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.

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.

CT findings of the temporal bone in CHARGE syndrome: aspects of importance in cochlear implant surgery.

To provide an overview of anomalies of the temporal bone in CHARGE syndrome relevant to cochlear implantation (CI), anatomical structures of the temporal bone and the respective genotypes were analysed. In this retrospective study, 42 CTs of the temporal bone of 42 patients with CHARGE syndrome were reviewed in consensus by two head-and-neck radiologists and two otological surgeons. Anatomical structures of the temporal bone were evaluated and correlated with genetic data. Abnormalities that might affect CI surgery were seen, such as a vascular structure, a petrosquamosal sinus (13 %), an underdeveloped mastoid (8 %) and an aberrant course of the facial nerve crossing the round window (9 %) and/or the promontory (18 %). The appearance of the inner ear varied widely: in 77 % of patients all semicircular canals were absent and the cochlea varied from normal to hypoplastic. A stenotic cochlear aperture was observed in 37 %. The middle ear was often affected with a stenotic round (14 %) or oval window (71 %). More anomalies were observed in patients with truncating mutations than with non-truncating mutations. Temporal bone findings in CHARGE syndrome vary widely. Vascular variants, aberrant route of the facial nerve, an underdeveloped mastoid, aplasia of the semicircular canals, and stenotic round window may complicate cochlear implantation.

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.

Vestibular function and temporal bone imaging in DFNB1.

DFNB1 is the most prevalent type of hereditary hearing impairment known nowadays and the audiometric phenotype is very heterogeneous. There is, however, no consensus in literature on vestibular and imaging characteristics. Vestibular function and imaging results of 44 DFNB1 patients were evaluated in this retrospective study. All patients displayed a response during rotational velocity step testing. In 65% of the cases, the caloric results were within normal range bilaterally. The video head impulse test was normal in all patients. In 34.4% of the CT scans one or more temporal bone anomalies were found. The various anomalies found, were present in small numbers and none seemed convincingly linked to a specific DFNB1genotype. The group of DFNB1 patients presented here is the largest thus far evaluated for their vestibular function. From this study, it can be assumed that DFNB1 is not associated with vestibular dysfunction or specific temporal bone anomalies.

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.

Audiometric characteristics of two Dutch families with non-ocular Stickler syndrome (COL11A2).

OBJECTIVE: To evaluate hearing impairment and cochlear function in non-ocular Stickler syndrome. STUDY DESIGN: Multifamily study. PATIENTS & METHODS: Ten patients from two different families with non-ocular Stickler syndrome (Stickler syndrome type 3) were included. Six members of the first family and four members of the second family participated in this study. Otorhinolaryngologic examinations were performed. Pure-tone and speech audiograms were obtained. Longitudinal analysis was performed. Psychophysical measurements, including loudness scaling, gap detection, difference limen for frequency and speech perception in noise were administered to assess cochlear function at a deeper level. RESULTS: Affected individuals in the first family were carriers of a heterozygous splice donor mutation in the COL11A2 gene. Affected individuals in the second family were carriers of a novel heterozygous missense mutation in COL11A2. Both families showed bilateral, non-progressive hearing impairment with childhood onset. The severity of the hearing impairment exhibited inter- and intrafamilial variability and was mostly mild to moderate. The results of the psychophysical measurements were similar to those previously published for DFNA8/12 (TECTA) and DFNA13 (COL11A2) patients and thus consistent with an intra-cochlear conductive hearing impairment. This is in line with the theory that mutations in COL11A2 affect tectorial membrane function. CONCLUSION: Hearing impairment in non-ocular Stickler syndrome is characterized by non-progressive hearing loss, present since childhood, and mostly mild to moderate in severity. Psychophysical measurements in non-ocular Stickler patients were suggestive of intra-cochlear conductive hearing impairment.