Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.

Waardenburg syndrome type 2 (WS2) is a dominantly inherited syndrome of hearing loss and pigmentary disturbances. We recently mapped a WS2 gene to chromosome 3p12.3-p14.1 and proposed as a candidate gene MITF, the human homologue of the mouse microphthalmia (mi) gene. This encodes a putative basic-helix-loop-helix-leucine zipper transcription factor expressed in adult skin and in embryonic retina, otic vesicle and hair follicles. Mice carrying mi mutations show reduced pigmentation of the eyes and coat, and with some alleles, microphthalmia, hearing loss, osteopetrosis and mast cell defects. Here we show that affected individuals in two WS2 families have mutations affecting splice sites in the MITF gene.

A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1.

Waardenburg syndrome (WS), an autosomal dominant syndrome of hearing loss and pigmentary disturbances, comprises at least two separate conditions. WS type 1 is normally caused by mutations in PAX3 located at chromosome 2q35 and is distinguished clinically by minor facial malformations. We have now located a gene for WS type 2. Two families show linkage to a group of microsatellite markers located on chromosome 3p12-p14.1. D3S1261 gave a maximum lod score of 6.5 at zero recombination in one large Type 2 family. In a second, smaller family the adjacent marker D3S1210 gave a lod of 2.05 at zero recombination. Interestingly, the human homologue (MITF) of the mouse microphthalmia gene, a good candidate at the phenotypic level, has recently been mapped to 3p12.3-p14.4.

Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2.

Waardenburg syndrome (WS) is a combination of deafness and pigmentary disturbances, normally inherited as an autosomal dominant trait. The pathology involves neural crest derivatives, but WS is heterogeneous clinically and genetically. Some type I WS families show linkage with markers on distal 2q and in three cases the disease has been attributed to mutations in the PAX3 gene. PAX3 encodes a paired domain, a highly conserved octapeptide and probably also a paired-type homeodomain. Here we describe a further three PAX3 mutations which cause WS; one alters the octapeptide motif plus the presumed homeodomain; a second alters all three elements and the third alters the paired box alone. The latter occurs in a family with probable type 2 WS, a clinical variant usually considered not to be allelic with type 1 WS.

Waardenburg syndrome type II: phenotypic findings and diagnostic criteria.

The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum.

Noise levels within the ear and post-nasal space in neonates in intensive care.

BACKGROUND: Noise exposure in neonatal units has long been suspected of being a cause of hearing loss associated with such units. The noise intensity to which the neonate is exposed varies with the type of ventilatory support used. Also, the post-nasal space is an enclosed cavity that is close to the inner ear and an area of turbulent and hence potentially noisy airflow. AIM: To determine noise intensities within the ear and post-nasal space in neonates on different modes of ventilatory support using probe microphones, measures previously not undertaken. METHODS: A portable instrument with a probe microphone was used for the measurements. Three groups of infants were included: (a) those receiving no respiratory support (NS); (b) those receiving conventional ventilation (CV); (c) those receiving continuous positive airways pressure (CPAP) support. RESULTS: The mean in-the-ear noise intensities (at 1 kHz) were 41.7 dB SPL (NS), 39.5 dB SPL (CV), and 55.1 dB SPL (CPAP). The noise intensities in the post-nasal space in those receiving CPAP support were higher than in the other groups, reached mean levels of up to 102 dB SPL at some frequencies, and increased with increasing flow rates. CONCLUSIONS: The most important finding is the high noise intensities in the post-nasal space of those receiving CPAP support. Given the proximity of the post-nasal space to the inner ear, enough noise could be transmitted, especially in infants receiving the higher flow rates, to cause cochlear damage and hence hearing loss. It would therefore be wise, wherever possible, to avoid using the higher flow rates.

Distortion product emissions in normal-hearing and low-frequency hearing loss carriers of genes for Waardenburg's syndrome.

Eight patients with Waardenburg's syndrome (WS) with normal hearing and 3 additional patients exhibiting a low-frequency hearing loss were tested for the level of the acoustic distortion product 2f1-f2 by means of the Otodynamics Distortion Product Analyser (ILO92). Wide notches in distortion product otoacoustic emissions (DPOAEs) between 1,000 and 3,000 Hz were found in 7 (12 ears, 87.5%) examined patients with normal audiograms, which was a significantly higher rate than that found in the control group (10%). The 3 patients with low-frequency hearing loss a gave a consistent pattern in audiometric configuration shown by both pure tone audiograms and DPOAEs. It is concluded from these initial results that DPOAEs may be a useful approach to identifying subclinical pathologic aberrations in the inner ear in WS patients, and may be a predictor of low-frequency sensorineural hearing loss.

An evaluation of the use of the auditory brain-stem electric response test in paediatric audiological assessment.

A retrospective study was made of hearing thresholds determined by the click-evoked Brain Stem Electric Response (BSER) and behavioural tests of hearing in 200 babies and children. BSER thresholds were found to agree within 20 dB with high frequency hearing levels in 89 out of 99 children who performed free-field tests of hearing and in 87% of ears in children tested with pure-tone audiometry. In 61 children who were too young or too handicapped to perform on behavioural tests of hearing, a hearing loss was indicated by BSER in 48 out of 121 ears. The majority of these losses occurred in the handicapped group. The advantages and limitations of behavioural tests and BSER are discussed.

Evaluation of the use of a questionnaire to detect hearing loss in babies in China.

A questionnaire was used to screen hearing of 1020 babies 6-8 months in China. All babies failing the questionnaire and 10% of those who passed were tested using auditory brainstem audiometry (ABR). Babies with unilateral or bilateral hearing thresholds 30 dBnHL or more were investigated to determine the cause of the hearing impairment. Sixty-seven failing the questionnaire were tested and 23 were confirmed to have a hearing loss, 20 with bilateral hearing impairment. The causes were: 13 otitis media with effusion (OME), one hypoxia, one genetic and five unknown. One child with an OME related hearing loss passed the screen. The sensitivity of the questionnaire was estimated to be 70%, specificity 96%.

Evaluation of the use of a questionnaire to detect hearing loss in Kenyan pre-school children.

In developing countries, there is a lack of trained personnel and testing equipment to facilitate the early detection of hearing impairment in children. A questionnaire offers a low cost option and the value of this for detecting hearing impairment in pre-school children was determined in several districts in Kenya. The questionnaire was completed by either teachers, parents/carers or community nurses. The children were subsequently tested using pure tone audiometry and visual examination of the ear by ENT Clinical Officers, who were not given prior access to the results of the questionnaire. A total of 757 (88%) questionnaires were completed. Of the 735 children, who could be tested using pure tone audiometry, four were found to have a unilateral hearing impairment and one was detected by the questionnaire. A total of 13 children had a bilateral hearing impairment >40 dB HL. All were detected using the questionnaire. There were eight males and five females with ages ranging from 4.2 to 6.9 years, mean age 5.7 years and median age 5.8 years. Eight had a sensorineural hearing impairment and two a mixed hearing impairment. Three of the children with a sensorineural hearing loss had a family history of hearing impairment. No question detected all children with a hearing impairment and some questions were more discerning than others. There was 100% sensitivity for the questionnaire when a hearing loss of >40 dB was considered, but specificity was lower at 75%. Negative predictive value was 100%, but the positive predictive value was low, 6.75%. It was concluded that a questionnaire of this nature could be usefully applied at Primary Health Care level for detecting hearing impairment at the pre-school stage. There would be need for services available for diagnosis, treatment and habilitation before a screening programme was introduced.

Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations--molecular and audiological findings.

We screened DNA from 72 sibships and 138 sporadically affected individuals with congenital non-syndromal sensorineural hearing impairment (NSSNHI) for mutations in the 26 (CX26) gene. A total of 20 (27.8%) of the sibships and 11 (7.9%) of the sporadically affected individuals were homozygous or compound heterozygotes for CX26 mutations. A total of 11 (17.2%) of 64 individuals with severe and 30 (30%) of 100 with profound NSSNHI compared to eight (8.7%) of 92 persons with moderate and none (0%) of 19 individuals with mild hearing impairment were homozygous or compound heterozygotes for CX26 mutations (chi2 test, 3 df, P = 0.000). CX26 mutation status bad no effect on the symmetry of the hearing impairment or configuration of the audiogram. In addition, serial audiograms showed no evidence of progression of the hearing impairment or differences in the severity of the hearing impairment in affected siblings in persons whether or not due to CX26 mutations. Sporadically affected individuals with congenital NSSNHI should be routinely tested for mutations in CX26, especially if the hearing impairment is severe or profound in severity, since identification of a mutation in CX26 allows use of Mendelian recurrence risks.

Sensorineural hearing loss and the Marinesco-Sjögren syndrome.

Sensorineural hearing loss has not been previously reported in patients with the Marinesco-Sjögren Syndrome. Two siblings are described where hearing was initially normal but subsequently deteriorated.

Genetic counselling for isolated hearing loss.

An investigation into the causes of sensorineural hearing loss in young children has been used as a basis for determining risk factors for parents of children with a hearing loss of unknown origin having a further affected child and for the defect to be passed on to a subsequent generation. The degree of hearing loss likely to be found if further children are affected, is examined.

Sound localization. Part II: a clinical procedure.

Difficulty in localizing sound has been shown to be associated with severe unilateral hearing impairment, middle-ear conditions and lesions of the cerebello-pontine angle. This was in contrast to the performance of subjects with cochlear lesions and certain brain conditions who had mainly normal ability to localize sound. The investigation appeared to indicate that a sound localization test in the horizontal plane using low frequency stimuli may be a useful addition to the test battery employed in the differential diagnosis of cochlear and retrocochlear lesions involving the cerebello-pontine angle.

Prescription of hearing aids for the elderly: the views of general practitioners.

A questionnaire survey was carried out to examine the views of general practitioners in one Northern city regarding whether or not they thought that hearing aids should be prescribed from general practice, who they thought should prescribe them and whether or not additional resources and training would be needed if the responsibility for hearing aid prescription for the elderly was placed upon general practitioners. The survey indicated that whereas many general practitioners would be in favour of prescribing hearing aids from Health Centres, many would need extra training and resources to enable them to do so.

Hearing aids versus ventilation tubes in persistent otitis media with effusion: a survey of clinical practice.

A postal survey was carried out to determine the current clinical practice amongst consultant otolaryngologists in the UK, regarding re-insertion of ventilation tubes or recommendation of hearing aids in cases of recurrence of otitis media with effusion (OME) after ventilation tube extrusion. Amongst the 319 respondents, 15 (4.70 per cent) routinely, 146 (45.77 per cent) sometimes, and 158 (49.53 per cent) either never, or very rarely, recommend hearing aids. Hearing aids and ventilation tubes were both suggested to be equally good options by some consultants but they preferred surgery for a number of reasons. There were inconsistencies in practice and some of the reasons for re-inserting ventilation tubes are not evidence-based. A hearing aid is a non-invasive option and this survey shows a need for a randomized control trial of hearing aids and ventilation tubes in the management of persistent and recurrent OME.

A clinical, genetic and audiological study of patients and families with unilateral vestibular schwannomas. II. Audiological findings in 93 patients with unilateral vestibular schwannomas.

Nine-three patients with histologically or radiologically confirmed unilateral vestibular schwannomas were recruited. Audiological testing for retrocochlear pathology was undertaken. Patients' hospital records were examined for previous audiological and radiological results. The audiometric configuration was designated as one of the following: normal, sloping, low frequency, peak, trough or flat. A sloping sensorineural audiometric configuration was present in 68 per cent of cases. No significant correlation was found between tumour size and average pure tone threshold 500 Hz to 4000 Hz, optimum discrimination score or interaural differences for wave V. Ninety-one per cent of cases had abnormalities on auditory evoked potential; 92 per cent of cases showed abnormalities on stapedial reflex testing. The limitations of audiological testing in the investigation of patients with suspected unilateral vestibular schwannomas are discussed. A protocol for the investigation of such patients is presented.

A clinical, genetic and audiological study of patients and families with unilateral vestibular schwannomas. I. Clinical features of neurofibromatosis in patients with unilateral vestibular schwannomas.

Ninety-three patients with unilateral vestibular schwannomas were examined in a clinical, genetic and audiological study, to determine whether they had features associated with neurofibromatosis Type 1 or neurofibromatosis Type 2. In 91 families, one patient only was found to be affected with a unilateral vestibular schwannoma. Patients did have a few café-au-lait macules, but fewer than six in number. None of the patients satisfied the cutaneous diagnostic criteria for neurofibromatosis Type 1. Neither Lisch nodules nor presenile posterior subcapsular lenticular opacities or cortical opacities were a feature. Five patients with unilateral vestibular schwannomas are described where the clinical findings raised the possibility of neurofibromatosis Type 2. It is suggested that certain individuals with unilateral vestibular schwannomas are at risk of developing neurofibromatosis Type 2. Furthermore, the possibility of neurofibromatosis Type 2 should be considered if more than one individual in a family is found to be affected with a unilateral vestibular schwannoma.

A clinical, genetic and audiological study of patients and families with bilateral acoustic neurofibromatosis.

The neurofibromatoses consist of at least two distinct autosomal dominant hereditary disorders. Neurofibromatosis type 1 (NF1) is due to a lesion on chromosome 17q. Neurofibromatosis type 2 (NF2) is caused by a defect on chromosome 22q. The hallmark of NF2 is the development, in the second and third decades, of bilateral acoustic neuromas. NF1 is characterized by the appearance of café-au-lait spots and neurofibromas in addition to iris hamartomas, or Lisch nodules, of the eye, during the first and second decades. Ten families were personally studied. A total of 16 members were found to be affected with NF2. A protocol for evaluation and review of subjects and relatives of NF2 families is proposed. A team approach, coordinating the expertise of multiple specialties is recommended.