[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.

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.

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.

Three-dimensional morphology of first molars in relation to ethnicity and the occurrence of cleft lip and palate.

OBJECTIVES: This study aims to describe morphological peculiarities of maxillary and mandibular first molars in Europeans, Asians and Europeans with cleft lip and palate. MATERIAL AND METHODS: Reflex microscopy was used to obtain three-dimensional morphometric landmarks from 40 models (11 Europeans and 13 Asians without cleft lip and palate, 16 Europeans with unilateral cleft lip and palate). The cases were examined using traditional morphometry and geometric morphometry, and visualized using thin-plate splines. RESULTS: Classic morphometry showed no right/left differences in the study groups and no significant differences with regard to the cleft side in patients with cleft lip and palate. In Asians, a significantly greater mesiodistal width was found. Geometric morphometry showed an enlarged centroid size in Asians (maxilla and mandible). In cleft patients, the cleft site did not appear to impact the morphology of first molars. CONCLUSION: Unilateral clefting did not affect the size and shape of molars; however, characteristic ethnicity-based differences were in fact identified. The results are relevant for orthodontic treatment with preadjusted appliances, and prosthetic CAD/CAM restorations.

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.

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.

Moving the mandible in orthognathic surgery - A multicenter analysis.

Orthognathic surgery has always been a classical focus of maxillofacial surgery. Since more than 100 years, various surgical techniques for mandibular repositioning have been developed and clinically tested. Since the establishment of plate and screw osteosynthesis, orthognathic surgery became more stable and safe. Nowadays, different surgical methods for mobilising the mandible are existing. This international multicenter analysis (n = 51 hospitals) is providing first evidence based data for the current use of different surgical methods. The dominating techniques were Obwegeser/dal Pont (61%) followed by Hunsuck/Epker (37%) and Perthes/Schlössmann (29%). The main osteosynthesis materials were plates (82%), bicortical screws (23.5%), or a combination of both (5.9%). 47% of all centers reported to use several surgical methods at the same time, depending on the anatomical problem and the surgeon's preference. This shows that different surgical methods seem to work as comparable, safe, and reliable procedures in everydays clinical practise. On this basis, further prospective studies could evaluate possible advantages for our patients.

Three-dimensional analysis of maxillary development in patients with unilateral cleft lip and palate during the first six years of life.

OBJECTIVES: The purpose of this work was to analyse early upper-jaw development in patients with unilateral cleft lip and palate (UCLP) treated using two different concepts and to compare shape and size developments between these two groups and a group of noncleft patients. MATERIALS AND METHODS: A total of 204 maxillary casts available for this study from 50 UCLP patients were analyzed for upper-jaw development based on three-dimensional measurements performed with a Reflex Microscope from birth up to 71 months of age. Thirty-five of these 50 patients were part of an early treatment group (two-stage cleft closure with single-stage palatoplasty at an age of 10-14 months) and 15 were part of a late treatment group (two-stage cleft closure with palatoplasty at an age of 4-7 years). The control group included 39 casts of 17 noncleft patients. RESULTS: Analysis of shape and size between the patients in the three groups yielded statistically significant differences between the cleft and the noncleft patients. In both treatment groups, we made observations typically associated with cleft formation like lateralization, asymmetry of the greater and lesser cleft segments, and pronounced vertical deviations of the segments. Viewed in all dimensions, however, the patients in the early treatment group approached the control group more closely, although a statistically significant difference was still observed. CONCLUSION: Our results suggest that the timing of hard-palate closure is not a decisive factor for upper-jaw development. Intrinsic factors (initial cleft width, presence of tooth buds) and the surgeon's skills appear to have a much more defining role.

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.

Dependence of columella development on the technique used for primary cleft lip closure.

OBJECTIVE: Primary cleft lip closure can be achieved by use of different types of surgery. The procedures of Millard, Veau, and Delaire are among the techniques most frequently performed worldwide. The factors which affect development of the columella have not been studied, however. SETTING: University Hospital of Leipzig, Germany, Department of Oral, Craniomaxillofacial and Facial Plastic Surgery. PATIENTS, PARTICIPANTS: In a comparative, retrospective, non-randomised study, we obtained anthropometric details from photographs of 120 unilateral and bilateral cleft patients after cleft lip closure by use of the techniques of Millard or Veau (n = 60) and Delaire (n = 60). Length and shape of the columella was assessed twice-first at the age of 10 months and again at the age of 10 years. Anthropometric characteristics of columella morphology and development were compared between the two groups. RESULTS: At the age of 10 months, the ratio of nasal height to width (interalar distance) was significantly different for unilateral and bilateral cases, and results were better for the Delaire groups (p = 0.001 unilateral and p > 0.001 bilateral). This effect was no longer apparent at 10-year follow up. Another index which tended to indicate better results in the Delaire groups was the nasal width index. In the summary of the anthropometric values investigated, however, differences between the Millard or Veau group and the Delaire group were marginal. CONCLUSION: Cleft lip closure by the technique of Millard for unilateral cleft lips and of Veau for bilateral cases is neither better nor worse than Delaire cheiloplasty for unilateral and bilateral clefts.

Using medical silicone to ensure an airtight negative pressure wound therapy dressing seal in challenging wounds: a case series.

Negative pressure wound therapy (NPWT) has been used for a broad range of indications and wound types. However, it can be difficult to maintain an airtight dressing seal when the wound is located in an anatomically challenging area or environment. To address this problem, medical silicone, used to create intraoral vacuum dressings, was used in five patients (one woman, four men, age range 57 to 66 years) to seal leaking NPWT dressings (four polyurethane dressings and one polyurethane silver foam dressing). The wounds were located in the head and neck, abdominal, lower extremity, and anogenital areas. Initial wound sizes ranged from 2.5 cm² to 700 cm², and periwound areas were characterized by irregular surfaces (scars, skin folds, or curved surfaces), humid milieu, or mobile structures. In all five patients, negative pressure was set at -125 mm Hg constant suction, and the silicone was able to seal the leaking dressings. Wound size reductions from 2.5 cm² to 13.5 cm² were observed during 9 to 64 days (range) of NPWT treatment. In these patients, medical silicone was found to be a suitable material to facilitate airtight sealing of the dressings used with NPWT.

Biomechanical investigation of naso-orbitoethmoid trauma by finite element analysis.

Naso-orbitoethmoid fractures account for 5% of all facial fractures. We used data derived from a white 34-year-old man to make a transient dynamic finite element model, which consisted of about 740 000 elements, to simulate fist-like impacts to this anatomically complex area. Finite element analysis showed a pattern of von Mises stresses beyond the yield criterion of bone that corresponded with fractures commonly seen clinically. Finite element models can be used to simulate injuries to the human skull, and provide information about the pathogenesis of different types of fracture.

[Paget´s disease of the mandible: a differential diagnosis of the osteomyelitis of the jaw]. / Morbus Paget des Unterkiefers: eine Differenzialdiagnose der Kieferosteomyelitis.

Paget´s disease of bone is a common, progressive disorder with uncertain etiology. It results in the replacement of normal skeletal areas with highly vascularized, low density bone. The most frequent symptom is bone pain, which is a result of periostal irritation due to increased metabolic activity. However, the disease may run without any symptoms. In these cases, an abnormal radiograph or an elevated serum alkaline phosphatase can indicate the disorder. Most cases are discovered accidentally. The average age of patients at the time of diagnosis is about 50 years. Male individuals are preferentially diseased. Paget´s disease affects either single bone (monostotic) or many bones (polyostotic). It typically involves the pelvis, femur and lumbar spine rather than skull and tibia. In the head and neck area, the skull is the most frequently affected localization. Lesions of the mandible and maxilla are less common. For the therapy of active Paget´s disease, antiresorptive agents like bisphosphonates are effective drugs. Additional treatment with analgesic drugs, antiinflammatory and antineuropathic agents is recommended. We present a case of polyostotic Paget´s disease of the mandible and of the thoracic skeleton.

Panel perception of facial appearance of cleft patients generated by use of a morphing technique.

OBJECTIVE: Perception of the facial appearance of cleft patients has, until now, been evaluated on the basis of photographs of the patients. Research based on photographs generated by use of a morphing technique has not yet been reported. The purpose of this study was to investigate female and male raters' panel perception with regard to the following: (1) patient age, (2) attractiveness, (3) gender appearance, and (4) likeability of faces of cleft patients generated by the use of a morphing technique. SETTING: The study was conducted at the Department of Oral, Craniomaxillofacial and Facial Plastic Surgery, University Hospital of Leipzig, Germany. PATIENTS, PARTICIPANTS: We used photographs of 32 adult German nonsyndromic cleft patients, mean age 18.9 ± 1.3 years, and surveyed 93 students, mean age 25.3 ± 3.2 years, by use of a standardized questionnaire. RESULTS: All respondents rated the mean age of cleft patients equally in unmorphed and morphed pictures. For all respondents, attractiveness of morphed patient pictures was rated significantly higher than for unmorphed pictures (mean 4.8 ± 1.0 vs. 6.4 ± 2.4; p < 0.001), although significance was reached only if morphed pictures of eight patients were rated. Female respondents rated attractiveness significantly higher than did males, especially for pictures of female patients. CONCLUSION: Facial morphing of patient pictures is a suitable method for creation of standard cleft faces. Despite the modification of the pictures, the faces generated remain human and assessable by panel members. Perception of faces of cleft patients' depended on raters' gender.

Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVES: Principles and workflow are described to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ) when oral surgery is necessary in patients taking bisphosphonates. MATERIAL AND METHOD: A total of 117 surgical procedures were performed on 68 patients taking bisphosphonates. The basis of the treatment was (1) use of perioperative antibiotics; (2) after dentoalveolar surgical procedures, bone edges were smoothed and mucoperiosteal flaps were prepared to ensure tension-free wound closure; (3) sutures were not removed until 14 days postsurgery; (4) long-term results were evaluated. RESULTS: Ninety-seven percent of all procedures were simple and showed no complications. Only 3 patients with a long history of intravenous bisphosphonate medication developed BRONJ within 4 weeks after surgery. No patient receiving oral bisphosphonates developed BRONJ. No long-term failure was observed when primary wound healing was successful. CONCLUSIONS: The high success rate of the described surgical procedures imply dentoalveolar surgery with low risk of development of BRONJ is possible for patients taking bisphosphonates.

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).

Biomechanical mechanisms of orbital wall fractures - a transient finite element analysis.

As the biomechanical mechanisms of orbital wall fractures are still under research, three different fracture mechanisms were tested in a finite element based investigation. In contrast to earlier studies, a finer skeletal model and a transient dynamic simulation were used to test pure hydraulic, pure buckling and a mixed force transmission. Results showed that each set-up led to different orbital fracture patterns, which correlate well with clinical findings. Therefore the conclusion is that different mechanisms may act together explaining the variety of clinical fracture situations. Biomechanical testing has proven to be appropriate in answering questions regarding fracture mechanisms.

Prevalence of cone beam computed tomography imaging findings according to the clinical stage of bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVES: Investigations of cone beam computed tomography (CBCT) for bisphosphonate-related osteonecrosis of the jaw (BRONJ) imaging are rare. The purpose of this study was to investigate the prevalence of typical radiological findings of BRONJ in CBCT. METHODS: Twenty-seven CBCTs of BRONJ sites were assessed on the basis of the radiological findings (cancellous bone destruction, cortical bone erosion, sequestration, osteosclerosis, and periostal bone formation) and put in relation to the severity of the BRONJ sites. RESULTS: Cancellous bone destruction and cortical bone erosion were the most common findings. Occurrence seems to decrease with decreasing BRONJ severity. Sequestration and osteosclerosis were less frequent and could be seen across all stages. Periosteal bone formation occurred in high-stage BRONJ only. CONCLUSION: Cancellous bone destruction, cortical bone erosion, sequestration, and osteosclerosis can be seen across all stages and prevalence seems to decrease with decreasing severity of BRONJ. The occurrence of periosteal new bone formation seems to start in high-stage BRONJ.

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.