[Auditory processing in children and adolescents with cleft palate]. / Auditive Verarbeitung und Wahrnehmung bei Kindern und Jugendlichen mit Gaumenspalte.

BACKGROUND: Patients with cleft palate often suffer from recurrent otitis media chronica with effusion during infancy. The consecutive binaural conductive hearing loss is seen as a risk factor for developing auditory processing disease. Since there are just a few studies examining auditory processing in this population this study aimed to investigate on an own patient cohort with different cleft manifestations in terms of auditory processing disorders in context to given studies. MATERIAL AND METHODS: This study included 48 patients (5-16 years): all patients had a non-syndromic cleft palate and normal peripheral hearing at the time of examination. The protocol included otoscopy, pure tone audiogram, speech intelligibility in noise, dichotic speech discrimination, auditory short-term memory and a parental questionnaire. RESULTS: The majority of the parents did not indicate problems in the parental questionnaire. 69 % of the participants showed conspicuous results in the speech intelligibility in noise, whereas the dichotic speech discrimination and the auditory short-term memory were suspicious in 16.7 % only. The results in both tests proved mainly a problem in younger children. Noticeable results in speech intelligibility in noise were found in all age groups. CONCLUSION: Children and adolescents with cleft palate are at risk to develop auditory processing disorders. In this study population speech intelligibility in noise was the most common problem. 90 % of the children had received a speech therapy which could have already compensated problems concerning dichotic speech discrimination and the auditory short-term memory but not problems in speech intelligibility in noise.

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

Further evidence for deletions in 7p14.1 contributing to nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft with or without cleft palate (nsCL/P) is a common birth defect. Although genome-wide association studies (GWAS) have identified numerous risk variants, a considerable fraction of the genetic heritability remains unknown. The aim of the present study was to replicate a previous finding that de novo deletions in a 62 kb region of chromosome 7p14 are a risk factor for nsCL/P, using an independent cohort. METHODS: Data from a published case-control GWAS cohort of 399 patients and 1318 controls were used. Copy number variant (CNV) detection in the 62 kb candidate region of 7p14 was performed using QuantiSNP. Putative CNVs in probands were verified and validated by quantitative polymerase chain reaction. Segregation analyses were performed in family members for whom DNA was available. RESULTS: Within the 62 kb candidate region, a deletion of 7.4 kb showed association with nsCL/P (13/387 cases, 20/1300 controls, plowest = 0.024, odds ratio = 2.22). In all families with a sporadic case (n = 3), the deletion occurred de novo. In multiplex families, both incomplete segregation and incomplete penetrance were observed. CONCLUSION: The present data support the hypothesis that deletions at 7p14 are a common risk factor for nsCL/P. Genome-wide CNV analyses in nsCL/P cohorts are warranted to explore the functional relevance of these deletions and their contribution to nsCL/P, and to determine exact breakpoints. Birth Defects Research (Part A) 106:767-772, 2016. © 2016 Wiley Periodicals, Inc.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Dental caries in the primary dentition of german children with cleft lip, alveolus, and palate.

Objective : The purpose of this cross-sectional study was to assess the prevalence of dental caries in children with cleft lip, alveolus, and/or cleft palate living in central Germany between 1996 and 2010. Participants : A total of 295 children 1 to 6 years of age from three birth cohorts (BC) with clefts from central Germany were included in the study. They were compared with 548 1- to 6-year-old cleft-free children from the same region. Setting : Children with clefts underwent a dental examination in an outpatient dental clinic at the University of Leipzig. The first BC was examined between 1996 and 1998, the second between 2002 and 2004, and the third between 2008 and 2010. Controls were examined at day-care centers in Leipzig during the same periods. Main Outcome Measure : The standard dental caries index for the primary dentition (dmf/t3-4) was used for clinical assessment. Results : Over the entire study period, the mean prevalence of dental caries in deciduous teeth was significantly higher (1.32 dmf/t3-4) in children with clefts compared with cleft-free children. However, a decline in caries (approximately 1 dmf/t3-4) and an increase in the proportion of children with healthy primary dentition were observed in both groups. These results represent a caries decline of 61% in children with clefts. Conclusions : Caries rates for children 1 to 6 years of age with clefts from central Germany showed a considerable decline over the last years. The caries rates for clefts patients in the third BC (2008 to 2010) was similar to that of cleft-free children in the first BC (1996 to 1998).

Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P. METHODS: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level. RESULTS: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees. CONCLUSION: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012.

Swine-origin H1N1 influenza A virus and dental practice: a critical review.

Since the spring of 2009, there have been a considerable number of infected as well as fatal cases by virologically confirmed swine-origin H1N1 influenza A virus (S-OIV). The virus continues to spread globally. The World Health Organization (WHO) has now raised the level of S-OIV influenza pandemic alert to phase 6 ('the pandemic phase') because of the human-to-human transmission of the virus and the community-level outbreaks worldwide. The WHO also issues its concerns about the global surveillance, the diagnostic capacity for the infection and the pandemic preparedness plan in every country. However, no critical review on S-OIV influenza and dental practice published in the literature exists hitherto. Based on information up to November 2009, the aim of this article was to summarise significant data on this novel virus and a clinical practice guideline for dental professionals.

Inclusion mucous cysts of the nose: a late complication after septorhinoplasty in two cleft lip patients.

BACKGROUND: Mucous cysts of the nose are a rare complication of rhinoplasty. They may develop as a result of implantation or herniation of mucosa. The entrapped epithelium may proliferate, forming a subcutaneous cyst. PATIENTS AND METHODS: Two patients with unilateral cleft lip nose deformity had previously undergone corrective rhinoplasty. Years after the operation, they noticed a growing mass in the nasal dorsum and presented for revision rhinoplasty. Complete surgical removal was performed by an open approach, and plastic reconstruction was performed with a rib cartilaginous graft. RESULTS: In both cases, histopathological investigation revealed a mucous cyst. No recurrence of disease was observed over 2 years of monitoring. CONCLUSION: Nasal mucous cysts are not specific complications of corrective surgery for cleft lip nose. Displacement of fragments of epithelium should be avoided to prevent this unwanted sequela. For complete removal, open rhinoplasty is recommended.

Retrospective cohort study of three-wall orbital resection for treatment of endocrine orbitopathy using 3D tomographic data and biomechanical modeling.

BACKGROUND: Surgical treatment of endocrine orbitopathy can be performed by way of resecting orbital walls, which effectively releases superfluous tissue from the surgically enlarged orbital space allowing the eyeballs to move back. Existing approaches aim to select an optimal surgical strategy based on statistical correlations between the extent of the surgical procedure and the resulting bulbus displacement but do not provide an individual surgery plan or predict surgery outcome. METHODS: In this retrospective study, we performed a quantitative analysis of pre- and post-surgery 3D tomographic data of six patients and applied explorative biomechanical modeling of orbital mechanics to dissect factors influencing patient-specific outcome. FINDINGS: Our experimental results showed a large variability of the backward eyeball displacement in dependency on the amount of orbital volume flow, which could partially be described by computational simulation. Our detailed analysis revealed that patients with regular fat tissue show a good correlation between bulbus displacement and relative volume of decompressed tissue, which, in turn, correlates with decrease in hydrostatic pressure. In contrast, patients with fibrotic tissue exhibit significantly reduced and computationally less predictable eyeball translation in response to surgical tissue decompression. INTERPRETATION: Based on the results of this study we see a great potential for quantitative planning of surgical exophthalmos treatment using 3D biomechanical modeling. Conventional approaches to planning of soft tissue interventions consider, however, only the patient's 3D anatomy and widely disregard individual tissue properties. Further investigations are required to establish reliable procedures for assessment of individual tissue properties and incorporating them into patient-specific models of orbital mechanics.

Genome-wide linkage scan of nonsyndromic orofacial clefting in 91 families of central European origin.

Orofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome-wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome-wide linkage analyses, we searched for sex-specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21-q26 and 1p31-p21, with the chromosome 1 locus showing a male-specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC-associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex-specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO.

Further evidence for the involvement of MYH9 in the etiology of non-syndromic cleft lip with or without cleft palate.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects and has a multifactorial etiology that includes both genetic and environmental components. MYH9, the gene coding for the heavy chain of non-muscle myosin II, has been considered as a good candidate gene in NSCL/P on the basis of its expression profile during craniofacial morphogenesis. Reports in an Italian sample, as well as in an ethnically mixed North American sample, of a positive association between single-nucleotide polymorphisms in the MYH9 gene and NSCL/P have provided further support for the role of MYH9 in the development of NSCL/P. In the present study, we aimed to replicate these findings by conducting a family-based association study with seven single nucleotide polymorphisms in MYH9 using a sample of 248 NSCL/P patients and their parents. Single marker analysis resulted in a highly significant association for rs7078. In haplotype analysis, the most significant result was obtained for the SNP combination (rs7078; rs2071731; rs739097; rs5995288). Our results thus confirm the potential involvement of MYH9 in the etiology of NSCL/P in our patients of Central European origin, although further studies are warranted to determine its exact pathogenetic role.

IRF6 gene variants in Central European patients with non-syndromic cleft lip with or without cleft palate.

Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non-syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case-control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non-synonymous coding variant V274I (rs2235371) and five IRF6-haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 x 10(-6)) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38-2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21-3.10) for the homozygous genotype, values that are similar to those reported in a previously published family-based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP-based and resequencing studies using large samples of patients.

Reconstructive and ophthalmologic outcomes following resection of spheno-orbital meningiomas.

PURPOSE: To assess long-term stability and aesthetic and functional outcomes of orbital reconstruction after resection of spheno-orbital meningiomas using calvarial bone grafts. METHODS: A series of 21 patients were retrospectively examined after an average follow-up period of 65.6 months with regard to their personal satisfaction and also proptosis, ocular function, and reconstructive outcome. The sagittal position of the globe was analyzed by CT and MRI. Patients were treated surgically in an interdisciplinary approach between 1997 and 2006. RESULTS: A permanent postoperative decrease in globe protrusion of 2.7 mm on average was achieved. Most patients (76%) reported identical or improved vision, 85% were satisfied with the reconstructive result, and 55% were free of discomfort in daily life. Seven patients suffered from recurrences that were invariably accompanied by globe protrusion. CONCLUSIONS: Calvarial bone grafts provide good, stable long-term results in the reconstruction of orbital defects. Globe protrusion is a reliable indicator for the detection of recurrences in spheno-orbital meningiomas. Because of high recurrence rates, it is advisable to continue follow-up for 20 or more years.

Results of a prospective anthropometric and functional study about aesthetics and nasal respiration after secondary rhinoplasty in cleft lip and palate patients.

In contrast to the multitude of investigations regarding aesthetic changes in nasal surgery, few data are available concerning nasal function. This is especially important for cleft patients with a compromised nasal respiration.In this prospective study, 68 cleft patients, who underwent nasal surgery, were evaluated concerning aesthetic and respiratory outcome. To assess nasal respiration, active anterior rhinomanometry, rhinoresistometry, and acoustic rhinometry were performed preoperatively and 6 months postoperatively (without and with nasal decongestion, according to international standards). For analyzing the changes in aesthetic parameters, photographs from 3 directions, which were taken preoperatively and at least 6 months postoperatively, were compared. Thus, 57 angles and relations of lines were created out of 54 anthropometric points. The Wilcoxon test was used to compare preoperative and postoperative data (P < 0.05). Regarding aesthetic outcome, a significant improvement in many parameters was seen. The noses postoperatively proved to be significantly narrower and more symmetric and showed a better projection.Although analysis of functional respiratory data showed a significant increase in nasal volume, no change in nasal airflow and hydraulic diameter could be found.Whereas aesthetic improvement of the cleft nose is a goal, which can be achieved regularly, nasal respiration still seems to be a challenge in cleft patients. This study highlights the necessity of taking functional data to learn more about the effects of surgery. Objective methods to assess nasal respiratory function are important for planning and performing nasal surgery and are a means of quality control.

Combination of surgical resection and HDR-brachytherapy in patients with recurrent or advanced head and neck carcinomas.

AIM: Due to the limited therapeutic options, the management of previously pre-treated recurrent head and neck carcinomas remains a challenging problem. The use of hyper-fractionated-accelerated interstitial high-dose-rate brachytherapy (HDR-BT) might be able to improve safety and survival after surgical resection. MATERIAL AND METHODS: From 2000 to 2006, 13 patients with pre-treated, recurrent head and neck cancer (oral, maxillary sinus, lips) were treated in a curative approach by resection the recurrent tumour and HDR-BT. The concept included coverage of the surgical defect and sealing of the brachytherapy applicators with free microvascular or myocutaneous flaps. Conventional radiotherapy and chemotherapy were added as required. The patient group was re-examined with respect to survival and outcome. Additionally 5 patients, who received this combination therapy for primary carcinomas were included in this report observation in order to evaluate the rate of complications and adverse effects. RESULTS: Kaplan-Meier-curves revealed a 2-year overall survival of 65.3%. The mean survival for recurrent carcinomas was 22.8 months. Patients treated for primary carcinoma had a mean survival of 34.5 months. Four out of five (80%) patients with primary head and neck cancer were alive and without evidence of disease 2 years after treatment. The acute and chronic adverse side effects were manageable. There were no relevant complications concerning tissue transfer. CONCLUSIONS: Surgical resection combined with HDR-BT can lead to long-lasting remissions. A simultaneous microvascular defect reconstruction provides tissue cover for brachytherapy.

Safety and practicability of percutaneous translaryngeal tracheotomy (Fantoni technique) in surgery of maxillofacial and oropharyngeal tumours--own results and review of the literature.

BACKGROUND: The study examines the suitability of the Fantoni method of translaryngeal tracheotomy (TLT) for airway management after surgery due to oropharyngeal and maxillofacial tumours. PATIENTS AND METHODS: During a 4-year period, 156 translaryngeal pull-through tracheotomies were performed in 145 patients. This method is the only puncture tracheotomy technique that involves a dilatation process from inside the trachea to the outside through the skin and differs from other established puncture methods regarding practicability and frequency of complications. RESULTS: The mean puncture time (from puncture of the trachea to correct tube placement) was 10.1+/-4.8 min. With an oxygen supply of FiO(2)=1.0 the oxygen saturation prior to TLT was 98.4+/-1.29%, and the lowest median saturation value during the TLT procedure was 96.7+/-3.9%. No serious complications such as bleeding, loss of airway, pneumothorax or death were observed. Complications occurring during the TLT procedure were exclusively technical and at no time were they life-threatening. CONCLUSIONS: TLT is a technique with few complications and a straightforward procedure for those familiar with the method. It has some advantages compared with other puncture techniques which appear to commend TLT in terms of safety for the patient.

Usage characteristics and adverse event rates ​of the direct puncture and pull techniques for percutaneous endoscopic gastrostomy in patients with malignant tumors of the upper aerodigestive tract.

BACKGROUND AND STUDY AIMS: Patients with malignant tumors of the upper gastrointestinal tract are at risk of weight loss. Early supportive nutrition therapy is therefore recommended and usually requires placement of a percutaneous endoscopic gastrostomy (PEG). The aim of this study was to compare adverse events and usage characteristics of the direct puncture technique with those of the traditional pull technique when used in patients with endoscopically passable tumors. The primary endpoint was the rate of inflammatory adverse events (AEs) at the gastrostomy fistula. The secondary endpoint was the long-term rate of puncture-site metastases. PATIENTS AND METHODS: One hundred twenty patients (median age 56; IQR 36, 86 years) were randomized and treated per protocol in this prospective open randomized single-center study. Follow-ups were conducted on the third and seventh post-interventional days, after 1, 3 and 6 months and the last follow-up 5 years after intervention. RESULTS: Within the short-term follow-up period of 6 months after PEG placement, AEs were noted in 47 patients (39.2 %). These included 22 inflammations and 16 device dislocations and were mainly found in the puncture group (33 vs. 14 in the pull group) with a significantly increased incidence in the first month after PEG insertion ( P  = 0.001). Evaluation of the 5-year data did not reveal any significant differences. The gastrostomy tube was used in 101 patients (84.2 %) (range 18 days to 5 years). CONCLUSIONS: Our results favor the pull technique for patients with endoscopically passable tumors of the upper gastrointestinal tract due to less short-term adverse events. Both systems contributed equally to secure long-term use.