GJB2: the spectrum of deafness-causing allele variants and their phenotype.

Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.

Bilateral sensorineural hearing disorders in children: etiology of deafness and evaluation of hearing tests.

OBJECTIVE: The purpose of this study was to determine the etiology of bilateral sensorineural hearing disorders in children and to evaluate the performed hearing tests by comparison of the results of the objective and subjective tests. METHODS: The medical history and the hearing tests (behavioral observation audiometry, acoustic evoked potentials and pure tone audiometry) of 106 bilaterally hearing impaired children were analyzed in a retrospective follow-up study. RESULTS: The total group included 52 males and 54 females. The ages at first diagnosis ranged from 4 months to 11 years with a mean age of 42 months and a median of 33 months. The degree of hearing loss for the better hearing ear was mild in one child, moderate in 28 children, severe in 29 children, profound in 32 children and total in 16 children. The delay between the first examination and diagnosis ranged from 0 to 597 days with a mean of 83 days and a median of 28 days. In 47 children (44%) no cause of hearing impairment could be determined. Nineteen children (18%) had a history of familial hearing loss, 40 (38%) suffered from acquired hearing loss (seven children had prenatal causes, 21 perinatal and 12 postnatal). A comparison between behavioral observation audiometry and brainstem evoked response audiometry revealed a statistically good agreement. Twenty-nine children (32%) showed progressive hearing loss, which was defined as a threshold shift of +10 dB or more in the pure tone average in at least one ear. CONCLUSIONS: In a significant number of children with early hearing impairments the etiology still remains uncertain. Further research in the field of genetic disorders will diminish this number. Evaluation of hearing tests showed that behavioral observation audiometry still is an excellent tool in the hands of an experienced examiner. The age at identification of hearing disorders in industrialized countries still is unacceptably high. To obtain ideal care of hearing impaired children, universal neonatal hearing screening programs are mandatory.

[Genetic causes of hearing loss--status and perspectives]. / Genetiske årsaker til hørselstap--status og perspektiver.

Hearing impairment, defined as > or = 40 dB hearing loss, is the most prevalent sensory handicap, present in 1:750 children and in 4-36% of adults, depending on age. Genetic factors are of major importance in more than 50% of all hearing loss. An important distinction is made between syndromic deafness and isolated deafness depending on the presence or not of associated manifestations from other organs. The knowledge about genetic deafness has increased dramatically in the last few years. As of March 1999, at least 53 loci for isolated deafness of different types of monogenic inheritance have been identified. Suspected genetic heterogeneity has thus been confirmed. At least 15 genes for syndromic deafness have been cloned, leading to increased biological insight in shared developmental pathways in different species and leading to better diagnostic tools applicable to patients. The identification of a particularly frequent mutation in a gap junction gene, GJB2 (connexin 26), may turn out to be of particular diagnostic importance in the aetiological evaluation of childhood deafness even in isolated cases. Application of early screening tests, like otoacoustic emission (OAE), in combination with genetic tests will facilitate early and specific diagnosis of hearing impairment and thereby improve audiological rehabilitation. Syndromic deafness involves all organs, and care for and evaluation of affected individuals should be a multiprofessional task.

[Genetic causes of hearing loss--status and perspectives]. / Genetiske årsaker til hørselstap--status og perspektiver.

Hearing impairment, defined as > or = 40 dB hearing loss, is the most prevalent sensory handicap, present in 1:750 children and in 4-36% of adults, depending on age. Genetic factors are of major importance in more than 50% of all hearing loss. An important distinction is made between syndromic deafness and isolated deafness depending on the presence or not of associated manifestations from other organs. The knowledge about genetic deafness has increased dramatically in the last few years. As of March 1999, at least 53 loci for isolated deafness of different types of monogenic inheritance have been identified. Suspected genetic heterogeneity has thus been confirmed. At least 15 genes for syndromic deafness have been cloned, leading to increased biological insight in shared developmental pathways in different species and leading to better diagnostic tools applicable to patients. The identification of a particularly frequent mutation in a gap junction gene, GJB2 (connexin 26), may turn out to be of particular diagnostic importance in the aetiological evaluation of childhood deafness even in isolated cases. Application of early screening tests, like otoacoustic emission (OAE), in combination with genetic tests will facilitate early and specific diagnosis of hearing impairment and thereby improve audiological rehabilitation. Syndromic deafness involves all organs, and care for and evaluation of affected individuals should be a multiprofessional task.

Controlled trial of universal neonatal screening for early identification of permanent childhood hearing impairment. Wessex Universal Neonatal Hearing Screening Trial Group.

BACKGROUND: Congenital permanent childhood hearing impairment (PCHI) impairs communication skills and, possibly, mental health and employment prospects. Management within 1 year of birth can alleviate most of its adverse effects. Neonatal screening for this disorder is feasible but its benefit for all babies is disputed. We investigated whether neonatal screening of all babies born in hospital, in addition to the standard health visitor distraction test, would increase the rates of early referral, confirmation, and management. METHODS: Between 1993 and 1996, two teams of four part-time testers and equipment moved between two pairs of hospitals to achieve four periods with neonatal screening and four without neonatal screening, each of 4-6 months' duration. Babies did or did not undergo neonatal screening dependent on during which periods they were born. We used a transient evoked otoacoustic emissions test and, in babies who failed this test, an automated auditory brainstem response test on the same day. We referred babies with positive results for audiological assessment. FINDINGS: 53,781 babies were included in the trial, and 25,609 were born during periods with neonatal screening. Neonatal screening achieved 87% coverage of births, with a false-alarm rate of 1.5%, and an overall yield of 90 cases of bilateral PCHI of 40 dB or more relative to hearing threshold level per 100,000 target population, equivalent to 80% of the expected prevalence of the disorder in the population. 71 more babies with moderate or severe PCHI per 100,000 target population were referred before age 6 months during periods with neonatal screening than during periods without. Early confirmation and management of PCHI were significantly increased. The rate of false-negative results from neonatal screening was significantly lower than that for the distraction test (4 vs 27% p=0.041). INTERPRETATION: Neonatal screening is effective in identification of congenital PCHI early and may be particularly useful for babies with moderate and severe PCHI for whom early management may have the most benefit.

Study on the distribution of hearing levels in idiopathic bilateral sensorineural hearing loss.

The pattern of aggravation in hearing was investigated in 105 patients who were diagnosed as having idiopathic bilateral sensorineural hearing loss at the Hearing Loss Clinic, Department of Otolaryngology, Kitasato University Hospital. Audiograms were taken 1,069 times from the 105 cases over more than 3 years, and were used to obtain the distribution of hearing levels at each test frequency. The clinical course of idiopathic bilateral sensorineural hearing loss was divided into three stages: Stages I, II and III, based on the pattern of aggravation. The pattern of distribution of hearing levels at different stages was compared with each other with reference to peaks or clustering points. Similar peaks were noted at Stage II and Stage III as aggravation proceeded from Stage I. Another peak was noted in the zone of scale-out.

Electronystagmographic findings in a case of Lermoyez's syndrome.

A 40-year-old female patient with Lermoyez's syndrome is presented. Prior to the vertiginous attack, right low-tone hearing loss and tinnitus were noted. During the vertiginous attack, spontaneous nystagmus was directed to the right (lesioned) side, with improvement of cochlear symptoms. After the vertiginous attack, nystagmus was positional rather than spontaneous, and was directed to the left (opposite) side, with the subsidence of cochlear symptoms. One week later, follow-up audiometry revealed bilateral normal hearing.

Bilateral progressive sensorineural hearing loss of unknown etiology.

Clinical observations of 28 cases with bilateral idiopathic progressive sensorineural hearing loss (BIPSNHL) were made in comparison with the data from the Research Committee of the ministry of Health and Welfare of Japan. Two types with correlation to the age of onset were found in BIPSNHL; the juvenile type which starts at an early age, and the adult type which is found after maturity. The significance of these two types was discussed. Correct diagnosis is only possible after long-term observations and regular audiometry.