Velopharyngeal Incompetence in Children With 22q11.2 Deletion Syndrome: Velar and Pharyngeal Dimensions.

ABSTRACT: The surgical management of velopharyngeal incompetence (VPI) in children with 22q11.2 deletion syndrome (22q11.2 DS) is challenging. There are numerous approaches and children often undergo more than one operation. Our aim was to develop a method using images from routine lateral videofluoroscopy to study the dimensions of the velopharynx in this cohort.We analyzed 22 pre-operative lateral videofluoroscopy recordings of children with 22q11.2 DS and VPI. Fourteen had a submucous cleft palate (SMCP) and 8 had no obvious palatal abnormality but who were subsequently labelled as having an occult submucous cleft palate (OSMCP). The control data were 10 historic records of children with cleft lip and an intact palate. The authors identified key points on radiographs of the velum at rest and when elevated to measure the total velar length, functional velar length and pharyngeal depth and compared them ratiometrically.The intra-observer reliability was > 0.9 whereas the inter-observer reliability was > 0.74. The velopharyngeal depth/total velar length was significantly greater in 22q11.2 DS than the control group P < 0.001. There was no difference between SMCP and OSMCP patients, P = 0.556. There was no difference in the functional velar length/total velar length between 22q11.2 DS and controls (P = 0.763).In this study, the authors demonstrate a reliable method to gain useful ratiometric measurements of the velopharynx. This may help with treatment planning. Children with 22q11.2 DS and VPI have a larger velopharyngeal depth/total velar length ratio that may explain some of the difficulty in management.

Familial Absent Uvula With Velopharyngeal Incompetence-A New Syndrome?

We present a family with a previously undescribed abnormality of the palate and oropharynx which involved the absence of the uvula and the anterior pillar of the fauces, rudimentary posterior pillar of the fauces, and hypernasality. Eight family members over 4 generations are affected in a pattern consistent with autosomal dominant inheritance. A causal role for the FOXF2 gene has been identified and previously reported. We describe the management of the proband, which involved attempting to lengthen the palate and to retroposition the abnormally anteriorly directed velar musculature, along with speech therapy.

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.

Use of the Sphenoid Flap in Repair of the Wide Cleft Palate.

OBJECTIVE: In wide palatal defects, closure of the nasal layer can prove a considerable challenge. Mobilizing nasal flaps posteriorly usually facilitates soft palate closure. However, the defect is often too wide within the hard palate; hence, bilateral vomerine flaps are frequently required. Despite this, there is often a small defect in the nasal layer at the posterior septum (typically equating to the hard-soft palate junction), which has to be left to heal by secondary intention with the resulting increased risk of fistula formation and the potential deleterious long-term effect on speech due to cicatricial migration of the reconstructed levator sling anteriorly. We describe our experience in the use of the sphenoid flap to obtain tension-free primary closure of the nasal layer. METHODS: A retrospective multi-center study assessing all sphenoid flap procedures undertaken at both Birmingham Children's Hospital and Great Ormond Street Hospital. Key demographic and medical data was collected pre-, peri-, and postoperatively across the 2 sites. RESULTS: A total of 66 patients underwent the use of a sphenoid flap to aid closure of the nasal layer. The average age at time of repair was 9.7 months. More than half (55%, n = 36) were isolated cleft palates, and 35% (n = 23) were BCLPs. Forty-two percent of all patients had Robin sequence. The average cleft width was 14.4 mm. The overall fistula rate was 25.8% (n = 17). CONCLUSIONS: We describe the operative technique, indications, and our experience in the use of the sphenoid flap in wide cleft palate repair.

Retrospective analysis of cellulitis of the floor of the mouth.

OBJECTIVES: To analyze clinical data of patients treated for mouth floor cellulitis during 2003-2006 years at the Department of Maxillofacial Surgery, Vilnius University Hospital Zalgiris Clinic and to compare the results with existing data. MATERIAL AND METHODS: Patient's gender, age, social insurance, demographic profile, preference of first visit, previous treatment, origin of inflammation, symptoms of disease, treatment protocol and outcomes were evaluated from 240 clinical records. RESULTS: The male-female ratio was 1.3:1. The mean age of patients was 43.18+/-7.56 years. 65% of patients were from urban. 47% of patients were employed, 15% retirees, 22% unemployed, 10% children, 2% students and 4% handicapped people. In 65% of cases primary diagnosis was incorrect. Majority of patients appealed to doctor on the first five days from the beginning of the disease. 93.7% of mouth floor cellulites were odontogenic origin. In 32.9% of the patients at the time of first examination the extension of inflammation into parapharyngeal, pterygomandibular spaces or neck together with mouth floor cellulitis was diagnosed. In 1.7% (in 4 out of 240) of cases infection extended into the neck and parapharyngeal spaces despite treatment. In 2% (in 5 out of 240) of cases infection extended to mediastinum. CONCLUSIONS: Despite the aggressive treatment serious complications still are possible. Delayed treatment procedures might determine poor prognosis.

Diverse species-specific phenotypic consequences of loss of function sorting nexin 14 mutations.

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects.

Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP. MVPs were enriched in regulatory and active regions of the genome and in pathways already implicated in craniofacial development. In an independent UK cohort (171 NSCLP, 177 controls), we replicated 4 out of 11 tested MVPs. We demonstrated a significant positive correlation between blood and lip tissue DNA methylation, indicating blood as a suitable tissue for NSCLP methylation studies. Next, we quantified CDH1 promoter methylation levels in CDH1 mutation-positive families, including penetrants, non-penetrants or non-carriers for NSCLP. We found methylation levels to be significantly higher in the penetrant individuals. Taken together, our results demonstrated the association of methylation at specific genomic locations as contributing factors to both non-familial and familial NSCLP and altered DNA methylation may be a second hit contributing to penetrance.

Predictors of Success in Furlow Palatoplasty for Submucous Clefts: An Experience with 91 Consecutive Patients.

BACKGROUND: The aim of this study was to evaluate, through multivariate ordinal logistic regression, variables contributing to good postoperative speech outcomes following Furlow palatoplasty. METHODS: A series of 91 consecutive patients was evaluated. Variables analyzed included demographics; speech perceptual assessment; and measures on videonasopharyngoscopy and videofluoroscopy such as preoperative closure pattern, velopharyngeal gap, and lateral pharyngeal wall motion. Univariate and multivariate analysis of predictors of high scores of articulation, nasal resonance, and resolution of velopharyngeal insufficiency were performed using simple and multinomial logistic regression. A summative perceptual assessment score was generated and analyzed for correlation with postoperative speech outcomes. RESULTS: There were 39 patients (42.9 percent) with a good outcome as defined by adequate articulation and lack of velopharyngeal insufficiency with normal nasal resonance. There was improvement of articulation in 53 patients (58.2 percent), of nasal resonance in 75 patients (82.4 percent), and of velopharyngeal insufficiency in 80 patients (87.9 percent). Predictors of good postoperative speech outcomes (p < 0.05) were preoperative articulation, nasal resonance, and lateral pharyngeal wall movement greater than 37.5 percent on one side. Preoperative severity of velopharyngeal insufficiency, velopharyngeal gap, pattern of closure, age, and sex were not predictive of a good outcome. Logistic regression demonstrated that the preoperative perceptual assessment score was predictive of postoperative outcome, with a significant difference (p < 0.05) between mild and severe groups. CONCLUSION: A scoring system based on summated perceptual assessment parameters is predictive of good postoperative speech outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Craniofacial neurofibromatosis and tissue expansion: long-term results.

The role of tissue expansion for coverage of soft-tissue defects of the face following neurofibroma resection has been briefly described previously with good results but limited follow-up. Recent scientific evidence has arisen that neurofibromas adversely affect the rheological properties of normal surrounding skin resulting in hyper-extensibility of dermal elements. In this context, we believe that long-term outcomes of tissue expansion for treatment of soft-tissue defects in patients with craniofacial neurofibromatosis would demonstrate suboptimal results because of loss of contour. Between June 1981 and June 2011, two patients underwent five tissue expander placements during the course of treatment for craniofacial neurofibromatosis at our institution. In both patients, tissue expansion was used to recruit tissue for fascio-cutaneous flaps following radical excision of adjacent neurofibromas. Three cervical expansions were performed for cheek and lateral face recontouring. One forehead expansion was used for nasal reconstruction and a second forehead expansion was performed for temporo-orbital recontouring. No perioperative complications occurred related to the tissue expander placement, expansions or radical excisions. Photographic follow-up of 15 years is available in each case. Cervical tissue expanded to provide cheek coverage demonstrated early loss of contour. Loss of lateral cheek contour resulted in increased morbidity from lateral and caudal displacement of the mid-face and orbital tissues requiring multiple revisional procedures. Tissue expansion of the forehead for both nasal reconstruction and temporo-orbital reconstruction demonstrated excellent long-lasting results.

Principles of head and neck reconstruction: an algorithm to guide flap selection.

Advances in head and neck reconstruction have resulted in improved outcomes with single-stage repair of defects ranging from intraoral to pharyngoesophageal to skull base defects. Key to success of surgery is choosing an appropriate reconstructive option based on the patient's wishes and fitness for major surgery. Where possible, free tissue transfer provides the best functional and aesthetic outcomes for the vast majority of defects. In this article, we present an algorithm to guide choice of flap selection and review principles of reconstruction and secondary surgery for head and neck defects.