Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an ‘SDH-like’ molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.

To define germs involved, clinical presentation, treatment regimen, and prognostic factors in necrotizing external otitis. Retrospective study reviewing a series of 46 patients treated during 10 years in a tertiary care center. Diagnosis was confirmed by using otomicroscopy, computed tomographic and/or magnetic resonance imaging scan and bone scintigraphy (Te 99 and Ga 26 bone scan). Patients were provided ceftazidime and ciprofloxacin intravenously and monitored using a Ga-67 bone scan. The following were assessed: presenting symptoms, general context, bacteriological analysis, imaging protocol sensitivity, complications, delay to healing, and cure rate. Sex ratio was 2.29 (mean age, 73.6 yr). The most common presenting symptoms were otalgia and otorrhea in 97.8 and 91.3%, respectively. Facial paralysis was present in 19.6% of cases. Thirty patients had diabetes mellitus (65.2%), and 8 were immunocompromised (17.4%). Pseudomonas aeruginosa was isolated in 69.2% of cases and was resistant to ciprofloxacin in 18.5%, but was susceptible to ceftazidime in all cases. Four patients died during the treatment (4.4%), but only 2 of disease. The mean delay to healing was 14 weeks (SD, 9.7). Healing rate was 95.6%. No relapse was observed after a mean follow-up of 78.4 weeks (SD, 36.5 wks). Two factors significantly influenced the prognosis: facial paralysis and existence of systemic factors for immune deficiency (p = 0.023 and 0.038, respectively). The association of ciprofloxacin and ceftazidime was efficient in countering the increasing resistance of P. aeruginosa to quinolones. We propose a prognostic classification of necrotizing external otitis based on the presence of facial paralysis and/or systemic factors.

To systematically review and meta-analyze the results of all randomized controlled trials comparing corticosteroids with placebo for the treatment of patients with vestibular neuritis. An electronic search was performed in MEDLINE, EMBASE, Cochrane Library, and CENTRAL databases, and then extensive hand-searching was performed for the identification of relevant studies. No time and language limitations were applied. Prospective randomized controlled trials comparing corticosteroids with placebo for the treatment of patients with vestibular neuritis. Odds ratios (ORs), weighted mean differences (WMD), 95% confidence intervals (CIs), and tests for heterogeneity were reported. Four studies were eventually identified and systematically reviewed. Meta-analysis was feasible for 3 studies. Regarding the recovery of clinical symptoms, the proportion of patients with clinical recovery at 1 month after the initiation of therapy did not differ significantly between the corticosteroids and placebo groups (OR, 1.45; 95% CI, 0.26-8.01; p = 0.67). The proportion of patients with caloric complete recovery was significantly different between the corticosteroids and placebo groups both at 1 (OR, 12.64; 95% CI, 2.6-61.52; p = 0.002; heterogeneity, p = 0.53; fixed effects model) and 12 months (OR, 3.35; 95% CI, 1.45-7.76; p = 0.005; heterogeneity, p = 0.03; random effects model) after the initiation of therapy. The caloric extent of canal paresis at 12 months after the initiation of therapy seemed to differ significantly between patients who received corticosteroids and those who received placebo (WMD, −12.15; 95% CI, −19.85 to −4.46; p < 0.05; heterogeneity, p < 0.05; random effects model). The present systematic review and meta-analysis, based on the currently available evidence, suggests that corticosteroids improve only the caloric extent and recovery of canal paresis of patients with vestibular neuritis. At present, clinical recovery does not seem be better in patients receiving corticosteroids.

To describe the presentation of intralabyrinthine schwannomas (ILSs). Retrospective multicenter study involving 12 European skull base surgery tertiary referral centers. One hundred ten patients with the diagnosis of ILS, either labyrinth confined or extending into the internal auditory meatus for less than 50% of their volume. Data collected were age, sex, nature and timing of presenting symptoms, hearing (according to the AAO-HNS grading system), results of vestibular tests (caloric tests and cervical vestibular-evoked myogenic potentials [c-VEMPs]), and tumor localization. Presenting symptoms and laboratory test results were studied according to the extension of the lesion into the cochlea (C) and vestibule (V), on one hand, and according to unifocal (L1) or plurifocal (L2) extension into the labyrinth, on the other. Intracochlear type was more common (50%) than vestibular (19.1%) and more diffuse forms (30.9%). The mean delay for diagnosis was long (72.5 mo; SD, 76.6). Mean age was 53.9 years (SD, 13.2). Deafness was the most common symptom (77.8 dB HL [SD, 33.6], with only 24.6% of patients keeping viable hearing. Caloric tests (65.5% of patients) were abnormal in 77.8% of cases. c-VEMPs were abnormal in 65.7% of the 36 cases analyzed. In V forms, hearing was significantly better (class A + B in 21.1% in C and 45.8% in V forms) (p = 0.03), and vestibular function was more altered (C: 57%, V: 100%, p = 0.0009*). L2 forms were diagnosed later (L1: 59.1 mo, L2: 104.5 mo; p = 0.004*) and were associated more frequently with a dead ear (L1: 13.1%, L2: 41.2%, p = 0.002*) than L1 forms. This series, which is the largest in the literature, demonstrates that even very small and localized ILSs heavily compromise labyrinthine functions.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1^N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy. Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.

To assess the qualitative and quantitative aspects of multifrequency tympanograms in patients with Ménière's disease. Prospective study of adults. University medical center. Forty patients with Ménière's disease outside of episodes and 24 normal-hearing subjects with no otologic history. Resonance frequency sweep and tympanograms of admittance, conductance, and susceptance at 2 kHz and at resonance frequency were performed in each ear. A qualitative assessment was performed to find reproducible and comparable tympanograms (Student's t test) as a prerequisite for quantitative assessment. Four measurement criteria were compared between the groups to establish a diagnostic test (chi Pearson test). A p value less than 0.05 was considered statistically significant. Resonance frequency was decreased in Ménière's disease. Only conductance tympanograms at 2 kHz had a constant pattern. Width of conductance tympanograms at 2 kHz was increased in symptomatic Ménière's disease compared with normal ears. Using conductance width at 2 kHz as a diagnostic test with a threshold of 235 daPa, we found a statistically significant difference between symptomatic ears of patients with Ménière's disease and ears of normal subjects (p < 10). More than 95% of normal subjects' ears had a negative test; 56.5% of affected ears of patients with Ménière's disease and 45.8% of nonaffected ears of patients with Ménière's disease had a positive test. Width of conductance at 2 kHz seems to be a sensitive, simple diagnostic test in Ménière's disease. It would also be of great interest in studying Ménière's disease bilaterality.