholesteatoma is established A WES strategy and bioinformatics pipeline have been developed in the pilot study and preliminary filtering has identified candidate variants that could have an impact on relevant biological pathways. There are no other published descriptions of a WES strategy to investigate the genetics of familial cholesteatoma. The potential impact of an understanding of the genetic basis of cholesteatoma is discussed

Cholesteatoma and family history: An international survey

Objective To explore the relative frequency of a family history of cholesteatoma in patients with known cholesteatoma, and whether bilateral disease or earlier diagnosis is more likely in those with a family history. Associations between cleft lip or palate and bilateral disease and age of diagnosis were also explored. Design An online survey of patients with diagnosed cholesteatoma was conducted between October 2017 and April 2019. Participants The sample consisted of patients recruited from two UK clinics and self‐selected respondents recruited internationally via social media. Main outcome measures Side of cholesteatoma, whether respondents had any family history of cholesteatoma, age of diagnosis and personal or family history of cleft lip or palate were recorded. Results Of 857 respondents, 89 (10.4%) reported a positive family history of cholesteatoma. Respondents with a family history of cholesteatoma were more likely to have bilateral cholesteatoma (P = .001, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.35‐3.43), but there was no difference in the age of diagnosis (P = .23). Those with a history of cleft lip or palate were not more likely to have bilateral disease (P = .051, OR 2.71, CI 1.00‐7.38), and there was no difference in age of diagnosis (P = .11). Conclusion The relatively high proportion of respondents that reported a family history of cholesteatoma offers supporting evidence of heritability in cholesteatoma. The use of social media to recruit respondents to this survey means that the results cannot be generalised to other populations with cholesteatoma. Further population‐based research is suggested to determine the heritability of cholesteatoma

The genetics of cholesteatoma study. Loss‐of‐function variants in an affected family

The aetiology of cholesteatoma remains elusive. In a recent systematic review, we discussed reports of multiple cases of cholesteatoma within families, which suggests a genetic predisposition in some cases (1). We have established a U.K. database and DNA sample bank that can be used to identify genetic variants that co‐segregate with cholesteatoma in multiply‐affected families. Recruitment to this Genetics of Cholesteatoma (GOC) Study is via the U.K. National Institute of Health Research Clinical Research Network. This preliminary communication describes the results of whole exome sequencing (WES) of DNA extracted from participants in the first fully sequenced family recruited to the study. Rare variants were filtered for co‐segregation with the cholesteatoma phenotype, and for their putative functional impact. We have identified loss of function variants in the genes EGFL8 and BTNL9 as candidate variants of interest. These are preliminary observations and the variants are of unknown significance to the disease pathology without replication or further investigation

The Burden of Revision Sinonasal Surgery in the UK – Data from the Chronic Rhinosinusitis Epidemiology Study (CRES); a cross sectional study

Objectives/Hypothesis The aim of this study was to investigate the surgical revision rate in patients with Chronic Rhinosinusitis (CRS) in the UK CRS Epidemiology Study (CRES). Previous evidence from national Sinonasal Audit showed that 1459 CRS patients demonstrated a surgical revision rate 19.1% at 5 years, with highest rates seen in those with polyps (20.6%). Setting Thirty secondary care centres around the UK. Participants A total of 221 controls and 1249 patients with CRS were recruited to the study including those with polyps (CRSwNPs), without polyps (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). Interventions Self-administered questionnaire. Primary outcome measure The need for previous sinonasal surgery. Results A total of 651 patients with CRSwNPs, 553 with CRSsNPs and 45 with AFRS were included. A total of 396 (57%) of patients with CRSwNPs/AFRS reported having undergone previous endoscopic nasal polypectomy (ENP), of which 182 of the 396 (46%) reported having received more than one operation. The mean number of previous surgeries per patient in the revision group was 3.3 (range 2 to 30) and a mean duration of time of 10 years since the last procedure. The average length of time since their first operation up to inclusion in the study was 15.5 years (range 0-74). Only 27.9% of all patients reporting a prior ENP had received concurrent endoscopic sinus surgery (ESS) (n=102). For comparison, surgical rates in patients with CRSsNPs were significantly lower; 13% of cases specifically reported ESS and of those only 30% reported multiple procedures (chi-squared p < 0.001). Conclusions This study demonstrated there is a high burden of both primary and revision surgery in patients with CRS, worst in those with AFRS and least in those with CRSsNPs. The burden of revision surgery appears unchanged in the decade since the Sinonasal Audit

Current use of baseline medical treatment in chronic rhinosinusitis: Data from the National Chronic Rhinosinusitis Epidemiology Study (CRES)

Objectives: According to clinical and comissioning guidelines for chronic rhinosinusitis (CRS), patients being referred to secondary care should have failed primary medical treatment with nasal douching (ND) and intranasal corticosteroids (INCS). The study objectives were to identify the rate of specific medical therapy in CRS patients and establish any differences in medication use, for both CRS and associated medical conditions, between CRS phenotypes.  Design and setting: Case-control study in a secondary care setting.  Methods: Participant-reported study-specific questionnaire capturing free text data on current medication use at the time of study entry. Qualitative interviews with 21 participants also explored their experience of CRS and its management.  Particpants: Patients with both without (CRSsNPs) and with polyps (CRSwNPs). Main outcome measuresReported use of CRS-related and non-related medications.ResultsWithin a total of 1243 CRS participants, current INCS usage was low (18% in CRSwNPs, 12% in CRSsNPs); ND was being performed by only 1% of all participants. Bronchodilators and inhaled corticosteroids use was significantly higher in CRSwNPs participants (p < 0.0001). Antidepressants use was significantly higher in CRSsNPs (14% versus 7%, p < 0.0002). There were no significant regional variations in rates of INCS use, nor any significant influence of social deprivation.  Conclusions: The current use of baseline medical therapy in CRS appears to be very low, representing a combination of poor patient compliance, possible ineffectiveness of treatment and a lack of familiarity with current guidelines amongst general practitioners and some ENT specialists. Work is needed to disseminate guidelines to all practitioners involved and reduce unnecessary burden on existing healthcare resources for this common condition by ensuring timely referral and definitive management