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.

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.

BACKGROUND: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. METHODS: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. RESULTS: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. CONCLUSIONS: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

Changes in the aetiology of hearing impairment in deaf-blind pupils and deaf infant pupils at an institute for the deaf.

An aetiological study was performed on 57 pupils at the deaf-blind department of the Institute for the Deaf at Sint-Michielsgestel, The Netherlands, in the school year 1998-1999 and on 49 deaf-blind pupils at the same department in the school year 1986-1987. The pupils were 5-20 years of age. In addition, the aetiologies were studied in 55 deaf infant pupils in 1998 and compared with those of 68 deaf infant pupils in 1988. Their age was 1-5 years. All the pupils showed hearing impairment with thresholds of >60 dB HL. Among the deaf-blind pupils and deaf infant pupils, there were several cases with rare hereditary syndromes. The prevalence of acquired causes of deafness, especially congenital rubella, had decreased over the years, whereas perinatal causes of deafness had increased. Chromosomal anomalies were found in 15% of the infant pupils in 1998. Over the study period, the percentage of pupils with multiple handicaps increased from 25 to 38%.

Hearing loss in the nonocular Stickler syndrome caused by a COL11A2 mutation.

OBJECTIVE: Evaluation of hearing impairment as a feature of the nonocular Stickler syndrome (type II) linked to COL11A2. STUDY DESIGN: Family study. METHODS: General, orthopaedic, ophthalmologic, and otorhinolaryngologic examinations were performed on 15 affected persons in a Dutch family. Audiograms were obtained and/or retrieved from elsewhere. Cross-sectional and longitudinal analyses were conducted on the hearing threshold (sensorineural component) in relation to the patient's age to evaluate whether hearing impairment was progressive. RESULTS: Mixed hearing loss, i.e., including a substantial air-bone gap of up to 20 to 60 dB, was present in six cases, concomitantly with a submucous or overt cleft palate in five of them. The audiograms in 14 evaluable cases showed the following types of threshold: U-shaped (n = 3), flat (n = 2), flat or gently (downward) sloping (n = 3), gently sloping (n = 3), or steeply sloping (n = 3). Cross-sectional analysis did not reveal any significant effect of age on sensorineural hearing impairment. CONCLUSION: In contrast to the classic Stickler syndrome (type I) with high myopia, this nonocular type shows a high prevalence of sensorineural hearing impairment. The mean sensorineural hearing threshold in our patients was about 40 dB HL (95% CI, 15-65 dB) and was liable to increase (presumably by presbycusis) by several tens of decibels at the highest frequencies. Given the tendency for otitis media to develop in many of these patients, appropriate otologic care is of major importance.

Causes of hearing impairment in deaf pupils with a mental handicap.

An aetiological study was performed on 122 deaf pupils (57 aged < 20 years, 65 aged > 20 years) at the Institute for the Deaf in Sint-Michielsgestel, The Netherlands. Besides hearing impairment with thresholds of > 60 dB HL, all the participants had a mental handicap with a non-verbal IQ of 40-80. Sixteen per cent of them were of non-Dutch origin. The cause of hearing impairment was acquired in 48%, inherited in 17%, chromosomal in 4% and unknown in 30%. In comparison with other studies on the aetiology of childhood deafness, acquired causes predominated over inherited causes, which may be typical of deafness combined with a mental handicap. We found a significant predominance of non-Dutch pupils among the rubella aetiology cases and male predominance among the hearing impaired pupils in general.

Progressive hearing loss, hypoplasia of the cochlea and widened vestibular aqueducts are very common features in Pendred's syndrome.

Long-term hearing threshold-on-age follow-up data, including non-linear regression analysis, are given for 12 consecutive Pendred patients. The clinical diagnosis of Pendred's syndrome was confirmed by a mutation analysis of the PDS gene in 11 out of the 11 cases tested. Recent imaging of the temporal bones in seven out of these 12 patients showed widened vestibular aqueducts in each case. The diagnostic perchlorate test was negative in one patient, but this test was positive in her affected sister. Mutation analysis of the PDS gene in these patients confirmed that Pendred's syndrome is a monogenetic disorder. Progressive sensorineural hearing loss and widened vestibular aqueducts are characteristic features of Pendred's syndrome, which provides the opportunity to diagnose Pendred's syndrome clinically in the first few years of life, as has recently been suggested in a case report (Cremers et al., Progressive sensorineural hearing loss and a widend vestibular aqueduct in Pendred syndrome, Arch. Otolaryngol. 124 (1998) 501-505). Mutation analysis of the involved gene can be used to confirm the clinical diagnosis.

Temporal bone CT findings in the CHARGE association.

Ten out of 20 cases with the CHARGE association and two CHARGE-like cases underwent temporal bone CT scanning and/or MRI: they all showed bilateral aplasia of the semicircular canals and obliteration of the oval windows. Vestibular examination was performed in nine CHARGE cases and the two CHARGE-like cases, which disclosed vestibular areflexia in all of them. Of the 16 evaluable CHARGE cases, eight had bilateral mixed hearing impairment, while eight had sensorineural hearing impairment which was bilateral in six and unilateral in two cases. Temporal bone CT scanning is therefore indicated in suspected CHARGE cases, even if they show normal hearing or a relatively good bone conduction threshold in one or both ears.

Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome.

Pendred syndrome is an autosomal recessive inherited disorder. Obligatory features are profound deafness in childhood and defective organic binding of iodine in the thyroid gland. Therefore, goiter is a common symptom. Hypoplasia of the cochlea is another feature. Recently, the gene for Pendred syndrome was identified. We describe a boy whose sensorineural hearing loss in both ears progressed rapidly from about 50 to 60 dB at the age of 3 years and 3 months to more than 100 dB at the age of 4 years and 4 months. This loss was preceded by a medical history of a progressive hearing loss. The progressive nature of the hearing loss motivated a search for the cause. Dysplasia of the cochlea and a widened vestibular aqueduct were found. The results of thyroid function tests were normal, but he had an elevated level of thyroglobulin. The diagnosis of Pendred syndrome was confirmed by the positive results of a potassium perchlorate test, indicating defective organic binding of iodine in the thyroid gland. It is possible that the widened vestibular aqueduct was responsible for the increase in the hearing impairment. Aside from the branchio-otorenal syndrome, Pendred syndrome is the only other known genetic disorder with a widened vestibular aqueduct. If a child has progressive sensorineural deafness and a widened vestibular aqueduct, it is important to consider a diagnosis of Pendred syndrome. A widened vestibular aqueduct may help to elucidate the pathophysiologic characteristics of hearing loss in these genetic types of deafness in childhood.

Vestibular areflexia as a cause of delayed motor skill development in children with the CHARGE association.

Six cases of the CHARGE association are described that were encountered consecutively at an institute for the deaf. Five of them showed external ear anomalies and according to expectations all of them showed some degree of hearing impairment: two had moderate mixed hearing loss; three had severe to profound sensorineural hearing loss; and one was completely deaf. In addition, they all had vestibular areflexia and the five cases examined with computer tomography of the petrosal bones showed aplasia of the semicircular canals. One case with poor visual acuity also showed subnormal optokinetic responses and horizontal pendular nystagmus during visual fixation. All these children were initially diagnosed as having severe psychomotor retardation, because of their failure to acquire speech and their delayed motor skill development. Given the fact that (mild) mental retardation was found in only one case, the delayed development could at least in part have been caused by vestibular areflexia. The vestibular findings support previously reported temporal bone findings that indicate dysplasia or aplasia of the superior part of the labyrinth. Early detection of the full extent of (multiple) sensory deficits is necessary in children with the CHARGE association who have similar abnormalities, because aggressive intervention and special educational support are likely to be of great benefit to sensorimotor development.

Audiovestibular sequelae of congenital cytomegalovirus infection in 3 children presumably representing 3 symptomatically different types of delayed endolymphatic hydrops.

Three cases of congenital cytomegalovirus (CMV) infection with long-term audiovestibular sequelae are presented. Case 1 had no hearing in one ear and severe progressive hearing loss in the other ear; he showed vestibular symptoms at the age of 4.5 years. Case 2 had severe but stationary hearing loss in one ear and showed hearing impairment symptoms in the other ear at 9-13 years of age. Case 3 did not have hearing impairment symptoms, or vestibular symptoms, but was found to have severe progressive hearing loss from the age of 15 months onwards, which led to profound deafness at the age of 2 years and vestibular areflexia at or before the age of 4 years. These cases may represent 3 symptomatically different types of delayed endolabyrinthine hydrops. Type 1 (ipsilateral hydrops) incorporates vestibular symptoms only because of a lack of hearing in the offending labyrinth. Type 2 (contralateral hydrops) incorporates hearing impairment symptoms only because of a lack of vestibular function on both sides and type 3 does not incorporate hearing impairment symptoms or vestibular symptoms (other than those relating to a complete lack of function). Given the present findings, those described by Weiss and Ronis (Trans. Pa. Acad. Opthalmol. Otolaryngol., 30 (1977) 52-54) in one case and other reported findings relating to histopathological or imaging methods in somewhat similar cases, it seems appropriate to include congenital CMV infection in the differential diagnosis of delayed endolymphatic hydrops.

The risk of vestibular function loss after intracochlear implantation.

Sixty patients were selected for cochlear implantation and 50 of them received an intracochlear implant (Nucleus). Vestibular function was evaluated before and after surgery using a caloric test and a velocity step test. Sixteen patients had normal or residual vestibular function before surgery, 11 bilateral and 5 unilateral; in 3 of the latter patients, the ear with vestibular areflexia was elected for implantation, which reduced the number of patients at risk for vestibular dysfunction to 13. Vestibular function was preserved in all of these patients except for 4; the risk of vestibular function loss can therefore be rated at about 31%.

Does intracochlear implantation jeopardize vestibular function?

We present the results of the vestibular function tests of 35 patients who were selected for cochlear implantation. Vestibular function was evaluated with a caloric test and a velocity step test. The preimplant data were compared to those in previously reported series. Intracochlear implantation was performed in 25 patients. The vestibular complications encountered in this group are presented and discussed. Six patients had normal or residual (but substantial) vestibular function in the ear eligible for implantation. Vestibular function was preserved in 3 patients and was lost in 3 patients, in 1 case through an iatrogenic cause. We estimate the risk of losing vestibular function as a result of intracochlear implantation as between 50% and 60% on the basis of the present and previously reported data.

Vestibular function in cochlear implant patients.

Thirty-five patients receiving a cochlear implant were evaluated using vestibular function tests. Twenty-five patients received an intracochlear implant (Nucleus). Three out of 6 patients with normo- or hyporeflexia before implantation showed postoperative vestibular damage. In one case this was iatrogenic. Together with available data from the literature the risk of losing preoperative vestibular function is estimated to be around 60%. Improvement of implantation techniques can probably reduce this risk considerably.