Etiology of Childhood Profound Sensorineural Hearing Loss: The Role of Hearing Loss Gene Panel Testing.

OBJECTIVE: Establishing the cause of hearing loss (HL) is important and rewarding, though not without its challenges. While our ability to identify the etiology for HL has improved with advances in scientific knowledge, a significant proportion of cases remain of unknown etiology. Recent protocol changes within the NHS Genomic Medicine Service support the utilization of the HL gene panel test, rather than individual gene tests. In light of these changes, determining the yield of these more extensive panel tests is important in informing future practice. STUDY DESIGN: Retrospective study. SETTING: The Cochlear Implant (CI) Department at Great Ormond Street Hospital (GOSH). METHODS: Four hundred seventy-six children with profound HL were identified from a database of referrals to the GOSH CI Department. Data on etiology of HL including genetic diagnosis was collected from hospital notes on an electronic patient records system and hospital genetics database. RESULTS: We identified a positive result in 163/476 (34%) cases through the gene panel test, representing an additional 19% yield to current level 1 investigations. Genetic HL, including both syndromic (including those not covered by the HL gene panel) and nonsyndromic (209/476, 44%) was the most common etiology in our cohort. Perinatal, intrauterine, ototoxicity, meningitis, and encephalitis categories altogether comprised 97/476 (20%) cases. CONCLUSION: Gene panel testing provides significant additional yield over current level 1 investigations which include GJB2 testing only. This has far-reaching implications for how we optimize investigations into HL in children and counsel families, and for future early interventions.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.

Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Impact of sight and hearing loss in patients with Norrie disease: advantages of Dual Sensory clinics in patient care.

Norrie disease (ND) is a rare, X-linked condition of visual and auditory impairment, often presenting with additional neurological features and developmental delays of varying severity. While all affected patients are born blind, or lose their vision in infancy, progressive sensorineural hearing loss develops in the majority of cases and is typically detected in the second decade of life. A range of additional symptoms of ND, such as seizure disorders, typically appear from a young age, but it is difficult to predict the range of symptoms ND patients will experience. After growing up without vision, hearing loss represents the greatest worry for many patients with ND, as they may lose the ability to participate in previously enjoyed activities or to communicate with others. Dual sensory loss has a physical, psychosocial and financial impact on both patients with ND and their families. Routine monitoring of the condition is required in order to identify, treat and provide support for emerging health problems, leading to a large burden of medical appointments. Many patients need to travel long distances to meet with specialists, representing a further burden on time and finances. Additionally, the rare nature of dual sensory impairment in children means that few clinical environments are designed to meet their needs. Dual Sensory clinics are multidisciplinary environments designed for sensory-impaired children and have been suggested to alleviate the impact of diseases involving sensory loss such as ND. Here, we discuss the diagnosis, monitoring and management of ND and the impact it has on paediatric patients and their caregivers. We describe the potential for dual sensory clinics to reduce disease burden through providing an appropriate clinical environment, access to multiple clinical experts in one visit, and ease of monitoring for patients with ND.

Usher syndrome: clinical features, molecular genetics and advancing therapeutics.

Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction. It is the most common cause of deaf-blindness worldwide with a prevalence of between 4 and 17 in 100 000. To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome. Variants in these genes can also cause non-syndromic RP and deafness. Genotype-phenotype correlations have been described for several of the Usher genes. Hearing loss is managed with hearing aids and cochlear implants, which has made a significant improvement in quality of life for patients. While there is currently no available approved treatment for the RP, various therapeutic strategies are in development or in clinical trials for Usher syndrome, including gene replacement, gene editing, antisense oligonucleotides and small molecule drugs.

Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

Consensus Statement of the Indian Academy of Pediatrics on Newborn Hearing Screening.

JUSTIFICATION: Hearing impairment is one of the most critical sensory impairments with significant social and psychological consequences. Evidence-based, standardized national guidelines are needed for professionals to screen for hearing impairment during the neonatal period. PROCESS: The meeting on formulation of national consensus guidelines on developmental disorders was organized by Indian Academy of Pediatrics in Mumbai, on 18th and 19th December, 2015. The invited experts included Pediatricians, Developmental Pediatricians, Pediatric Neurologists and Clinical Psychologists. The participants framed guidelines after extensive discussions. OBJECTIVE: To provide guidelines on newborn hearing screening in India. RECOMMENDATIONS: The first screening should be conducted before the neonate's discharge from the hospital - if it 'fails', then it should be repeated after four weeks, or at first immunization visit. If it 'fails' again, then Auditory Brainstem Response (ABR) audiometry should be conducted. All babies admitted to intensive care unit should be screened via ABR. All babies with abnormal ABR should undergo detailed evaluation, hearing aid fitting and auditory rehabilitation, before six months of age. The goal is to screen newborn babies before one month of age, diagnose hearing loss before three months of age and start intervention before six months of age.

The bony cochlear nerve canal in children with absent or hypoplastic cochlear nerves.

OBJECTIVE: To correlate presence and size of the bony cochlear nerve canal [BCNC] with size of the internal auditory meatus [IAM] on CT in children with absent or hypoplastic cochlear nerves [CNs] as compared to age matched controls. METHODS: This retrospective case-notes review was based in the departments of Cochlear Implantation and Neuroradiology at a tertiary paediatric hospital. Twenty-five ears of fifteen children (subjects) with profound sensorineural deafness (SND) and absent or hypoplastic CN on MRI scan were compared to age matched controls. Two groups of controls were included; a control group of nineteen ears of twelve children with normal hearing or conductive hearing loss [control group 1] and a second control group of twenty one ears of eleven children with severe to profound hearing loss related to GJB2 mutations [control group 2]. Both control groups had evidence of the presence of the CN. Two neuroradiologists independently assessed presence and size of BCNC and IAM on CT and presence of CN on MRI in subjects and controls. The BCNC and IAM size was compared between subjects and both control groups. The presence of BCNC was correlated with the IAM size on CT, presence/absence of CN on MRI and audiological evaluation in subjects. RESULTS: The mean IAM width was significantly smaller in subjects as compared to controls. The BCNC was absent in 17/25 subject ears and present in all control ears. Absent BCNC correlated with a narrow IAM in 13/17 subject ears. Presence of the BCNC supported presence of a CN although this was not seen on MRI. However, BCNC absence may be associated with presence of a CN as was seen in two subject ears. Five subject ears out of 22 [22%] with absent CN on MRI had other evidence of a present cochlear nerve. CONCLUSIONS: BCNC is an additional parameter to assess presence of the cochlear branch of the CN. Presence of the BCNC may indicate cochlear nerve presence. Caution should be used in assessing candidacy of cochlear implants based on MRI alone and a combination of imaging and audiological tests should be used to assess presence of the CN.

Subjective visual vertical and horizontal: effect of the preset angle.

OBJECTIVES: (1) To study the subjective visual vertical (SVV) and subjective visual horizontal (SVH) in patients with long-standing unilateral peripheral vestibular dysfunction (PVD) and unilateral Ménière's disease (MD) compared with controls. (2) To study the relationship between the direction of deviation of the linear marker (preset angle) and measures of SVV and SVH values. DESIGN: Prospective case-control study. SETTING: Outpatient clinic in a tertiary neuro-otology department. PATIENTS: Seventeen healthy volunteers (mean age, 35.5 years), 9 patients with PVD (mean age, 43.1 years), and 10 patients with MD (mean age, 50.7 years) were included in the analysis. INTERVENTIONS: All subjects had a detailed neuro-otological evaluation. Twelve replicate readings of SVV and SVH were taken for each subject, with random preset angles, 6 in the clockwise and 6 in the counterclockwise direction. MAIN OUTCOME MEASURE: The SVV and SVH values were correlated with clinical features and the direction of the preset angle. RESULTS: The 2 subjects with PVD who had abnormal mean SVV and SVH values had symptoms of dysequilibrium and otolithic involvement. The 5 patients in the MD group who had abnormal mean SVV and SVH values had either recent acute vertiginous attacks or total canal paresis on the affected side. A previously unreported finding, to our knowledge, is that the SVV value depends on the direction of the preset angle in all subject groups, more so in the PVD and MD groups compared with controls. The SVV is inclined toward the direction of the preset angle. A weaker relation is seen between the SVH and preset angle. CONCLUSION: The preset angle should be considered when comparing SVV and SVH values.

Late postnatal onset of hearing loss due to GJB2 mutations.

GJB2 mutations account for approximately 50% of recessive non-syndromic deafness, with 35delG being the most prevalent. Homozygous 35delG mutations cause pre-lingual, non-progressive hearing loss that is detected on newborn hearing screening programmes. We present a sibling pair with homozygous 35delG mutations, who passed hearing tests in early infancy and developed progressive sensorineural hearing loss, one requiring a cochlear implant. These cases illustrate that deafness due to such mutations may have a late onset and consequently be missed on neonatal screening programmes and they may present an argument to consider neonatal screening for GJB2 mutations in order to aid early intervention.