Nicolas Gürtler

Role of ultrasound-guided core-needle biopsy in the assessment of head and neck lesions: A meta-analysis and systematic review of the literature

Core‐needle biopsy (CNB) has occasionally been used in the work‐up of head and neck lesions. However, no systematic review of this simple, minimally invasive method has yet been performed.

COMPARISON OF ULTRASOUND-GUIDED CORE-NEEDLE BIOPSY AND FINE-NEEDLE ASPIRATION IN THE ASSESSMENT OF HEAD AND NECK LESIONS

Core‐needle biopsy (CNB) has been successfully applied in other medical specialties, but its value is undetermined in otolaryngology.

Audiologic testing and molecular analysis of 12S rRNA in patients receiving aminoglycosides.

Background: Pathogenic mutations in the mitochondrial genome are associated with a wide variety of maternally inherited human diseases including sensorineural hearing loss (HL). A specific mutation, m.1555A>G in the mitochondrial 12S rRNA gene, is associated with predisposition to aminoglycoside ototoxicity and HL. Mutation screening in this gene has been recommended before use of aminoglycosides as a preventative strategy to reduce the risk of ototoxicity.

Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1

Although hereditary hearing loss is highly heterogeneous, only a few loci have been implicated with low-frequency hearing loss. Mutations in one single gene, Wolfram syndrome 1 (WFS1), have been reported to account for most familial cases with this type of hearing impairment. This study was conducted to determine the cause of nonsyndromic low-frequency hereditary hearing impairment in two large families. Two large families from Switzerland and United States with low-frequency hearing loss were identified. Genomewide linkage analysis was performed followed by mutation screening in the candidate gene WFS1 with direct DNA sequencing and restriction fragment analysis. Both families were linked to DFNA6/14/38 with lod scores>3. Two novel heterozygous missense mutations in WFS1 were identified: c.2311G>C leading to p.D771H in the Swiss family and c.2576G>C leading to p.R859P in the US family. The sequence alteration was absent in 100 control chromosomes. Nonsyndromic low-frequency hereditary hearing impairment seems to be predominantly a monogenic disorder due to WFS1. We confirm that most mutations in WFS1 associated with isolated low-frequency hearing loss are clustered in the C-terminal protein domain coded by exon 8.

Etiology of syndromic and nonsyndromic sensorineural hearing loss.

The past 10 years have seen an explosive gain in our understanding of molecular mechanisms of hearing and deafness. This has already resulted in improved diagnosis for the population with hereditary hearing loss. For syndromic hearing loss, we will see a shift from the historical terminology to a more precise genetic definition based on specific genetic abnormality. Functional studies of nonsyndromic deafness genes will elucidate the complex functional and hemostatic mechanisms in the inner ear. Ultimately, availability of gene therapy for the affected patients will bring to closure the circle of detection, identification, and correction of the disease.

Molecular analysis of aquaporin genes 1 to 4 in patients with Menière's disease

Background: Menière′s Disease (MD) is an episodic cochleovestibular dysfunction of unknown etiology, still lacking a specific test and therapy. The proposed theories on the pathophysiology include genetic factors and factors relating to inner ear homeostasis. Various aquaporins (AQP), water channels, expressed in the inner ear and the vestibular organ, are involved in homeostasis. Mutations in AQP genes could result in disturbed inner ear homeostasis and endolymphatic hydrops, and therefore be involved in the pathogenesis of MD. Aim: To search for mutations in AQP1 to 4 in patients suffering from MD. Methods: In patients with definite MD, DNA was extracted from whole blood. The coding sequences of AQP1 to 4 were amplified by PCR reaction and sequenced. Results: One sequence alteration, homozygous c.105G->C (conservative change without alteration of amino acid) in AQP3was detected in 11 out of 34 patients but not in 100 control chromosomes. Conclusion: By itself the detected alteration is unlikely to play a role in the pathogenesis of MD. However, together with an additional modifying gene an effect can not be excluded. Additional regions (introns, splice-sites) and other genes involved in inner ear homeostasis need to be analyzed to identify a possible molecular alteration in MD.

DFNA54, a third locus for low-frequency hearing loss

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low- frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction θ=0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding gene POU4F3 yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region of POU4F3 it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI.

GJB2 mutations in the Swiss hearing impaired.

Objective Mutations in the GJB2 gene encoding connexin 26 (Cx26) protein are a major cause for nonsyndromic autosomal recessive and sporadic deafness. However, its contribution to hearing impairment in Switzerland remains undefined. To determine the frequency and type of GJB2 mutations in the Swiss hearing-impaired population diagnosed under the age of 2 yr and at 2 yr and older and to assess the effectiveness of denaturing high-performance liquid chromatography (DHPLC) in screening for mutation in GJB2. Methods Thirty-four patients with hearing impairment underwent mutation screening of the single coding exon of GJB2 with DHPLC followed by bidirectional sequencing to identify sequence alterations. Results GJB2 mutations were more common in children diagnosed with hearing impairment under the age of 2 yr compared to the group 2 yr and older. In patients under age 2 yr, 9 of 20 (45%) harbored 13 GJB2 mutations including a common 313del14nt mutation; four of these patients were homozygous or compound heterozygous for GJB2 mutations. In contrast, 2 of 14 patients in the 2 yr and older group (14%) had a single mutation in GJB2. The 35delG mutation was exclusively found in 5 patients under the age of 2 yr. DHPLC for mutation screening was 100% sensitive and 83% specific for detecting sequence alterations in GJB2. Conclusions In Switzerland, GJB2 mutations are a major cause of nonsyndromic hearing impairment in children under the age of 2. Similar to other populations, GJB2 mutations are uncommon in the affected Swiss patients identified after 2 yr. Although 35delG mutation is common in the hearing-impaired children under the age of 2, it was absent in patients diagnosed with hearing impairment after the age of 2. DHPLC is a highly sensitive tool for detection of GJB2 mutations.

Paediatric otogenic lateral sinus thrombosis: Therapeutic management, outcome and thrombophilic evaluation

OBJECTIVE Otogenic lateral sinus thrombosis (LST) in children represents a serious condition with potential long-lasting morbidity. The role of adjunct anticoagulation therapy and the benefit of an analysis of prothrombotic factors are unclear. The aim of the study was to report therapeutic management and outcome, analyze prothrombotic factors in children with otogenic LST treated with mastoidectomy/antibiotics/anticoagulation and to evaluate the results with a review of the literature. METHODS Retrospective chart review of 9 children with otogenic LST (2000-2009) and literature search in PubMed. RESULTS The most frequent sign was fever in 88%, while neurologic findings were seen in 55%. Streptococci was the most common bacteria (55%). Prothrombotic factors were normal in all children. All patients received therapeutic anticoagulation, without experiencing bleeding complications. Eight children made a full recovery, neurologic sequelae persisted in one. The literature review of 115 children identified fever as the most prominent sign, reported the absence of neurologic findings in almost 50% of cases and confirmed the major role of streptococci. Anticoagulation, as adjunct therapy, was given to 38% of patients in the therapeutic range with a trend towards better neurologic outcome. A prothrombotic analysis was reported in 5 studies with positive results in 2. CONCLUSIONS Surgery and antibiotics represent the mainstay of the therapy. Anticoagulation can be safely added in view of the high potential for morbidity and might reduce neurologic sequelae. Bacteria with thrombotic activity seem to be an important aetiology. In contrast, a prothrombotic disposition seems to play a minor role in the development of otogenic LST.

Mutation analysis of the Cx26, Cx30, and Cx31 genes in autosomal recessive nonsyndromic hearing impairment

Conclusion. Biallelic Cx26 mutations are the most common cause of autosomal recessive nonsyndromic hearing impairment (ARNHI) in Switzerland. Mutations in Cx30 and 31, digenic mutations as well as large deletions/duplications, are unlikely to be a major cause of hearing loss in Swiss patients with ARNHI. Multiplex ligation-dependent probe amplification (MLPA) is a highly accurate screening method for detection of c.del(GJB6-D13S1830). Objectives. The intent of this study was to investigate the prevalence of the point and digenic mutations including large deletions and duplications in the Cx26, 30, and 31 genes in a Swiss patient cohort with ARNHI and cochlear implant. Patients and methods. The coding regions of Cx26, 30, and 31 were sequenced in 32 patients. Large deletions/duplications were assessed by MLPA. Results. In one patient digenic heterozygous mutations involving Cx26 (c.35delG) and Cx30 (c.del(GJB6-D13S1830)) were identified. Biallelic Cx26 mutations were detected in 31%. One putative mutation (c.94C>T) was found in Cx31. MLPA analysis did not reveal any additional deletion or duplication in all three Cx genes, except for the heterozygous c.del(GJB6-D13S1830) deletion.