Whole exome sequencing study identifies candidate loss of function variants and locus heterogeneity in familial cholesteatoma.

Cholesteatoma is a rare progressive disease of the middle ear. Most cases are sporadic, but some patients report a positive family history. Identifying functionally important gene variants associated with this disease has the potential to uncover the molecular basis of cholesteatoma pathology with implications for disease prevention, surveillance, or management. We performed an observational WES study of 21 individuals treated for cholesteatoma who were recruited from ten multiply affected families. These family studies were complemented with gene-level mutational burden analysis. We also applied functional enrichment analyses to identify shared properties and pathways for candidate genes and their products. Filtered data collected from pairs and trios of participants within the ten families revealed 398 rare, loss of function (LOF) variants co-segregating with cholesteatoma in 389 genes. We identified six genes DENND2C, DNAH7, NBEAL1, NEB, PRRC2C, and SHC2, for which we found LOF variants in two or more families. The parallel gene-level analysis of mutation burden identified a significant mutation burden for the genes in the DNAH gene family, which encode products involved in ciliary structure. Functional enrichment analyses identified common pathways for the candidate genes which included GTPase regulator activity, calcium ion binding, and degradation of the extracellular matrix. The number of candidate genes identified and the locus heterogeneity that we describe within and between multiply affected families suggest that the genetic architecture for familial cholesteatoma is complex.

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.

Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. METHODS: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. RESULTS: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. CONCLUSIONS: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway.

Nasal oncocytoma causing unilateral epiphora in an elderly patient: the vital role of nasendoscopy.

Oncocytomas are rare glandular tumours, typically found in salivary glands and kidneys. A 76-year-old man presented to an ophthalmology department after 3 months of persistent right-sided epiphora. Lacrimal syringing and a fluorescein dye test demonstrated an obstruction at the level of the nasolacrimal duct (NLD). Owing to the patient's history of dacryocystitis, endoscopic dacryocystorhinostomy was organised. When in theatre however, nasendoscopy identified a polypoid mass at the lateral aspect of the inferior turbinate, obstructing the right NLD opening. Histopathology confirmed an oncocytoma. There was no local destruction or distant metastases. The mass was resected, a Monoka stent inserted and symptomatic relief achieved. In this case, the cause of epiphora was initially missed because no direct nasal examination was performed. It is vital that patients with unilateral epiphora undergo an endoscopic nasal examination before arranging treatment. This could prevent delayed diagnoses, ensure prompt and appropriate management, and reduce morbidity and mortality.

Combined external and endonasal approach to fronto-ethmoidal mucocele involving the orbit.

PURPOSE: To present a technique to improve the surgical treatment of frontal sinus mucocele and its recurrence. METHODS: Nine procedures performed on eight patients by a team of ENT and Ophthalmic orbital surgeons. Data collected included patient demographics, surgical details, pathological findings and complications. The surgical technique involved an external approach via the upper eyelid skin crease combined with an internal approach with a rigid 4 mm endoscope described below. Following evacuation of the mucocele the sinus was anastomosed to nasal cavity with insertion of silicon stent. All patients had preoperative and postoperative CT scans of the orbit and paranasal sinuses. RESULT: There were nine operations on eight patients (six males, two female patients, mean age of 57.25: range, 15-71). Two patients had inverted papillomas. All patients presented with non-axial proptosis and diplopia. The mean follow up period was 38.7 months (range 11-99). The only intraoperative complication noted was a cerebrospinal fluid (CSF) leak in a patient with a post traumatic mucocele. Post-operative complications included lid scarring in 2 patients. One of the patients had a fistula overlying the affected sinus at presentation. Both patients underwent dermis fat grafting as a second stage procedure and responded well. One patient presented with asymptomatic superior oblique weakness that could be attributed to trauma to the superior oblique intra operatively. There was no case of recurrence of mucocele in our series. One of the inverted papillomas had an early recurrence (within 6 months) that required repeat surgery. CONCLUSION: Fronto nasal anastomosis restores the anatomy and reduces the chance of recurrence in our experience. The final cosmetic result is excellent and the patient's satisfaction is high.

The burden of revision sinonasal surgery in the UK-data from the Chronic Rhinosinusitis Epidemiology Study (CRES): a cross-sectional study.

OBJECTIVES: 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 patients with CRS 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%) 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 2-30) 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 (χ(2) p<0.001). CONCLUSIONS: This study demonstrated that 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.

An unusual headache: sphenoiditis in children and adolescents.

Sphenoid sinus infection is a rare cause of headaches in children and adolescents. Its symptoms are often non-specific and confusing. The diagnosis is made on the history, examination, nasendoscopy, cultures and CT or MRI. Prompt and aggressive medical treatment in the form of parenteral antibiotics and nasal decongestants is advised to reduce the risk of serious complications such as permanent cranial neuropathies or intracranial spread. Surgical intervention is advocated when symptoms persist or complications develop. Although sphenoiditis is potentially devastating, early collaboration between pediatric medical and ENT surgical teams generally leads to an excellent outcome. This article presents three cases of adolescent sphenoid sinus infection, and reviews the literature on this uncommon condition.

A unified hypothesis for vestibular dysfunction?

It is our hypothesis that three distinct syndromes of vertigo (ie, labyrinthitis, Ménière's disease, and BPPV), which arise from a malfunction of the vestibular labyrinth, are in fact a spectrum of disorders all resulting from the presence of free-floating particles within the vestibular fluid chambers.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with sudden sensorineural hearing loss.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an autosomal dominant angiopathy characterized by recurrent cerebrovascular events, migraine and dementia. We describe a case of sensorineural hearing loss as the presenting feature of this condition. We have found no previous reports in the world literature of CADASIL presenting with a sudden sensorineural hearing loss. The significance of questioning a patient with regard to family history is exemplified in this case.