No abstract

Sensorineural hearing loss is a very diffuse pathology (about 1/1000 born) with several types of transmission. X-linked hearing loss accounts for approximately 1% - 2% of cases of non-syndromic forms, as well as for many syndromic forms. To date, six loci (DFNX1-6) and five genes (PRPS1 for DFNX1, POU3F4 for DFNX2, SMPX for DFNX4, AIFM1 for DFNX5 and COL4A6 for DFNX6) have been identified for X-linked non-syndromic hearing loss. For the syndromic forms, at least 15 genes have been identified, some of which are also implicated in non-syndromic forms. Moreover, some syndromic forms, presenting large chromosomal deletions, are associated with mental retardation too. This review presents an overview of the currently known genes related to X-linked hearing loss with the support of the most recent literature. It summarizes the genetics and clinical features of X-linked hearing loss to give information useful to realize a clear genetic counseling and an early diagnosis. It is important to get an early diagnosis of these diseases to decide the investigations to predict the evolution of the disease and the onset of any other future symptoms. This information will be clearly useful for choosing the best therapeutic strategy. In particular, regarding audiological aspects, this review highlights risks and benefits currently known in some cases for specific therapeutic intervention.

Purpose When referring to enlarged vestibular aqueduct (EVA) we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA) and Pendred Syndrome (PDS), a disease continuum associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases. The study was aimed to analyse the clinical and audiological features of a monocentric cohort of Caucasian patients with NSEVA/PDS, their genetic assessment and morphological inner ear features. Methods We retrospectively reviewed the audiologic, genetic and anamnestic data of 66 patients with NSEVA/PDS followed by our audiology service. Results SLC26A4 mutations was significantly correlated with the presence of PDS rather than NSEVA (p < 0.019), with the expression of inner ear malformations (p < 0.001) and with different severity of hearing loss (p = 0.001). Furthermore, patients with PDS showed significantly worse pure tone audiometry (PTA) than patients with NSEVA (p = 0.001). Anatomically normal ears presented significantly better PTA than ears associated with Mondini Malformation or isolated EVA (p < 0.001), but no statistically significative differences have been observed in PTA between patients with Mondini Malformation and isolated EVA. Conclusion NSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology. Our findings can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association with thyroid dysfunction.

We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA. Myosin VIIA has already been implicated in several forms of deafness, but this is the third mutation causing a dominant form of deafness, located in the myosin VIIA motor domain in a region never involved in hearing loss until now. A modelled protein structure of myosin VII motor domain provides evidence for a significant functional effect of this missense mutation.

The GJB2 gene located on chromosome 13q12 and encoding the connexin 26 (Cx26) protein, a transmembrane protein involved in cell-cell attachment of almost all tissues, including the skin, causes autosomal recessive and sometimes dominant nonsyndromic sensorineural hearing loss. GJB2 mutations have also been identified in syndromic disorders exhibiting hearing loss associated with skin problems. Recently, a new mutation, p.G130V in the GJB2 gene has been reported as causative for Vohwinkel syndrome. In this case the p.G130V mutation was found in two patients (son and father) with palmoplantar keratoderma. The father also showed also skin constrictions of the 2nd and 3rd toes of the right foot. Here, we report on another family with palmoplantar keratoderma associated with a dominant form of hearing loss confirming the genotype-phenotype correlation between the mutation p.G130V and the skin abnormalities observed in syndromic disorders with hearing loss as described by [Snoeckx et al. (2005) Hum Mutat 26:60-65].