Thomas Parzefall

A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia

Analysis of association between genotype and phenotype.

A Novel Mutation in SLC26A4 Causes Nonsyndromic Autosomal Recessive Hearing Impairment.

BACKGROUND Heterozygous mutations in GJB2 (MIM: 121011) encoding the gap junction protein connexin 26 are overrepresented in patient groups suffering from nonsyndromic sensorineural hearing impairment (HI) implying the involvement of additional genetic factors. Mutations in SLC26A4 (MIM: 605646), encoding the protein pendrin can cause both Pendred syndrome and autosomal recessive, nonsyndromic HI locus 4 type sensorineural HI (MIM: 600791). OBJECTIVES Aim of this study was to investigate the role of SLC26A4 coding mutations in a nonsyndromic hearing impairment (NSHI) patient group bearing heterozygous GJB2 35delG mutations. DESIGN We analyzed the 20 coding exons of SLC26A4 in a group of patients (n = 15) bearing heterozygous 35delG mutations and exclusively suffering from congenital HI. RESULTS In a case of bilateral congenital hearing loss we identified a rare, novel SLC26A4 exon 2 splice donor mutation (c.164+1delG) predicted to truncate pendrin in the first cytoplasmic domain, as a compound heterozygote with the pathogenic missense mutation c.1061T>C (p.354F>S; rs111033243). CONCLUSIONS Screening for SLC26A4 mutations may identify the genetic causes of hearing loss in patients bearing heterozygous mutations in GJB2. HYPOTHESIS SLC26A4 coding mutations are genetic causes for nonsyndromic HI in patients bearing heterozygous GJB2 35delG mutations.

Impact of Sonic Hedgehog Pathway Expression on Outcome in HPV Negative Head and Neck Carcinoma Patients after Surgery and Adjuvant Radiotherapy.

Introduction HPV positive patients suffering from head and neck cancer benefit from intensified radiotherapy when applied as a primary as well as an adjuvant treatment strategy. However, HPV negative patients treated with surgery and adjuvant radiotherapy lack validated prognostic biomarkers. It is therefore important to define prognostic biomarkers in this particular patient population. Especially, ´high-risk groups´ need to be defined in order to adapt treatment protocols. Since dysregulation of the sonic hedgehog pathway plays an important role in carcinogenesis, we aimed to assess whether members of the sonic hedgehog-signaling pathway may act as prognostic factors in patients with HPV negative head and neck squamous cell carcinoma. Materials and Methods In this prospective study, pretreatment tumor biopsies of patients with head and neck squamous cell carcinoma were taken during panendoscopy (2005 to 2008). All patients were treated with surgery and postoperative radiotherapy. After assessment of HPV and p16 status, protein expression profiles of the Sonic hedgehog-signaling pathway were determined by immunohistochemistry and tissue microarray analyses in 36 HPV negative tumor biopsies. Expression profiles of Sonic hedgehog, Indian hedgehog, Patched, Smoothened, Gli-1, Gli-2 and Gli-3 were correlated with patients´ clinical data, local-control rate, disease-free as well as overall survival. Data from The Cancer Genome Atlas databank were used for external validation of our results. Results Gli-1 (p = 0.04) and Gli-2 (p = 0.02) overexpression was significantly linked to improved overall survival of HPV negative patients. Gli-2 (p = 0.04) overexpression correlated significantly with prolonged disease-free survival. Cox-multivariate analysis showed that overexpression of Gli-2 correlated independently (HR 0.40, 95% CI 0.16–0.95, p = 0.03) with increased overall survival. Discussion Gli-1 and Gli-2 overexpression represents a substantial prognostic factor for overall and disease-free survival in patients with locally advanced HPV negative head and neck cancer undergoing surgery and postoperative radiotherapy.

The role of alternative GJB2 transcription in screening for neonatal sensorineural deafness in Austria.

Abstract Conclusion: Alterations within a novel putative Exon 1a within the gap junction beta 2 (GJB2) gene may play a role in the development of genetic hearing impairment in Austria. Objectives: Mutations in the GJB2 gene are the most common cause of hereditary sensorineural deafness. Genome-wide screening for alternative transcriptional start sites in the human genome has revealed the presence of an additional GJB2 exon (E1a). This study tested the hypothesis of whether alternative GJB2 transcription involving E1a may play a role in the development of congenital sensorineural deafness in Austria. Methods: GJB2 E1a and flanking regions were sequenced in randomized normal hearing control subjects and three different patient groups with non-syndromic hearing impairment (NSHI), and bioinformatic analysis was performed. Statistical analysis of disease association was carried out using the Cochran-Armitage test for trend. Results: A single change 2410 bp proximal to the translational start site (c.-2410T > C, rs7994748, NM_004004.5:c.-23 + 792T > C) was found to be significantly associated with the common c.35delG GJB2 mutation (p = .009). c.35delG in combination with c.-2410CC occurred at a 6.9-fold increased frequency compared to the control group. Additionally, one patient with idiopathic congenital hearing loss was found to be homozygous c.-2410CC.

A novel missense NDP mutation [p.(Cys93Arg)] with a manifesting carrier in an austrian family with Norrie disease.

Norrie disease is a rare, X-linked genetic syndrome characterized by combined congenital blindness and progressive hearing impairment. Norrie disease is caused by alterations in the NDP gene encoding the growth factor norrin that plays a key role in vascular development and stabilization of the eye, inner ear and brain. We identified a family with 3 affected deafblind males and a single female carrier presenting with a serous retinal detachment but normal hearing. Genetic analysis revealed a novel c.277T>C missense mutation causing the substitution of a hydrophobic cysteine to a hydrophilic arginine [p.(Cys93Arg)] within the highly conserved cysteine knot domain of the norrin protein. These results should expand the scope for amniocentesis and genetic testing for Norrie disease which is gaining in importance due to novel postnatal therapeutic concepts to alleviate the devastating retinal symptoms of Norrie disease.

Effect of postoperative use of diclofenac on pharyngocutaneous fistula development after primary total laryngopharyngectomy: Results of a single-center retrospective study

Primary total laryngopharyngectomy is the treatment of choice in many cases of locally advanced hypopharyngeal and laryngeal cancer. Development of pharyngocutaneous fistulae is the most common postoperative complication. A recent Danish study showed significantly increased rates of anastomosal leakage after colorectal resection in patients receiving diclofenac treatment.

Delayed auditory pathway maturation and prematurity.

SummaryBackgroundHearing loss is the most common sensory disorder in developed countries and leads to a severe reduction in quality of life. In this uncontrolled case series, we evaluated the auditory development in patients suffering from congenital nonsyndromic hearing impairment related to preterm birth.MethodsSix patients delivered preterm (25th–35th gestational weeks) suffering from mild to profound congenital nonsyndromic hearing impairment, descending from healthy, nonconsanguineous parents and were evaluated by otoacoustic emissions, tympanometry, brainstem-evoked response audiometry, and genetic testing. All patients were treated with hearing aids, and one patient required cochlear implantation.ResultsOne preterm infant (32nd gestational week) initially presented with a 70 dB hearing loss, accompanied by negative otoacoustic emissions and normal tympanometric findings. The patient was treated with hearing aids and displayed a gradual improvement in bilateral hearing that completely normalized by 14 months of age accompanied by the development of otoacoustic emission responses.ConclusionsWe present here for the first time a fully documented preterm patient with delayed auditory pathway maturation and normalization of hearing within 14 months of birth. Although rare, postpartum development of the auditory system should, therefore, be considered in the initial stages for treating preterm hearing impaired patients.ZusammenfassungGrundlagenSchwerhörigkeit ist die häufigste sensorische Erkrankung in den Entwicklungsländern, welche zu einer schweren Einschränkung der Lebensqualität führt. In dieser unkontrollierten Studie haben wir die auditorische Entwicklung von Frühgeborenen mit kongenitaler nicht-syndromaler Schwerhörigkeit evaluiert.MethodikIn diese Studie wurden sechs Frühgeborene (25.-35. Schwangerschaftswoche), welche an milder bis profunder Schwerhörigkeit leiden, eingeschlossen. Alle Patienten haben gesunde Eltern, die in keinem Verwandtschaftsverhältnis zueinander stehen. Die Evaluierung erfolgte mittels otoakustischer Emissionen, Tympanometrie, Hirnstammaudiometrie and genetischer Testung. Alle Patienten wurden mit Hörgeräten und ein Patient mit Cochlear Implantation versorgt.ErgebnisseEin frühgeborener Patient (32. Schwangerschaftswoche), mit regulären Tympanogrammen, hatte initial einen Hörverlust von 70 Dezibel und negative otoakustische Emissionen. Nach der Versorgung mit Hörgeräten zeigte sich eine schrittweise Verbesserung des bilateralen Hörens mit kompletter Normalisierung mit 14 Lebensmonaten, einhergehend mit positiven otoakustischen Emissionen.SchlussfolgerungenWir präsentieren erstmalig einen voll dokumentierten Fall eines Frühgeborenen mit verzögerter Hörbahnreifung und Normalisierung des Hörens mit 14 Lebensmonaten. Obgleich selten, sollte eine postpartale Reifung des auditorischen Systems in den ersten Stadien der Entwicklung bei frühgeborenen schwerhörigen Patienten bedacht werden.

Radiofrequency ablation in patients with large cervical heterotopic gastric mucosa and globus sensation: Closing the treatment gap

Symptomatic cervical heterotopic gastric mucosa, also known as cervical inlet patch (CIP), may present in various shapes and causes laryngopharyngeal reflux (LPR). Unfortunately, argon plasma coagulation, standard treatment of small symptomatic CIP, is limited in large CIP mainly because of concerns of stricture formation. Therefore, we aimed to investigate radiofrequency ablation (RFA), a novel minimally invasive ablation method, in the treatment of CIP focusing on large symptomatic patches.

Epistaxis grading in Osler's disease: comparison of comprehensive scores with detailed bleeding diaries

Use of reliable grading scores to measure epistaxis severity in hereditary hemorrhagic telangiectasia (HHT) is essential in clinical routine and for scientific purposes. For practical reasons, visual analog scale (VAS) scoring and the Epistaxis Severity Score (ESS) are widely used. VAS scores are purely subjective, and a potential shortcoming of the ESS is that it is based on self‐reported anamnestic bleeding data. The aim of this study was to validate the level of correlation between VAS scores, the ESS, and actual bleeding events, based on detailed epistaxis diaries of patients.

Whole-exome sequencing to identify the cause of congenital sensorineural hearing loss in carriers of a heterozygous GJB2 mutation

Bi-allelic variations in the gap junction protein beta-2 (GJB2) gene cause up to 50% of cases of newborn hearing loss. Heterozygous pathogenic GJB2 variations are also fivefold overrepresented in idiopathic patient groups compared to the normal-hearing population. Whether hearing loss in this group is due to unidentified additional variations within GJB2 or variations in other deafness genes is unknown in most cases. Whole-exome sequencing offers an effective approach in the search for causative variations in patients with Mendelian diseases. In this prospective genetic cohort study, we initially investigated a family of Turkish origin suffering from congenital autosomal recessive hearing loss. An index patient and his normal-hearing father, both bearing a single heterozygous pathogenic c.262G>T (p.Ala88Ser) GJB2 transversion as well as the normal-hearing mother were investigated by means of whole-exome sequencing. Subsequently the genetic screening was extended to a hearing-impaired cohort of 24 families of Turkish origin. A homozygous missense c.5492G>T transversion (p.Gly1831Val) in the Myosin 15a gene, previously linked to deafness, was identified as causative in the index family. This very rare variant is not listed in any population in the Genome Aggregation Database. Subsequent screening of index patients from additional families of Turkish origin with recessive hearing loss identified the c.5492G>T variation in an additional family. Whole-exome sequencing may effectively identify the causes of idiopathic hearing loss in patients bearing heterozygous GJB2 variations.