Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis.

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity

Novel molecular insights into human tooth agenesis

The development of dentition is a fascinating process that involves a complex series of epithelial-mesenchymel signaling interactions. That such a precise process frequently goes awry is not surprising. Indeed, tooth agenesis is one of the most commonly inherited disorders in humans that affects up to twenty percent of the population and imposes significant functional, emotional and financial burdens on patients. Mutations in the paired box domain containing transcription factor PAX9 result in autosomal dominant tooth agenesis that primarily involves posterior dentition. Despite these advances, little is known about how PAX9 mediates key signaling actions in tooth development and how aberrations in PAX9 functions lead to tooth agenesis. As an initial step towards providing evidence for the pathogenic role of mutant PAX9 proteins, I performed a series of molecular genetic analyses aimed at resolving the structural and functional defects produced by a number of PAX9 mutations causing non-syndromic posterior tooth agenesis. It is likely that the pathogenic mechanism underlying tooth agenesis for the first two mutations studied (219InsG and IIe87Phe) is haploinsufficiency. For the six paired domain missense mutations studied, the lack of functional defects observed for three of the mutant proteins suggests that these mutations altered PAX9 function through alternate mechanisms. Next, I explored further the nature of the partnership between Pax9 and the Msx1 homeoprotein and their role in the expression of a downstream effector molecule, Bmp4. When viewed in the context of events occurring in dental mesenchyme, the results of these studies indicate that the Pax9-Msx1 protein interaction involves the localized up-regulation of Bmp4 activity that is mediated by synergistic interactions between the two transcription factors. Importantly, these assays corroborate in vivo data from mouse genetic studies and support reports of Pax9-dependent expression of Bmp4 in dental mesenchyme. Taken together, these results suggest that PAX9 mutations cause an early developmental defect due to an inability to maintain the inductive potential of dental mesenchyme through involvement in a pathway involving Msx1 and Bmp4

Craniofacial Growth and Development: A Primer for the Facial Trauma Surgeon

Understanding craniofacial growth and development is important in the management of facial trauma in the growing pediatric patient. This manuscript is a review of craniofacial growth and development and clinical implications of pediatric facial fractures

Technical Modifications Specific to the Cleft Le Fort I Osteotomy

PURPOSE: To discuss technical modifications specific to the cleft Le Fort I osteotomy that improve mobilization and demonstrate the stability of the maxilla at the Le Fort I level in a cohort of patients with cleft palate (with or without cleft lip) who underwent traditional maxillary advancement. METHODS: This was a retrospective evaluation of patients with cleft palate (+/- cleft lip) who underwent orthognathic surgery for management of skeletal malocclusions. All study subjects had a Le Fort I osteotomy +/- bilateral mandibular sagittal split osteotomies. The cleft Le Fort I osteotomy technique is modified to extensively release fibrous tissue and scar from the posterior maxilla, including around the tuberosity, along the posterior maxillary sinus wall, and circumferentially around the descending palatine canal. Maxillary position was assessed using angular and linear measurements pre-operatively (T0), immediately post-operatively (T1), and at 1-year post-operatively (T2). Descriptive and bivariate statistics were computed; a P \u3c 0.05 was considered significant. RESULTS: Twenty-eight patients with cleft palate (with or without cleft lip) were included. The sample\u27s mean age was 18.9 ± 1.4 years and included 11 females. The majority of subjects (64.3%) underwent bimaxillary surgery; eight subjects (28.6%) had segmental maxillary surgery and 14 subjects (50%) had simultaneous maxillary interpositional bone grafting. The mean maxillary sagittal advancement was 6.1 mm (range: 0-10 mm). At 1-year post-operatively, the absolute change in SNA was 0.7 ± 0.9 degrees; the absolute change in maxillary sagittal position was 0.8 ± 0.6 mm. There was no association between the magnitude of advancement and the magnitude of position change (P = 0.86). Stability was not influenced by segmental surgery, bone grafting, or bimaxillary surgery (P \u3e 0.33). CONCLUSION: Using a modified technique with extensive release of posterior scar and graduated intra-operative traction, maxillary advancement of up to 10 mm can be performed in patients with cleft palate (± cleft lip) with sagittal relapse of \u3c 1 mm at 1-year post-operatively

Technical Modifications Specific to the Cleft Le Fort I Osteotomy

PURPOSE: To discuss technical modifications specific to the cleft Le Fort I osteotomy that improve mobilization and demonstrate the stability of the maxilla at the Le Fort I level in a cohort of patients with cleft palate (with or without cleft lip) who underwent traditional maxillary advancement. METHODS: This was a retrospective evaluation of patients with cleft palate (+/- cleft lip) who underwent orthognathic surgery for management of skeletal malocclusions. All study subjects had a Le Fort I osteotomy +/- bilateral mandibular sagittal split osteotomies. The cleft Le Fort I osteotomy technique is modified to extensively release fibrous tissue and scar from the posterior maxilla, including around the tuberosity, along the posterior maxillary sinus wall, and circumferentially around the descending palatine canal. Maxillary position was assessed using angular and linear measurements pre-operatively (T0), immediately post-operatively (T1), and at 1-year post-operatively (T2). Descriptive and bivariate statistics were computed; a P \u3c 0.05 was considered significant. RESULTS: Twenty-eight patients with cleft palate (with or without cleft lip) were included. The sample\u27s mean age was 18.9 ± 1.4 years and included 11 females. The majority of subjects (64.3%) underwent bimaxillary surgery; eight subjects (28.6%) had segmental maxillary surgery and 14 subjects (50%) had simultaneous maxillary interpositional bone grafting. The mean maxillary sagittal advancement was 6.1 mm (range: 0-10 mm). At 1-year post-operatively, the absolute change in SNA was 0.7 ± 0.9 degrees; the absolute change in maxillary sagittal position was 0.8 ± 0.6 mm. There was no association between the magnitude of advancement and the magnitude of position change (P = 0.86). Stability was not influenced by segmental surgery, bone grafting, or bimaxillary surgery (P \u3e 0.33). CONCLUSION: Using a modified technique with extensive release of posterior scar and graduated intra-operative traction, maxillary advancement of up to 10 mm can be performed in patients with cleft palate (± cleft lip) with sagittal relapse of \u3c 1 mm at 1-year post-operatively

Lefort II distraction with zygomatic repositioning versus Lefort III distraction: A comparison of surgical outcomes and complications

The aim of the study was to determine if the additional surgical complexity of Lefort II distraction with zygomatic repositioning (LF2ZR) results in increased complications compared to Lefort III distraction (LF3). A retrospective review was performed of all LF3 and LF2ZR advancements performed by the senior author over 15 years. Demographic, operative, postoperative, and cephalometric data were collected from initial procedure through greater than 1 year postoperatively. Univariate and multivariate analyses were performed to compare procedures. 19 LF2ZR and 39 LF3 in 53 patients met inclusion criteria. Diagnoses differed between procedures, with more Crouzon Syndrome in LF3 and more Apert Syndrome in LF2ZR. Complication rate was 7/19 for LF2ZR and 12/39 for LF3 with no severe morbidity or mortality, and no difference between procedures (p = 0.56). The types of complications encountered differed between procedures. LF2ZR had a significantly longer operative time (506 ± 18 vs. 358 ± 24 min, p\u3c0.001). However, a greater number of LF2ZR patients underwent concomitant procedures (15/19 vs. 13/39, p\u3c0.001). Multivariate analysis revealed that Apert Syndrome and reoperative midface advancement were the most significant predictors of increased blood loss. LF2ZR has an equivalent complication rate to LF3. Therefore, it is our treatment of choice for cases requiring differential sagittal and vertical distraction of the central midface

Association of baseline kidney disease with outcomes of transcatheter mitral valve repair by MitraClip.

OBJECTIVES: This study sought to determine the impact of baseline chronic kidney disease (CKD) on in-hospital outcomes of transcatheter mitral valve repair with MitraClip (MC). BACKGROUND: MC is now an established treatment in high surgical risk patients. However, limited data are available on outcomes of MC in patients with baseline renal dysfunction. METHODS: The authors used data from January 2014 to December 2017 National Readmission Database to identify all patients ≥18 years of age who underwent MC. International classification of diseases (ICD)-9 and ICD-10 codes were used to identify patients with no-CKD, CKD (without chronic dialysis), or end-stage renal disease (ESRD) on dialysis. Multivariable logistic regression models were constructed using generalized estimating equations to examine in-hospital outcomes. RESULTS: Of 13,563 patients undergoing MC, 8,935 (65.8%) had no-CKD, 4,152 (30.6%) had CKD, and 476 (3.5%) had ESRD. ESRD patients compared to CKD and no-CKD had significantly higher mortality (7.2% vs. 2.5% vs. 2.0%; p \u3c .001), higher incidence of bleeding, blood transfusions, and 30 day all cause readmission. CKD patients compared to no-CKD had significantly higher mortality (odds ratio-1.29; CI 1.01-1.65; p = .04), acute kidney injury (odds ratio-3.0; CI 2.69-3.34; p \u3c .001), new in-hospital hemodialysis (odds ratio- 2.70; CI 1.57-4.62; p \u3c .001), blood transfusions, 30 day all cause and congestive heart failure (CHF) readmissions. In-hospital stroke and cardiac tamponade did not differ between the three groups. Patients with baseline kidney disease undergoing MC had higher mortality at high volume centers compared to low volume centers. CHF was the most common cause of readmission postMC in patients with or without preprocedural kidney disease. CONCLUSION: Patients with baseline kidney disease have worse outcomes after MC with higher readmission rates requiring careful patient selection and follow up in this population