Monogenic nonsyndromic otosclerosis: audiological and linkage analysis in a large Greek pedigree.

OBJECTIVE: The aim of our study was to characterize the hearing impairment in a large multigenerational Greek family with autosomal dominant nonsyndromic otosclerosis and to perform genetic linkage analysis to known otosclerosis loci and collagen genes. In addition, we looked for mutations in the NOG gene to rule out congenital stapes ankylosis syndrome. METHODS: Audiological analysis of the affected persons was based on multiple linear regression (MLR) analysis and construction of age-related typical audiograms (ARTA). Genotyping of microsatellite DNA polymorphisms for known otosclerosis (OTSC) loci or collagen genes and linkage analysis using the MLINK computer program were performed. The coding region of the NOG gene was screened for mutations by direct DNA sequencing. RESULTS: The hearing loss in this family appears in childhood as conductive, but soon becomes mixed. Because the additional sensorineural component is progressive, this finally has lead to a pure sensorineural hearing loss in some family members, as the conductive component is masked. Audiological analysis showed an age-independent conductive component and a progressive frequency-specific sensorineural component. Linkage analysis excluded linkage to the four known otosclerosis loci (OTSC1, OTSC2, OTSC3, and OTSC5), as well as to the COL1A1 and COL1A2 genes. Mutation analysis of the coding region of the NOG gene did not reveal any disease causing mutation. CONCLUSIONS: This study represents the first description of a detailed audiological analysis in a large pedigree segregating otosclerosis as a monogenic autosomal dominant trait. Exclusion of the four known otosclerosis loci in this family shows that monogenic otosclerosis is a genetically heterogeneous disease involving at least five different genes. A mutation in the NOG gene is not the underlying molecular mechanism of the early onset otosclerosis segregating in this family.

Veria operation updated. I. The trans-canal wall cochlear implantation.

The Veria operation is a non-mastoidectomy technique for cochlear implantation. It uses the transcanal approach to the middle ear and the cochlea. The steps of the procedure are: (1) endaural approach, that offers a wide accessibility to the middle ear structures; (2) inspection of the middle ear anatomy; (3) straightening of the postero-superior bony canal wall, which is usually concave; (4) performing the cochleostomy through the outer ear canal; (5) drilling of the suprameatal hollow, which is used for the accommodation of the electrode excess; (6) drilling of the trans-wall direct tunnel, which is the pathway for the active electrode; (7) alignment of the direct tunnel to the cochleostomy; (8) extension of the incision and preparing of the flaps; (9) creating of the bed and fixing the device; (10) insertion of the electrodes; (11) manipulating the excess of the active electrode, and (12) closing. For this technique, two special instruments have been developed: a special perforator used for the drilling of the direct tunnel for the active electrode, making it completely safe, and a safety electrode forceps used to manipulate the active electrode during insertion. The direct tunnel can be enlarged superiorly permitting insertion of two electrodes, in cases where a double electrode array implant has to be used. The method is an efficient tool for handling all cochlear implant cases, including difficult ones such as revision cases, malformations, cochlear ossifications and poor mastoid development. It is safe without complications in over a hundred cases and easy to learn.

Veria Operation. II. Surgical results from 101 cases.

The 'Veria operation' is a new technique for cochlear implantation. It is a non-mastoidectomy technique and uses the endaural approach for the cochleostomy and a direct tunnel drilled through the supero-posterior bony canal wall for the electrode. Two special instruments have been developed for this technique: a special perforator for the drilling of the direct tunnel and a safety electrode forceps for the insertion of the electrode. The method has been used in 101 cases with an age range from 2.5 to 75 years. 78 of them were primary operations and 23 revision cases. From the revisions, 18 were surgical failures and 5 were device failures. There were two complications: in 1 case there was a thick skin flap, which was corrected under local anesthesia, and in 1 malformation case there was a retrograde insertion to the vestibule and the posterior semicircular canal, corrected 6 weeks later. The analysis of the results shows that this method has certain advantages, which are: it is simple and therefore the learning curve is fast; it is safe for the facial nerve, as the drilling is precisely controlled by the special perforator; it produces minimal bone trauma and due to fast healing, it permits early fitting a few days after operation; it is suitable for the difficult and revision cases and it can be used for very small children where the mastoid may have not been yet sufficiently developed.

Prevalence of GJB2 mutations in prelingual deafness in the Greek population.

OBJECTIVE: Mutations in the gene encoding the gap junction protein connexin 26 (GJB2) have been shown as a major contributor to prelingual, sensorineural, nonsyndromic, recessive deafness. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in Caucasian populations. The aim of our study was to determine the prevalence and spectrum of GJB2 mutations in prelingual deafness in the Greek population. METHODS: In a collaboration with the major referral centers for childhood deafness in Greece, patients were examined by an extensive questionnaire to exclude syndromic forms and environmental causes of deafness and by allele-specific polymerase chain reaction (PCR) for the detection of the 35delG mutation. Patients heterozygous for the 35delG mutation were further analyzed by direct genomic sequencing of the coding region of the GJB2 gene. RESULTS: The 35delG mutation was found in 42.2% of the chromosomes in 45 familial cases of prelingual, nonsyndromic deafness (18 homozygotes and 2 heterozygotes) and in 30.6% of the chromosomes in 165 sporadic cases (45 homozygotes and 11 heterozygotes). Direct genomic sequencing in heterozygous patients revealed the L90P (2 alleles), W24X (2 alleles), R184P (2 alleles), and 291insA (1 allele) mutations. CONCLUSION: Mutations in the GJB2 gene are responsible for about one third of prelingual, sensorineural, nonsyndromic deafness in the Greek population, and allele-specific PCR is an easy screening method for the common 35delG mutation.