A vestibular schwannoma in a patient with Birt-Hogg-Dube syndrome.

Birt-Hogg Dubé syndrome is an autosomal dominant disease with variable clinical expression. It is characterized by cutaneous manifestations, renal tumors and lung cysts. Other tumors, such as adrenal tumors and tumors originating from the neural crest cells such as meningioma and neurothekeoma have also been described. This syndrome is caused by germline mutations in the folliculin (FLCN) gene located on chromosome 17p. We report, for the first time, a patient with BHDS and a history of a vestibular schwannoma in adolescence. The diagnosis of BHDS was confirmed, by identifying a nonsense mutation in exon 10 of the FLCN gene. A vestibular schwannoma also originates from neural crest cells, just as other neural tumors, previously encountered in patients with BHDS. The reported mutations cause a truncation of the protein, folliculin. The exact role of folliculin is still undetermined. Two different theories suggest the effect of tumorigenesis. One is that folliculin plays an important role in the AMPK-mTOR pathway which leads to proliferation of cells when activated. The other is that the folliculin acts as a possible tumor suppressor gene, since there is a high frequency of second hits in the FLCN-gene. In order to confirm a possible relation of BHDS and neural crest tumors, further research is necessary in the tumorigenesis of the folliculin gene.

Cochlear implantation in 3 adults with auditory neuropathy/auditory dys-synchrony.

We describe 3 adult patients with auditory neuropathy/auditory dys-synchrony (AN/AD) who underwent cochlear implantation. All patients had absent or poorly formed auditory brainstem responses (ABRs) in combination with preserved otoacoustic emissions (OAEs). They exhibited various aetiologies and a large variation in clinical features known to be consistent with AN/AD. Cochlear implantation was successful in 2 out of 3 cases. We conclude that AN/AD implantee candidates should be counselled with care.

A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26).

Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the gamma-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the gamma 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.

Otosclerosis: a genetically heterogeneous disease involving at least three different genes.

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.

Etiological diagnosis in the hearing impaired newborn: proposal of a flow chart.

OBJECTIVE: Most industrialized countries have introduced some form of universal newborn hearing screening program. Both identification and rehabilitation of hearing loss in newborns have evolved to an acceptable standard and the need for a standardized etiological protocol is emerging. METHODS: Extensive literature search to determine which investigations can help identifying the cause of congenital hearing loss and how to limit extensive testing in these children by taking into account the most prevalent causes. FINDINGS: A stepwise approach to detect the cause of hearing loss in children with congenital sensorineural hearing loss was developed. CONCLUSION: In general it is advised to first rule out Cx26/Cx30 and infectious causes (cytomegalovirus and, if indicated, toxoplasmosis and rubella), and to preserve more extensive investigations for those children in whom these causes do not explain the hearing loss.