An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

The NHS visitor and migrant cost recovery programme - a threat to health?

BACKGROUND: In April 2014 the UK government launched the 'NHS Visitor and Migrant Cost Recovery Programme Implementation Plan' which set out a series of policy changes to recoup costs from 'chargeable' (largely non-UK born) patients. In England, approximately 75% of tuberculosis (TB) cases occur in people born abroad. Delays in TB treatment increase risk of morbidity, mortality and transmission in the community. We investigated whether diagnostic delay has increased since the Cost Recovery Programme (CRP) was introduced. METHODS: There were 3342 adult TB cases notified on the London TB Register across Barts Health NHS Trust between 1st January 2011 and 31st December 2016. Cases with missing relevant information were excluded. The median time between symptom onset and treatment initiation before and after the CRP was calculated according to birthplace and compared using the Mann Whitney test. Delayed diagnosis was considered greater or equal to median time to treatment for all patients (79 days). Univariable logistic regression was used to manually select exposure variables for inclusion in a multivariable model to test the association between diagnostic delay and the implementation of the CRP. RESULTS: We included 2237 TB cases. Among non-UK born patients, median time-to-treatment increased from 69 days to 89 days following introduction of CRP (p < 0.001). Median time-to-treatment also increased for the UK-born population from 75.5 days to 89.5 days (p = 0.307). The multivariable logistic regression model showed non-UK born patients were more likely to have a delay in diagnosis after the CRP (adjOR 1.37, 95% CI 1.13-1.66, p value 0.001). CONCLUSION: Since the introduction of the CRP there has been a significant delay for TB treatment among non-UK born patients. Further research exploring the effect of policies restricting access to healthcare for migrants is urgently needed if we wish to eliminate TB nationally.

Protocol for a cluster randomised control trial evaluating the efficacy and safety of treatment for latent tuberculosis infection in recent migrants within primary care: the CATAPuLT trial.

BACKGROUND: The identification and treatment of LTBI is a key component of the WHO's strategy to eliminate TB. Recent migrants from high TB-incidence countries are recognised to be at risk TB reactivation, and many high-income countries have focused on LTBI screening and treatment programmes for this group. However, migrants are the group least likely to complete the LTBI cascade-of-care. This pragmatic cluster-randomised, parallel group, superiority trial investigates whether a model of care based entirely within a community setting (primary care) will improve treatment completion compared with treatment in specialist TB services (secondary care). METHODS: The CATAPuLT trial (Completion and Acceptability of Treatment Across Primary Care and the community for Latent Tuberculosis) randomised 34 general practices in London, England, to evaluate the efficacy and safety of treatment for LBTI in recent migrants within primary care. GP practices were randomised to either provide management for LTBI entirely within primary care (GPs and community pharmacists) or to refer patients to secondary care. The target recruitment number for individuals is 576. The primary outcome is treatment completion (defined as taking at least 90% of antibiotic doses). The secondary outcomes assess adherence, acceptance of treatment, the incidence of adverse effects including drug-induced liver injury, the rates of active TB, patient satisfaction and cost-effectiveness of LTBI treatment. This protocol adheres to the SPIRIT Checklist. DISCUSSION: The CATAPuLT trial seeks to provide implementation research evidence for a patient-centred intervention to improve treatment completion for LTBI amongst recent migrants to the UK. TRIAL REGISTRATION: NCT03069807, March 2017, registered retrospectively.

Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Diagnostic accuracy of high-resolution T2-weighted MRI vs contrast-enhanced T1-weighted MRI to screen for cerebellopontine angle lesions in symptomatic patients.

OBJECTIVE: To evaluate diagnostic accuracy of high-resolution T2-weighted MRI (T2w) for detecting cerebellopontine angle (CPA) lesions compared to a combined protocol including gadolinium enhanced T1-weighted MRI (GdT1w). SETTING: Department of Radiology & Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. PARTICIPANTS: A random sample of MRIs from 350 patients (700 CPAs) with asymmetrical audiovestibular complaints was used, acquired between 2013 and 2016. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values of T2w results compared to GdT1w and, in patients with any suggestion of CPA pathology, to the complete examination (T1w, GdT1w and T2w). Inter-rater agreement between an experienced neuroradiologist and a less experienced observer was calculated. RESULTS: Results of 678 CPAs in 340 patients were analysed. On T2w, the neuroradiologist identified all 27 lesions >2 mm in size out of a total of 30 CPA lesions (sensitivity: 90% [95% CI: 73.5%-97.9%]). Negative predictive value reached 99.5% (95% CI: 98.7-99.9). One missed lesion of 2 mm would have been detected in clinical practice, as this was one of 14 patients for which additional GdT1w would have been ordered based on T2w alone, increasing sensitivity to 93% (95% CI: 77.9%-99.2%) and negative predictive value to 99.7% (95% CI: 98.9%-100%). Inter-rater agreement for T2w was 98% (95% CI: 96.4-98.8). CONCLUSION: T2w has a very high diagnostic accuracy for the presence of CPA lesions in patients with asymmetrical audiovestibular complaints. However, in a screening protocol with T2w only, smallest vestibular schwannomas as well as rare differential diagnoses that probably only would be detected on GdT1w may remain unnoticed.

Psychological impact of a genetic diagnosis on hearing impairment-An exploratory study.

OBJECTIVE: Genetic testing for hereditary hearing impairment has become more routinely available as a diagnostic tool in the outpatient clinic. However, little is known about the psychological impact of a genetic diagnosis. To evaluate this impact, an exploratory study was conducted. DESIGN: Prospectively, 48 individuals who underwent genetic testing for hereditary hearing impairment were included in this study. Study participants were asked to fill out the following questionnaires: Hospital Anxiety Depression Scale, Impact of Event Scale, Self-Efficacy 24, Illness Cognition Questionnaire and the Inventory for Social Reliance. Questionnaires were filled out on three occasions: before genetic testing, directly after counselling on either positive or negative test results, and six weeks thereafter. RESULTS: No significant differences were found between the group that received a genetic diagnosis for their hearing impairment and the group that did not. CONCLUSION: This study did not demonstrate differences between receiving a genetic diagnosis or not; however, special attention to psychological well-being should be offered to hearing-impaired patients who seek a genetic diagnosis for their hearing impairment. Additionally, the psychological impact of sensorineural hearing impairment might be greater than the impact of a genetic diagnosis itself. Based on the current exploratory study, there are no psychological reasons in favour of or against genetic testing for hereditary hearing impairment.

Potential savings in the diagnosis of vestibular schwannoma.

INTRODUCTION: Magnetic resonance imaging (MRI) is used to screen patients at risk for vestibular schwannoma (VS). These MRIs are costly and have an extremely low yield; only 3% of patients in the screening population has an actual VS. It might be worthwhile to develop a test to predict VS and refer only a subset of all patients for MRI. OBJECTIVE: To examine the potential savings of such a hypothetical diagnostic test before MRI. DESIGN: We built a decision analytical model of the diagnostic strategy of VS. Input was derived from literature and key opinion leaders. The current strategy was compared to hypothetical new strategies, assigning MRI to the following: (i) all patients with pathology, (ii) all patients with important pathology and (iii) only patients with VS. This resulted in potential cost savings for each strategy. We conducted a budget impact analysis to predict nationwide savings for the Netherlands and the United Kingdom (UK), and a probabilistic sensitivity analysis to address uncertainty. RESULTS: Mean savings ranged from €256 (95%CI €250 - €262) or approximately US$284 (95%CI US$277 - US$291) per patient for strategy 1 to €293 (95%CI €290 - €296) or approximately US$325 (95%CI US$322 - US$328) per patient for strategy 3. Future diagnostic strategies can cost up to these amounts per patient and still be cost saving. Annually, for the Netherlands, €2.8 to €3.2 million could be saved and €10.8 to €12.3 million for the UK. CONCLUSIONS: The model shows that substantial savings could be generated if it is possible to further optimise the diagnosis of VS.

A meta-analysis on the surgical management of paraganglioma of the carotid body per Shamblin class.

OBJECTIVE: The aim of this study was to evaluate the risk associated with different types of surgery for carotid body paraganglioma of different Shamblin class. A meta-analysis was conducted to evaluate per tumour class, the local control, cranial nerve damage and complication rates of different techniques using internal carotid artery (ICA) and external carotid artery (ECA) ligation, clamping or bypassing, as well as the craniocaudal vs caudocranial techniques. DESIGN: A meta-analysis is conducted after a systematic search in PubMed and the Cochrane library, in accordance with the PRISMA guidelines. MAIN OUTCOME MEASURES: Local control, cranial nerve damage, complications, function recovery. RESULTS: Out of 3565 articles, 27 were selected. The overall quality of evidence of studies was low. Cranial nerve damage (3%, 17% and 39%) and complication rates (0%, 1% and 10%) were significantly related to Shamblin class (class 1, 2 and 3, respectively, P < .01). For class 3 tumours, an increased risk of complications was found associated with routine ICA manipulation/reconstruction (RR 3.12 with a 95% CI of 1.29-7.59), as well as a trend towards enhanced risk of routine ECA ligation (RR 3.48 with a 95% CI of 0.88-13.81). CONCLUSIONS: For class 1 and 2 tumours, surgery seems a viable treatment option. For class 3 tumours, morbidity in terms of cranial nerve deficit and complications is considerable; particularly, the use of ICA manipulation/reconstruction and potentially ECA ligation seem to be accompanied by high stroke incidence.

Results of a systematic literature review of treatment modalities for jugulotympanic paraganglioma, stratified per Fisch class.

OBJECTIVE: Key for successful jugulotympanic paraganglioma management is a personalised approach aiming for the best practice for each individual patient. To this end, a systematic review is performed, evaluating the local control and complication rates for the different treatment modalities stratified by the broadly accepted Fisch classification. DESIGN: A systematic literature review according to the PRISMA statement was performed. A detailed overview of individual treatment outcomes per Fisch class is provided. MAIN OUTCOME MEASURES: Local control, cranial nerve damage, complications, function recovery. RESULTS: Eighteen studies were selected, resembling 83 patients treated with radiotherapy and 299 with surgery. Excellent local control was found post-surgery for class A and B tumours, and risk of cranial nerve damage was <1%. For class C1-4 tumours, local control was 80%-95% post-surgery (84% post-radiotherapy), and cranial nerve damage was found in 71%-76% (none post-radiotherapy; P < .05). There was no difference in treatment outcomes between tumours of different C class. For class C1-4De/Di tumours, local control was 38%-86% (98% post-radiotherapy; P < .05) and cranial nerve damage/complication rates were 67%-100% (3% post-radiotherapy; P < .05). C1-4DeDi tumours showed lesser local control and cranial nerve damage rates when compared to C1-4De tumours. CONCLUSIONS: An individual risk is constituted for surgery and radiotherapy, stratified per Fisch class. For class A and B tumours, surgery is a suitable treatment option. For class C and D tumours, radiotherapy results in lower complication rates and similar or better local control rates when compared to the surgical group.

Intestinal tuberculosis: a diagnostic challenge.

OBJECTIVE: To describe characteristics, presentation, time to diagnosis and diagnostic findings of patients with intestinal tuberculosis (ITB) in a low-burden country. METHOD: Retrospective study of 61 consecutive ITB patients diagnosed between 2008 and 2014 at a large East London hospital. RESULTS: Forty of sixty-one patients were male. Mean age was 34.6 years. 93% of patients were born abroad, mostly from TB-endemic areas (Indian subcontinent: 88%, Africa: 9%). 25% had concomitant pulmonary TB. Median time from symptom onset to ITB diagnosis was 13 weeks (IQR 3-26 weeks). Ten patients were initially treated for IBD, although patients had ITB. The main sites of ITB involvement were the ileocaecum (44%) or small bowel (34%). Five patients had isolated perianal disease. Colonoscopy confirmed a diagnosis of ITB in 77% of those performed. 42 of 61 patients had a diagnosis of ITB confirmed on positive histology and/or microbiology. CONCLUSION: Diagnosis of ITB is often delayed, which may result in significant morbidity. ITB should be excluded in patients with abdominal complaints who come from TB-endemic areas to establish prompt diagnosis and treatment. Diagnosis is challenging but aided by axial imaging, colonoscopy and tissue biopsy for TB culture and histology.

Maternal and perinatal mortality and morbidity associated with tuberculosis during pregnancy and the postpartum period: a systematic review and meta-analysis.

BACKGROUND: There is a dearth of data on the clinical features and outcomes of active tuberculosis (TB) in pregnancy. Studies have shown varied results and the relationship between TB and adverse pregnancy outcomes remains unclear. OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate pregnancy outcomes associated with TB. SEARCH STRATEGY: Major databases were searched from inception until December 2015 without restrictions using the terms: 'TB', 'pregnancy', 'maternal morbidity', 'mortality' and 'perinatal morbidity', 'mortality'. SELECTION CRITERIA: We included studies that compared the outcomes of pregnant women with and without active TB. DATA COLLECTION AND ANALYSIS: We computed odds ratios for maternal and perinatal complications, and pooled them using a random effects model. We assessed for heterogeneity using chi-squared tests and evaluated its magnitude using the I2 statistic. We used the Newcastle-Ottawa scale for quality assessment. MAIN RESULTS: Thirteen studies, including 3384 pregnancies with active TB and 119 448 without TB were included. Compared with pregnant women without TB, pregnant women with active TB was associated with increased odds of maternal morbidity [odds ratio (OR) 2.8, 95% CI 1.7-4.6; I2  = 60.3%], anaemia (OR 3.9, 95% CI 2.2-6.7; I2  = 29.8%), caesarean delivery (OR 2.1, 95% CI 1.2-3.8; I2  = 61.1%), preterm birth (OR 1.7, 95% CI 1.2-2.4; I2  = 66.5%), low birth weight (OR 1.7, 95% CI 1.2-2.4; I2  = 53.7%), birth asphyxia (OR 4.6, 95% CI 2.4-8.6; I2  = 46.3), and perinatal death (OR 4.2, 95% CI 1.5-11.8; I2  = 57.2%). AUTHOR'S CONCLUSION: Active TB in pregnancy is associated with adverse maternal and fetal outcomes. Early diagnosis of TB is important to prevent significant maternal and perinatal complications. TWEETABLE ABSTRACT: Active tuberculosis in pregnancy is associated with adverse maternal and perinatal outcomes.

Imaging features and diagnosis of tuberculosis of the breast.

AIM: To outline the pathophysiology, clinical presentation, imaging features, and relevant investigations of the different subtypes of breast tuberculosis (TB). MATERIALS AND METHODS: A review was undertaken of all cases (33 in total) of breast TB presenting to Barts Health NHS Trust within a 10-year period, including patient demographics, imaging features, and route of diagnosis. RESULTS: Thirty-three cases of proven granulomatous TB of the breast were identified (11 mastitis obliterans, 10 nodular caseous form, five sclerosing form, four disseminated disease, and three abnormal axillary lymph nodes). No cases of miliary breast TB were identified. Fine-needle aspiration cytology aided diagnosis in six patients (<20% of cases); however, the majority of patients required further investigation; namely core biopsy. Over a third of patients (12/33) had multiple clinic attendances prior to diagnosis. Mean delay in diagnosis was 3.7 months (median 0 months, IQR= 3). CONCLUSION: Breast TB is a rare challenging diagnosis with a wide range of imaging features. Core biopsy is essential for definitive diagnosis. A multidisciplinary approach involving surgeons, radiologists, TB consultants, and microbiologists is required, coupled with a high index of clinical suspicion in order to aid timely diagnosis, and initiate prompt treatment to reduce complications.

The diagnostic accuracy of non-imaging screening protocols for vestibular schwannoma in patients with asymmetrical hearing loss and/or unilateral audiovestibular dysfunction: a diagnostic review and meta-analysis.

BACKGROUND: Currently, all patients presenting with asymmetrical sensorineural hearing loss and/or unilateral audiovestibular dysfunction (i.e. tinnitus, dizziness) undergo MRI, leading to a substantial amount of MRIs with negative findings as the incidence of vestibular schwannoma (VS) in this screening population varies between 1% and 4.7% (i.e. more than 95% of MRIs are negative for VS). OBJECTIVE OF REVIEW: The aim was to assess the diagnostic accuracy of different non-imaging screening protocols that can be used prior to MRI to select patients at high risk of VS. TYPE OF REVIEW: Diagnostic review and meta-analysis. SEARCH STRATEGY: We systematically searched MEDLINE, Embase and The Cochrane Library as from inception up to 28 July 2016. We included studies that compared non-imaging screening protocols to MRI as gold reference standard. EVALUATION METHOD: Methodological quality was assessed by two independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies tool. Data necessary to complete 2 × 2 tables were obtained, and patient, study, screening and imaging characteristics were extracted. We calculated sensitivity and specificity of all tests and obtained pooled estimates using a bivariate random effects model. RESULTS: We analysed 12 studies (4969 patients) of poor to moderate quality according to the quality assessment. Most studies tested diagnostic accuracy of multiple screening protocols. Five pure-tone audiometry (PTA) protocols were studied by multiple authors; pooled estimates for sensitivity ranged from 88% [95% CI: 84-91] to 91% [95% CI: 52-99] and specificity from 31% [95% CI: 10-66] to 58% [95% CI: 49-65]. Due to heterogeneity, we were unable to pool other tests. In five studies testing auditory brainstem response, sensitivity values ranged from 37% [95% CI: 23-52] to 100% [95% CI: 40-100] and specificity from 57% to 96% [95% CI: 87-100]. Two authors studied PTA shape as a screening test. Presenting symptoms, electronystagmography, caloric irrigation and hyperventilation test were assessed by one study each. All reported low diagnostic accuracy. CONCLUSIONS: All identified studies had a moderate-to-high risk of bias, and none of the currently available non-imaging screening protocols appear to be accurate in detecting VSs.

Hearing aid fitting for visual and hearing impaired patients with Usher syndrome type IIa.

OBJECTIVES: Usher syndrome is the leading cause of hereditary deaf-blindness. Most patients with Usher syndrome type IIa start using hearing aids from a young age. A serious complaint refers to interference between sound localisation abilities and adaptive sound processing (compression), as present in today's hearing aids. The aim of this study was to investigate the effect of advanced signal processing on binaural hearing, including sound localisation. DESIGN AND PARTICIPANTS: In this prospective study, patients were fitted with hearing aids with a nonlinear (compression) and linear amplification programs. Data logging was used to objectively evaluate the use of either program. Performance was evaluated with a speech-in-noise test, a sound localisation test and two questionnaires focussing on self-reported benefit. RESULTS: Data logging confirmed that the reported use of hearing aids was high. The linear program was used significantly more often (average use: 77%) than the nonlinear program (average use: 17%). The results for speech intelligibility in noise and sound localisation did not show a significant difference between type of amplification. However, the self-reported outcomes showed higher scores on 'ease of communication' and overall benefit, and significant lower scores on disability for the new hearing aids when compared to their previous hearing aids with compression amplification. CONCLUSIONS: Patients with Usher syndrome type IIa prefer a linear amplification over nonlinear amplification when fitted with novel hearing aids. Apart from a significantly higher logged use, no difference in speech in noise and sound localisation was observed between linear and nonlinear amplification with the currently used tests. Further research is needed to evaluate the reasons behind the preference for the linear settings.

Features of autosomal recessive non-syndromic hearing impairment: a review to serve as a reference.

OBJECTIVE: Non-syndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counselling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient. TYPE OF REVIEW: Traditional literature review. DATA SOURCE: All articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed. CONCLUSION: This review aims to serve as a summary and a reference for counselling purposes when a causative gene has been identified in a patient with a non-syndromic autosomal recessively inherited sensorineural hearing impairment.

Patients with Pendred syndrome: is cochlear implantation beneficial?

OBJECTIVE: To evaluate the benefit of cochlear implantation in patients with Pendred syndrome. DESIGN: Retrospective study. SETTING: Tertiary centre. PARTICIPANTS AND MAIN OUTCOME MEASURES: Speech perception was measured using a phonetically balanced word list at a sound pressure level of 65 dB. Post-operative phoneme scores at 12-month for adults and 36-month for children with Pendred syndrome were compared to scores of patients with an enlarged vestibular aqueduct (EVA) and a reference group with an unknown cause of hearing impairment. Quality of life was measured with the Nijmegen Cochlear Implant Questionnaire to evaluate the differences between pre- and post-implantation. RESULTS: The mean post-operative phoneme scores were as follows: in the Pendred group, 91% (n = 16; SD = 10) for children and 78% (n = 7; SD = 14) for adults; in the reference group, 79% (n = 59; SD = 20) for children and 73% (n = 193; SD = 18) for adults; and in the EVA group, 84% (n = 6; SD = 7) for children and 66% (n = 12; SD = 22) for adults. A significant difference in speech perception was found between the children of the Pendred group and the reference group of 11.4% (SE = 5.2; P = 0.031). Between the adults, a difference of 11.2% (SE = 6.7; P = 0.094) was found. The difference between the Pendred group and the EVA group was 5.7%(SE = 4.5; P = 0.22) for children and 9.9% (SE = 8.7; P = 0.28) for adults. A significant improvement post-implantation in four of the six subdomains of the quality of life questionnaire was found: basic sound perception (P = 0.002), advanced sound perception (P = 0.004), speech production (P = 0.018) and activity limitations (P = 0.018). The two not significant subdomains were self-esteem (P = 0.164) and social interaction (P = 0.107). CONCLUSIONS: After cochlear implantation, children with Pendred syndrome performed better than the reference group with respect to speech perception, however, adults performed similar. No significant differences were found between the Pendred and EVA group. Consequently, during pre-operative counselling, the two groups of patients may be considered comparable in terms of expected speech perception performance after cochlear implantation.

R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17.

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disease caused by mutation of MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (NMMHC-IIA). MYH9-RD patients have macrothrombocytopenia and granulocyte inclusions (pathognomonic sign of the disease) containing wild-type and mutant NMMHC-IIA. During life they might develop sensorineural hearing loss, cataract, glomerulonephritis, and elevation of liver enzymes. One of the MYH9 mutations, p.R705H, was previously reported to be associated with DFNA17, an autosomal dominant non-syndromic sensorineural hearing loss without any other features associated. We identified the same mutation in two unrelated families, whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes. Our data suggest that DFNA17 should not be a separate genetic entity but part of the wide phenotypic spectrum of MYH9-RD characterized by congenital hematological manifestations and variable penetrance and expressivity of the extra-hematological features.

Genotype phenotype correlations for hearing impairment: approaches to management.

Hearing impairment is an extremely heterogeneous disorder, with both environmental as well as genetic causes. This review describes the known genes involved in non-syndromic hearing impairment and their genotype-phenotype correlations where possible. Furthermore, some of the more frequent syndromic forms of hearing impairment are described, in particular where they overlap with the non-syndromic forms. Given the heterogeneity of the disorder, together with the indistinguishable phenotypes for many of the genes, it is suggested that testing for mutations is performed using massive parallel sequencing techniques, either by a large targeted set of genes or by an exome wide analysis.

Audiometric characteristics of a dutch family with a new mutation in GATA3 causing HDR syndrome.

We present the case of a Dutch family with a new mutation (c523_528dup) in GATA3 causing HDR syndrome. HDR syndrome is characterised by hypoparathyroidism, deafness and renal defects. In this study, we describe the audiometric characteristics of 5 patients from this family. Their hearing impairment was congenital, bilateral and symmetric. Audiograms showed mild-to-moderate hearing impairment with a flat audiogram configuration. Higher frequencies tended to be affected more strongly. Cross-sectional analyses showed no progression, and a mean audiogram was established. Psychophysical measurements in 3 HDR patients - including speech reception in noise, loudness scaling, gap detection and difference limen for frequency - were obtained to assess hearing function in greater detail. Overall, the results of the psychophysical measurements indicated characteristics of outer hair cell loss. CT scanning showed no anomalies in 3 of the HDR patients. Although 2 patients displayed vestibular symptoms, no anomalies in the vestibular system were found by vestibulo-ocular examination. Our results are in agreement with the theory that outer hair cell malfunctioning can play a major role in HDR syndrome.