OBJECTIVE:To study the histopathological and neuroradiological features of Usher syndrome (USH), with particular focus on USH type II, an inherited disorder characterized by moderate to severe congenital hearing impairment and retinitis pigmentosa with onset in the late teens. METHODOLOGY:A report of four cases and literature review. RESULTS AND CONCLUSION:Rare examples of histopathological and neuroradiological findings from four USH type II cases are presented. More studies like these are encouraged so that correlation studies between the morphological and clinical findings can be performed on the path to elucidate the pathogenesis of this heterogeneous disorder.

Otogenic pneumocephalus is a rare condition. The case is described of pneumocephalus and meningitis secondary to acute otitis media. Although the rate of intracranial complications related to middle ear disease is only 0.5 to 4%, mortality still ranges between 5 and 15%.

Molecular screening for GJB2 (connexin 26) mutations represents the standard diagnostic approach for the genotype definition of non-syndromic deafness. Nevertheless, a single GJB2 pathogenic mutation is detectable in a relevant number of cases, therefore failing to explain the phenotype. We aimed at assessing the occurrence of the recently described del( GIB6 -D13S1830) mutation, occurring in the connexin 30 gene, in a group of Italian hearing-impaired patients carrying a single GJB2 mutated allele. A total of 59 non-syndromic hearing loss (NSHL) patients were screened for GJB2 mutations. Among these, nine NSHL patients were found to be heterozygous for a single GJB2 mutation. These patients, heterozygotes for different GJB2 mutated alleles (35delG, L90P, M34T, V153I), together with 11 additional 35delG/neg cases previously described, were studied for the presence of the del( GIB6 -D13S1830) mutation. Two double heterozygotes del( GIB6 -D13S1830)/35delG were identified. In both cases the degree of hearing loss was profound. Furthermore, GJB2 molecular screening led to the identification of a novel change (T55G) occurring in compound heterozygosity with the V37I mutation. In conclusion, our data suggest a significant frequency of del( GIB6 -D13S1830) mutation in Italian hearing-impaired subjects (10% of unexplained GJB2 heterozygotes) similar to that reported in other European countries.

Previous studies have suggested that many human leukocyte antigen (HLA)-A,-B,-C and -DR alleles are associated with Ménière's disease (MD), an inner ear disorder with a proposed autoimmune etiopathogenesis. Despite some discrepancies many reports are in agreement with a hypothesis suggesting an influence of serologically detected HLA-C products in the susceptibility to the disease. To confirm these data we investigated the distribution of HLA-A,-B,-C and-DR antigens that well define the HLA polymorphism using DNA typing. Furthermore, as autoimmune factors have been claimed to play a role in MD, we investigated the serum level of soluble HLA class I (sHLA-I). Molecular typing of HLA class I and II was performed using polymerase chain reaction sequence-specific primers in 41 patients affected by MD, 34 patients affected by other inner ear diseases (OIDs) and 101 healthy subjects. An ELISA technique was employed to investigate the serum level of sHLA-I in 17 MD patients, 10 OID patients and 83 healthy subjects. The results showed a significantly increased frequency of the Cw*07 specificities in MD patients when compared to OID patients (63.4% vs 32.3%; p =6.9 2 10 -3 ; relative risk [RR]=3.6) and healthy subjects (63.4% vs 35.6%; p =2.28 2 10 -3 ; RR =3.1). The sHLA-I concentrations detected in sera did not differ significantly between MD patients (616 - 271 ng/ml), OID patients (570 - 307 ng/ml) and healthy subjects (518 - 340 ng/ml).

GJB2 mutation analysis was performed in 179 unrelated subjects with sporadic or familial hearing loss (HL). Among 57 families, 18 showed a vertical transmission of HL, the disease being present in two or three generations. Besides 155 nonsyndromic cases, 24 patients presenting with extra-auditory clinical signs were included in the molecular study. GJB2 mutation analysis was also performed in 19 subjects with an anamnestic history of perinatal risks factors for acquired HL. The 35delG mutation accounted for 22.1% of analyzed chromosomes in sporadic cases and 39.4% in familial cases; 35delG prevalence reached 41% in autosomal recessive and 44.4% in pseudodominant pedigrees. Two novel GJB2 mutations were identified in compound heterozygosity with 35delG allele (D159V, 284ins/dup[CACGT]). Two 35delG homozygous subjects were identified among HL cases classified as environmental in origin. Four patients 35delG heterozygous (35delG/V95M, 35delG/L90P, 35delG/167delT, and 35delG/?) and two homozygous presented with extra-auditory clinical signs involving different organs (skin, vascular system, hemopoietic lineages, and thyroid). In a high proportion of 35delG heterozygous HL patients (52%), no second GJB2 mutation was detected. The reported data highlight the complexity of the genetic epidemiology of GJB2-linked deafness, further enlarging the spectrum of situations in which GJB2 mutation analysis should be performed. The presence of extra-auditory signs in a significant portion of GJB2-mutated patients suggests the possibility that GJB2 loss of function could contribute to clinical phenotypes presenting in association with deafness. This hypothesis deserves further investigation. The failure to identify a presumed partnering GJB2 mutation in a high proportion of deaf patients remains a challenging problem to be clarified.