Obstructive Sleep Apnea Syndrome in Children with 22q11.2 Deletion Syndrome after Operative Intervention for Velopharyngeal Insufficiency

Introduction: Surgical treatment of velopharyngeal insufficiency (VPI) in 22q11.2 deletion syndrome is often warranted. In this patient population, VPI is characterized by poor palatal elevation and muscular hypotonia with an intact palate. We hypothesize that 22q11.2 deletion patients are at greater risk of obstructive sleep apnea (OSA) after surgical correction of VPI, due, in part, to their functional hypotonia, large velopharyngeal gap size, and the need to surgically obstruct the velopharynx. Methods: We performed a retrospective analysis of patients with 22q11.2 deletion syndrome treated at a tertiary pediatric hospital between the years of 2002-2012. The incidence of VPI, need for surgery, post-operative polysomnogram, post-operative VPI assessment, and OSA treatments were evaluated. Results: Forty-three patients (18 males, 25 females, ages 1-14 years) fitting the inclusion criteria were identified. Twenty-eight patients were evaluated by speech pathology due to hypernasality. Twenty-one patients had insufficient velopharyngeal function and required surgery. Fifteen underwent pharyngeal flap surgery, three underwent sphincter pharyngoplasty, two underwent Furlow palatoplasty, and one underwent combined sphincter pharyngoplasty with Furlow palatoplasty. Of these, eight had post-operative snoring. Six of these underwent polysomnography. Four patients were found to have OSA based on the results of the polysomnography (average apnea/hypopnea index of 4.9 events/hour, median=5.1, SD=2.1). Two required continuous positive airway pressure (CPAP) due to moderate OSA.Conclusion: Surgery is often necessary to correct VPI in patients with 22q11.2 deletion syndrome. Monitoring for OSA should be considered after surgical correction of VPI due to a high occurrence in this population. Furthermore, families should be counseled of the risk of OSA after surgery and the potential need for treatment with CPAP

Regenerative Approaches to Treat Pediatric Maxillary Bone Deficiency

Presented on December 13, 2016 from 8:30 a.m.-9:30 a.m. at the Parker H. Petit Institute for Bioengineering and Bioscience (IBB), room 1128, Georgia Tech.Steven L. Goudy is an Associate Professor, Otolaryngology – Head & Neck Surgery at Emory University and Director, Division of Pediatric Otolaryngology, Children's Healthcare of Atlanta.CLINICAL FOCUS - While I provide comprehensive and compassionate care to all of my patients, I have a particular interest in treating development and neoplastic concerns of the head and neck region. Such craniofacial development abnormalities as cleft lip and palate, Pierre Robin Sequence, and velopharyngeal insufficiency are also a strong focus of my practice. Multidisciplinary collaboration is an important mechanism in my treatment approach, an example being my participation in teams of diverse specialists that evaluate and treat patients with vascular and neonplastic tumors of the head and neck region. RESEARCH FOCUS - Cleft and craniofacial disorders are my primary clinical and basic research interests. Even though the surgical repair of cleft lip and palate is highly effective, patients will continue to be faced with ongoing medical, dental, and surgical care. Surgical outcomes can be variable, and the patient's facial growth and development is primarily the result of their genetic composition. Therefore, much of my research focuses on the problems that can develop during the years that follow surgery. Underdevelopment of the upper jaw is one of the main sequelae of cleft palate repair and causes maxillary hypoplasia. To uncover why this happens, I have assembled a team of collaborators that includes Drs. Nick Willett (Emory Department of Orthopedics), Gregory Gibson (Center for Integrative Genomics, Georgia Institute of Technology), and Michael Davis (Coulter Department of Biomedical Engineering at Georgia Tech and Emory University), all of whom are experts in the fields of bone and vascular biology. Our goal is to determine how cell autonomous and noncell autonomous Jagged1 signaling during maxillary development contributes to final maxillary formation. I worked closely with Dr. Joey Barnett of the Department of Pharmacology at Vanderbilt while I was there, and he will continue to be my senior advisor as I evaluate the integration of Jagged1 and TgfßR3 signaling during maxillary mesenchymal cell differentiation and ossification. With assistance from Drs. Scott Boden (Emory Department of Orthopedics), Roberto Pacifici (Emory Department of Medicine), and Bob Taylor (Emory Department of Medicine), I am examining how intramembranous ossification of the maxillary and palatine bones contributes to later maxillary morphology. Dr. Greg Gibson (Director of the Center for Integrative Genomics, Georgia Tech) will help plan, execute, and analyze the RNAseq data to identify the targets of Jagged1 signaling. We have already published our observations involving the bony phenotype and our conclusion that Wnt1Cre;Jagged1 F/F mice are a viable model of postnatal maxillary hypoplasia. Once we have a wider understanding of maxillary development, we plan on developing targeted therapies for future in vitro and in vivo correction of maxillary hypoplasia in the Jag1CKO mice.Runtime: 62:03 minute

Biomedical engineering approaches for the delivery of JAGGED1 as a potential tissue regenerative therapy

JAG1 is a ligand that activates the NOTCH signaling pathway which plays a crucial role in determining cell fate behavior through cell-to-cell signaling. JAG1-NOTCH signaling is required for mesenchymal stem cell (MSC) differentiation into cardiomyocytes and cranial neural crest (CNC) cells differentiation into osteoblasts, making it a regenerative candidate for clinical therapy to treat craniofacial bone loss and myocardial infarction. However, delivery of soluble JAG1 has been found to inhibit NOTCH signaling due to the requirement of JAG1 presentation in a bound form. For JAG1-NOTCH signaling to occur, JAG1 must be immobilized within a scaffold and the correct orientation between the NOTCH receptor and JAG1 must be achieved. The lack of clinically translatable JAG1 delivery methods has driven the exploration of alternative immobilization approaches. This review discusses the role of JAG1 in disease, the clinical role of JAG1 as a treatment, and summarizes current approaches for JAG1 delivery. An in-depth review was conducted on literature that used both in vivo and in vitro delivery models and observed the canonical versus non-canonical NOTCH pathway activated by JAG1. Studies were then compared and evaluated based on delivery success, functional outcomes, and translatability. Delivering JAG1 to harness its ability to control cell fate has the potential to serve as a therapeutic for many diseases

Radiographic and endoscopic measurements of esophageal length in pediatric patients

Objectives: Knowledge of the length between the upper esophageal sphincter (UES) and the lower esophageal sphincter (LES) in pediatric patients is essential for intraluminal impedance and dual pH probe recordings. Methods: We measured the vertical distance between the true vocal cords (TVCs) and the LES in chest x-rays (CXRs) of 118 children (ages, 6 weeks to 13 years) and measured the vertical distance between the UES and the LES during endoscopy in 31 patients (ages, 14 months to 17 years) and correlated the measurements to height, weight, and age. Results: Esophageal length correlated best with patient height (R = 0.96 by CXR, R = 0.88 by endoscopy) and less well with weight (R = 0.87, R = 0.67) and age (R = 0.94, R = 0.86). Linear regression analyses using radiographic measurements revealed that esophageal length (TVC to LES) can be estimated from a patient\u27s height by the following equation: 1.048 + 0.167 × height (in centimeters). With the upper pH probe placed in the hypopharynx at the TVC level and the inferior probe placed in the esophagus 3 to 6 cm above the LES, the patients were divided into 6 groups corresponding to the currently available number of sizes of dual pH-impedance probes. With the patients\u27 heights between 71.5 and 161.3 cm, 64.7% to 100% of patients were within 1 cm of the desired location with preselected probes. Confirmation of placement was performed with CXR. Conclusions: A pediatric patient\u27s height can be used to estimate the esophageal length (TVC to LES) and facilitate the selection of dual pH-impedance probes. Our method decreases the risk of morbidity while increasing the accuracy of the study of extraesophageal reflux disease. © 2005 Annals Publishing Company. All rights reserved

Preliminary experience with black bone magnetic resonance imaging for morphometry of the mandible and visualisation of the facial skeleton

BACKGROUND: Children with orofacial deformity may require repeated imaging of the facial skeleton. OBJECTIVE: To test the feasibility and accuracy of "black bone" magnetic resonance imaging (MRI) for assessing facial deformity in children. MATERIALS AND METHODS: Three-dimensional (3-D) black bone gradient echo sequences (flip angle 5°, submillimetre spatial resolution) from 10 children (median age: 13 years, range: 2-16 years), who underwent MRI of the temporomandibular joints, were evaluated with multiplanar reconstruction and 3-D rendering tools. Intra- and inter-reader agreement was investigated for measuring the height of the mandibular ramus and condyle, basal length of the mandible, gonion angle and mandibular inclination angle by intraclass correlation coefficient (ICC) and Bland-Altman analysis. Absolute percentage error was calculated with the average of all measurements serving as reference. RESULTS: Sixty linear and 40 angle measurements were obtained on reformatted multiplanar black bone images with excellent inter-reader agreement (ICC > 0.99, agreement bias < 1.4 mm/ < 1.5°) and small error (median absolute error < 3%). The black bone images required inversion of the signal intensity and removal of air before they could be processed with standard volume rendering tools. The diagnostic utility of 3-D views for assessing the facial skeleton was sufficient except for assessing dental relationship. CONCLUSION: Morphometric measurements of the mandible can be obtained from black bone MRI with comparable inter-rater agreement to that reported for cone beam computed tomography (CT). With improvements of 3-D rendering techniques and software, black bone MRI may become a radiation-free alternative to CT in children with facial deformities

Lineage tracing SPM using <i>Myf5-Cre;R26R</i> in <i>Irf6</i>−/− Embryos.

<p>Coronal sections through anterior, middle and posterior tongue of control and <i>Irf6</i>−/− mice at E13.5, E14.5, and E15.5 performed in triplicate. In the E13.5 control tongues there was a strong contribution of the SPM (<i>Myf5</i>+) to the tongue (blue cells in A, C, E) with striations extending from the midline representing the transversal muscle (black arrow). In the <i>Irf6</i>−/− tongues there was reduced SPM (blue cells in B, D, F) with reduced and poorly organized striations of transversal muscle (black arrow). At E14.5 there was increased SPM in the control tongues (blue cells in G, I, K) and more striations of the transversal muscle (black arrow). In the E14.5 <i>Irf6</i>−/− tongue there was reduced SPM (blue cells in H, J, L) and reduction in striations of the transversal muscle and poor organization (black arrows). In the E15.5 control tongue there was primarily SPM (blue cells in M, O, Q) with increasing striations of the transversal muscle (black arrows). In the E15.5 <i>Irf6</i>−/− tongue there was a significant reduction of SPM (blue cells in N, P, R) with reduced striations of the transversal muscle and poor organization (black arrows). The inter-molar eminence was not populated by SPM and was absent in the <i>Irf6</i>−/− tongue (white arrows in E, K, Q).</p

Expression of <i>Irf6</i> in Tongue Occurs in <i>Myf5</i>+ Cell Lineage.

<p>Coronal sections through the anterior, middle and posterior tongue during critical stages of tongue differentiation performed in triplicate (E13.5–E15.5). At E13.5 there was moderate <i>Irf6</i> expression in the tongue giving a striated appearance representing the transversal muscle extending from the midline (A, B, C). At E14.5 there was intense <i>Irf6</i> staining throughout the tongue (D, E, F) with more prominent striations of the transversal muscle extending from the midline (white arrow) and an <i>Irf6</i>-free zone in the inter-molar eminence (white asterisk). At E15.5 there was a reduction in <i>Irf6</i> signaling throughout the tongue (G, H, I). Lineage tracing of segmental paraxial mesoderm was performed using <i>Myf5-Cre;R26R</i> mice. <i>Irf6</i> staining occurs in the striations of the transversal muscle of the tongue tissue (J, M, P) and detection of B-Galactosidase activity was found in the same region of the tongue of <i>Myf5-Cre;R262R</i> mice (K, N, Q). Overlay of these images demonstrated that <i>Irf6</i> staining occurred primarily in the <i>Myf5</i>+ cell lineage (L, O, R).</p

Altered Actin Cytoskeleton in <i>Irf6</i>−/− Tongue.

<p>Coronal sections of E14.5 control and <i>Irf6</i>−/− tongue stained with Phalloidin to detect F-actin performed in triplicate. In the <i>Irf6</i>−/− tongue there was reduced Phalloidin staining and poor organization of the stained fibers (B) compared to controls (A). Using confocal imaging on phalloidin-stained images of similar areas of the tongue (denoted by circle in images A, B) we identified reduced actin filament length and poor organization of actin fibers in the <i>Irf6</i>−/− fibers (D) compared to controls (C). Myosin heavy chain expression was greatly reduced in E15.5 <i>Irf6</i>−/− tongue using MF-20 staining (F) compared to controls (E). Myogenin was not effected in <i>Irf6</i>−/− tongue (H) compared to controls (G) * denotes inter-molar eminence.</p