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Antibodies are produced when naive B cells differentiate into plasma cells within germinal centres (GCs) of lymphoid tissues. Patients with B cell lymphoma on effective immunotherapies exhibit diminished antibody production, leading to higher infection rates and reduced vaccine efficacy, even after B cell recovery. Current ex vivo models fail to sustain long-term GC reactions and effectively test B cell responses. Here we developed synthetic hydrogels mimicking the lymphoid tissue microenvironment, enabling human GCs from tonsils and peripheral blood mononuclear cell-derived B cells. Immune organoids derived from peripheral blood mononuclear cells maintain GC B cells and plasma cells longer than tonsil-derived ones and exhibit unique B cell programming, including GC compartments, somatic hypermutation, immunoglobulin class switching and B cell clones. Chemical inhibition of transcriptional and epigenetic processes enhances plasma cell formation. While integrating polarized CXCL12 protein in a lymphoid organ-on-chip modulates GC responses in healthy donor B cells, it fails with B cells derived from patients with lymphoma. Our system allows rapid, controlled modelling of immune responses and B cell disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Notch signaling, an important signaling pathway in cardiac development, has been shown to mediate the reparative functions of c-kit+ progenitor cells (CPCs). However, it is unclear how each of the four canonical Notch-activating ligands affects intracellular processes in c-kit+ cells when used as an external stimulus. Neonatal c-kit+ CPCs were stimulated using four different chimeric Notch-activating ligands tethered to Dynabeads, and the resulting changes were assessed using TaqMan gene expression arrays, with subsequent analysis by principal component analysis (PCA). Additionally, functional outcomes were measured using an endothelial cell tube formation assay and MSC migration assay to assess the paracrine capacity to stimulate new vessel formation and recruit other reparative cell types to the site of injury. Gene expression data showed that stimulation with Jagged-1 is associated with the greatest pro-angiogenic gene response, including the expression of VEGF and basement membrane proteins, while the other canonical ligands, Jagged-2, Dll-1, and Dll-4, are more associated with regulatory and epigenetic changes. The functional assay showed differential responses to the four ligands in terms of angiogenesis, while none of the ligands produced a robust change in migration. These data demonstrate how the four Notch-activating ligands differentially regulate CPC gene expression and function.

Current treatments for congenital and acquired craniofacial (CF) bone abnormalities are limited and costly. Conventional methods involve surgical correction, short-term stabilization, and long-term bone grafting, which may include problematic allografts and limited autografts. While bone morphogenetic protein 2 (BMP2) has been used for bone regeneration, it can cause bone overgrowth and life-threatening inflammation. Bone marrow-derived mesenchymal stem cell therapies, though promising, are not Food and Drug Administration approved and are resource intensive. Thus, there is a need for effective, affordable, and less side-effect-prone bone regenerative therapies. Previous research demonstrated that JAGGED1 induces osteoblast commitment in murine cranial neural crest cells through a NOTCH-dependent non-canonical pathway involving JAK2-STAT5. We hypothesize that delivery of JAGGED1 and induction of its downstream NOTCH non-canonical signaling in pediatric human osteoblasts constitutes an effective bone regenerative treatment. Delivering pediatric human bone-derived osteoblast-like cells to an in vivo murine bone loss model of a critically sized cranial defect, we identified that JAGGED1 promotes human pediatric osteoblast commitment and bone formation through p70 S6K phosphorylation. This approach highlights the potential of JAGGED1 and its downstream activators as innovative treatments for pediatric CF bone loss., Competing Interests: AK, BT, SK, MR, AT, TC, SC, IM, SG, PB, SA, HD, AG, LW, SG No competing interests declared, (© 2024, Kamalakar et al.)

Orofacial clefts are the most common congenital craniofacial anomaly. Adverse healing following cleft palate repair can lead to oronasal fistula (ONF), a persistent connection between the oral and nasal cavities. Although human allograft tissues are currently the gold standard for ONF repair, these methods carry risks of infection and rejection, often requiring surgical revision. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. An FDA-approved immunomodulatory drug, FTY720, is repurposed to reduce lymphocyte egress and induce immune cell fate switching toward pro-regenerative phenotypes. In this study, a bilayer biomaterial system is engineered using Tegaderm to secure and control the delivery of FTY720-nanofiber scaffolds (FTY720-NF). The release kinetics of the bilayer FTY720-NF is optimized to maintain drug release for up to 7 days, ensuring safe transdermal absorption and tissue biodistribution. The comprehensive immunophenotyping results demonstrate a regenerative state transition in hybrid immune cells recruited to the wound site. Further, histological evaluations reveal a significant ONF closure in mice by day 7 following bilayer FTY720-NF implantation. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options in pediatric patients., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background Aims: Mesenchymal stromal cells (MSCs) are polymorphic, adherent cells with the capability to stimulate tissue regeneration and modulate immunity. MSCs have been broadly investigated for potential therapeutic applications, particularly immunomodulatory properties, wound healing and tissue regeneration. The exact physiologic role of MSCs, however, remains poorly understood, and this gap in knowledge significantly impedes the rational development of therapeutic cells. Here, we considered interferon γ (IFN-γ) and tumor necrosis factor alpha (TNF-α), two cytokines likely encountered physiologically and commonly used in cell manufacturing. For comparison, we studied interleukin-10 (IL-10) (anti-inflammatory) and interleukin-4 (IL-4) (type 2 cytokine)., Methods: We directly assessed the effects of these cytokines on bone marrow MSCs by comparing RNA Seq transcriptional profiles. Western blotting and flow cytometry were also used to evaluate effects of cytokine priming., Results: The type 1 cytokines (IFN-γ and TNF-α) induced striking changes in gene expression and remarkably different profiles from one another. Importantly, priming MSCs with either of these cytokines did not increase variability among multiple donors beyond what is intrinsic to non-primed MSCs from different donors. IFN-γ-primed MSCs expressed IDO1 and chemokines that recruit activated T cells. In contrast, TNF-α-primed MSCs expressed genes in alternate pathways, namely PGE2 and matrix metalloproteinases synthesis, and chemokines that recruit neutrophils. IL-10 and IL-4 priming had little to no effect., Conclusions: Our data suggest that IFN-γ-primed MSCs may be a more efficacious immunosuppressive therapy aimed at diseases that target T cells (ie, graft-versus-host disease) compared with TNF-α-primed or non-primed MSCs, which may be better suited for therapies in other disease settings. These results contribute to our understanding of MSC bioactivity and suggest rational ex vivo cytokine priming approaches for MSC manufacturing and therapeutic applications., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to quantify and describe baseline patient and parent-proxy health-related quality of life scores in patients with low-flow vascular malformations at a single, tertiary-care vascular anomalies clinic., Study Design: This is a retrospective study of data collected on patients with low-flow vascular malformations between the ages of 2 to 25 who were seen at a single, tertiary-care center vascular anomalies clinic. A total of 266 patients are included in this study., Results: Patients with lymphatic malformations report decreased quality of life scores as compared with venous malformations in the emotional, psychological, school, and social domains. Patients with lower extremity malformation report decreased quality of life scores as compared with head/neck, trunk, upper extremity, and multifocal malformations; most notably in the physical domain., Conclusions: Treatment of low-flow vascular malformations should aim to improve patient quality of life. The use of standardized health-related quality of life measures in this study quantifies baseline quality of life scores among patients with low-flow vascular malformations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kaimari, Kamalakar and Goudy.)

Objective: To present external airway splinting with bioabsorbable airway supportive devices (ASD) for severe, life-threatening cases of pediatric tracheomalacia (TM) or tracheobronchomalacia (TBM)., Methods: A retrospective cohort was performed for 5 pediatric patients with severe TM or TBM who underwent ASD placement. Devices were designed and 3D-printed from a bioabsorbable material, polycaprolactone (PCL). Pre-operative planning included 3-dimensional airway modeling of tracheal collapse and tracheal suture placement using nonlinear finite element (FE) methods. Pre-operative modeling revealed that triads along the ASD open edges and center were the most effective suture locations for optimizing airway patency. Pediatric cardiothoracic surgery and otolaryngology applied the ASDs by suspending the trachea to the ASD with synchronous bronchoscopy. Respiratory needs were trended for all cases. Data from pediatric patients with tracheostomy and diagnosis of TM or TBM, but without ASD, were included for discussion., Results: Five patients (2 Females, 3 Males, ages 2-9 months at time of ASD) were included. Three patients were unable to wean from respiratory support after vascular ring division; all three weaned to room air post-ASD. Two patients received tracheostomies prior to ASD placement, but continued to experience apparent life-threatening events (ALTE) and required ventilation with supraphysiologic ventilator settings. One patient weaned respiratory support successfully after ASD placement. The last patient died post-ASD due to significant respiratory co-morbidity., Conclusion: ASD can significantly benefit patients with severe, unrelenting tracheomalacia or tracheobronchomalacia. Proper multidisciplinary case deliberation and selection are key to success with ASD. Pre-operative airway modeling allows proper suture placement to optimally address the underlying airway collapse., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To explore patient-reported outcome measures of pediatric paradoxical vocal fold motion through a multi-institutional study of geographically diverse United States medical facilities to assess long-term management and outcomes., Methods: Eligible participants >8 years of age diagnosed with PVFM over a 10-year period from 7 tertiary pediatric hospitals were invited to complete a survey addressing study objectives., Results: 65 participants completed the survey, of whom 80% were female, 75% reported a 3.5 grade point average or better, and 75% identified as competitive athletes or extremely athletic individuals. Participants rated their perceived efficacy of 13 specific treatments. Only five treatments were considered effective by a majority of the participants who tried them. The treatments that participants tried most often were breathing exercises (89.2%), bronchodilator treatments (45%), and allergy medications (35.4%). 78.8% of participants reported receiving more than one treatment and 25% reported receiving a combination of bronchodilators, anticholinergics, and steroids. At the time of PVFM diagnosis, 38% of participants had no idea when their symptoms would completely resolve. 23.3% of participants did not experience symptom resolution until greater than 1 year after diagnosis., Conclusions: Traditional management tools such as breathing exercises and biofeedback treatments may not provide the long-term benefit that providers anticipate. In addition to these commonly used management strategies, highly efficacious techniques such as counseling and lifestyle management should be incorporated into the long-term management of patients whose symptoms are refractory to traditional care., Level of Evidence: 4 Laryngoscope, 133:970-976, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Implantable patient-specific devices are the next frontier of personalized medicine, positioned to improve the quality of care across multiple clinical disciplines. Translation of patient-specific devices requires time- and cost-effective processes to design, verify and validate in adherence to FDA guidance for medical device manufacture. In this study, we present a generalized strategy for selective laser sintering (SLS) of patient-specific medical devices following the prescribed guidance for additive manufacturing of medical devices issued by the FDA in 2018. We contextualize this process for manufacturing an Airway Support Device, a life-saving tracheal and bronchial implant restoring airway patency for pediatric patients diagnosed with tracheobronchomalacia and exhibiting partial or complete airway collapse. The process covers image-based modeling, design inputs, design verification, material inputs and verification, device verification, and device validation, including clinical results. We demonstrate how design and material assessment lead to verified Airway Support Devices that achieve desired airway patency and reduction in required Positive End-Expiratory Pressure (PEEP) after patient implantation. We propose this process as a template for general quality control of patient-specific, 3D printed implants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Scott J. Hollister reports a relationship with Tissue Regeneration Systems(Trs) Inc. that includes: equity or stocks. Scott J. Hollister has patent # US20160051385A1 Porous Bidirectional Bellowed Tracheal Reconstruction Device issued to Materilaise Inc., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: To illustrate how quality improvement can produce unexpected positive outcomes., Methods: We compared a retrospective review of perioperative management and outcomes of baseline 122 pediatric total thyroidectomies to 121 subsequent total thyroidectomies managed by an Electronic Medical Record protocol in a large, free-standing children's healthcare system. Process measures included serum calcium measurement 6-12 hours postoperatively; parathyroid hormone measurement 6 hours postoperatively; preoperative iodine for Graves disease, and postoperative prophylactic calcium carbonate administration. In addition, we completed 4 Plan-Do-Study-Act (PDSA) cycles, focusing on implementation, refinement, usage, education, and postoperative calcitriol administration. The primary outcome included transient hypocalcemia during admission., Results: All perioperative process measures improved over PDSA cycles. Measurement of postoperative serum calcium increased from 42% at baseline to 100%. Measurement of postoperative PTH increased from 11% to 97%. Preoperative iodine administration for Graves disease surgeries improved from 72% to 94%. Postoperative calcium carbonate administration increased from 36% to 100%. There was a trend toward lower rates of severe hypocalcemia during admission over the subsequent PDSA cycles starting at 11.6% and improving to 3.4%. With the regular review of outcomes, surgical volume consolidated among high-volume providers, associated with a decrease in a permanent hypoparathyroid rate of 20.5% at baseline to 10% by the end of monitoring., Conclusions: In standardizing care at 1 large pediatric institution, implementing a focused quality improvement project involving the perioperative management of transient hypocalcemia in total thyroidectomy pediatric patients resulted in additional, unanticipated improvements in patient care., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Controversy exists among head and neck surgical specialties regarding management of Langerhan's Cell Histiocytosis (LCH). The purpose of this study was to evaluate diagnosis, management, and treatment outcomes in children with LCH of the head and neck., Methods: This is a retrospective cohort study of children with LCH of the head and neck who presented to Children's Healthcare of Atlanta hospital from 2009 to 2021. The independent variables were demographic information, lesion locations, clinical presentation, radiographic findings, diagnostic workup, treatment, and length of follow-up. The patients were grouped based on these variables. The outcome variable was disease reactivation. Descriptive statistics were calculated., Results: There were 3 presentations of LCH of the head and neck. Group 1 presented as a lesion in 1 system without CNS risk (SS-). There were 24 patients with an average age of 10 years. Lesions were located in calvaria and/or mandible. Majority of the patients were treated with only debridement. Two of the patients experienced reactivation. Group 2 presented as a lesion in 1 system with CNS risk (SS+). There were 30 patients with an average age of 6 years. Common locations were temporal bone and/or orbit. These patients present with recurrent ear infections and ptosis. Majority of the patients were treated with chemotherapy (n = 28). One patient had disease reactivation. Group 3 presented with multisystem involvement. There were 13 patients with an average age of 2 years. LCH was found in skin and the lymphatic system. Imaging demonstrated extracranial organ involvement. All of them were treated with chemotherapy. There was 40% reactivation of LCH., Conclusions: Treatment of LCH depends on presentation. SS- subgroup can be adequately treated via surgical debridement. SS+ and multisystem groups benefit from an early disease diagnosis and require chemotherapy., (Copyright © 2021 The American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Primary cells isolated from the human respiratory tract are the state-of-the-art for in vitro airway epithelial cell research. Airway cell isolates require media that support expansion of cells in a basal state to maintain the capacity for differentiation as well as proper cellular function. By contrast, airway cell differentiation at an air-liquid interface (ALI) requires a distinct medium formulation that typically contains high levels of glucose. Here, we expanded and differentiated human basal cells isolated from the nasal and conducting airway to a mature mucociliary epithelial cell layer at ALI using a medium formulation containing normal resting glucose levels. Of note, bronchial epithelial cells expanded and differentiated in normal resting glucose medium showed insulin-stimulated glucose uptake which was inhibited by high glucose concentrations. Normal glucose containing ALI also enabled differentiation of nasal and tracheal cells that showed comparable electrophysiological profiles when assessed for cystic fibrosis transmembrane conductance regulator (CFTR) function and that remained responsive for up to 7 weeks in culture. These data demonstrate that normal glucose containing medium supports differentiation of primary nasal and lung epithelial cells at ALI, is well suited for metabolic studies, and avoids pitfalls associated with exposure to high glucose., (© 2022. The Author(s).)

Objective: The coronavirus disease 2019 (COVID-19) pandemic caused delays in medical and surgical interventions in most health care systems worldwide. Oral and maxillofacial surgeons (OMSs) delayed operations to protect themselves, patients, and staff. This article (1) presents one institution's experience in the management of pediatric craniomaxillofacial trauma during the COVID-19 pandemic and (2) suggests recommendations to decrease transmission., Methods: This was a retrospective review of children aged 18 years or younger who underwent surgery at Children's Healthcare of Atlanta in Atlanta, GA, between March and August 2020. Patients (1) were aged 18 years old or younger, (2) had one or more maxillofacial fractures, and (3) underwent surgery performed by an OMS, otolaryngologist, or plastic surgeon. Medical records were reviewed regarding (1) fracture location, (2) COVID-19 status, (3) timing, (4) personal protective equipment, and (5) infection status. Descriptive statistics were computed., Results: Fifty-eight children met the inclusion criteria. The most commonly injured maxillofacial location was the nose. Operations were performed 50.9 hours after admission. Specific prevention perioperative guidelines were used with all patients, with no transmission occurring from a patient to a health care worker., Conclusions: With application of our recommendations, there was no transmission to health care workers. We hope that these guidelines will assist OMSs during the COVID-19 pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Following injury, the oral mucosa undergoes complex sequences of biological healing processes to restore homeostasis. While general similarities exist, there are marked differences in the genomics and kinetics of wound healing between the oral cavity and cutaneous epithelium. The lack of successful therapy for oral mucosal wounds has influenced clinicians to explore alternative treatments and potential autotherapies to enhance intraoral healing. The present in-depth review discusses current gold standards for oral mucosal wound healing and compares endogenous factors that dictate the quality of tissue remodeling. We conducted a review of the literature on in vivo oral wound healing models and emerging regenerative therapies published during the past twenty years. Studies were evaluated by injury models, therapy interventions, and outcome measures. The success of therapeutic approaches was assessed, and research outcomes were compared based on current hallmarks of oral wound healing. By leveraging therapeutic advancements, particularly within in cell-based biomaterials and immunoregulation, there is great potential for translational therapy in oral tissue regeneration., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of bone requires carefully choregraphed signaling to bone progenitors to form bone. Our group recently described the requirement of transforming growth factor beta receptor 3 (TGFβR3), a receptor involved in TGFβ pathway signaling, during osteoblast lineage commitment in mice. The TGFβ pathway is known to play multiple osteo-inductive and osteo-inhibitory roles during osteoblast development and TGFβR3 human mutations are associated with reduced bone mineral density, making TGFβR3 a unique target for bone inductive therapy. In this article, we demonstrated increased mineralization of human pediatric bone-derived osteoblast-like cells (HBO) when treated with soluble TGFβR3 (sR3) using Alizarin Red staining. Osteogenic commitment of HBO cells was demonstrated by induction of osteogenic genes RUNX2, osteocalcin, osteopontin, and osterix. Evaluation of the canonical TGFβ pathway signaling demonstrated that sR3 was able to induce bone formation in HBO cells, mainly through activation of noncanonical targets of TGFβ pathway signaling including AKT, ERK, and p38 MAP kinases. Inhibition of these osteogenic noncanonical pathways in the HBO cells also inhibited mineralization, suggesting they are each required. Although no induction of SMAD1, 5, and 9 was observed, there was the activation of SMAD2 and 3 suggesting that sR3 is primarily signaling via the noncanonical pathways during osteogenic induction of the HBO. Our results highlight the important role of TGFβR3 in osteoblast induction of mineralization in human bone cells through noncanonical targets of TGFβ signaling. Future studies will focus on the ability of sR3 to induce bone regeneration in vivo using animal models., (© 2021 Wiley Periodicals LLC.)

Purpose: The use of a vascularized free fibula graft (FFF) for the reconstruction of a mandible in a child with a mandibular tumor is infrequent. The purpose of this study is to report our protocol for resection of mandibular jaw tumors and immediate reconstruction using FFF in pediatric patients., Methods: This was a retrospective case series of children with a mandibular tumor, which was resected and immediately reconstructed with FFF. All patients were treated via the same staged protocol: 1) presurgical digital planning, 2) surgical intervention (resection and immediate reconstruction), 3) postoperative care in the pediatric intensive unit, and 4) prosthodontic dental rehabilitation. Outcomes were complications and recurrence. Medical records were reviewed to document demographic information, tumor details, surgical interventions, postoperative course, and prosthodontic rehabilitation., Results: Fifteen patients (10 males, average age of 13.7 years) met inclusion criteria. Ten patients had mandibular ameloblastoma. All patients were treated by a dedicated pediatric team and followed the same protocol. The average tumor size was 4.87 × 3.22 × 2.03 cm. Most fibulas (n = 12) had one osteotomy to reestablish mandibular continuity and create appropriate contour. The most common microvascular anastomosis was with a facial artery (n = 13) and the external jugular vein (n = 9). At an average follow-up of 15.5 months, there were only 3 minor donor site complications. Eight implants were placed without complications. No tumors recurred., Conclusions: The results of this study suggest that pediatric mandibular tumors can be successfully treated using a specific protocol involving resection and immediate reconstruction using FFF with minimal complications and without recurrence., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Craniofacial bone loss is a complex clinical problem with limited regenerative solutions. Currently, BMP2 is used as a bone-regenerative therapy in adults, but in pediatric cases of bone loss, it is not FDA-approved due to concerns of life-threatening inflammation and cancer. Development of a bone-regenerative therapy for children will transform our ability to reduce the morbidity associated with current autologous bone grafting techniques. We discovered that JAGGED1 (JAG1) induces cranial neural crest (CNC) cell osteoblast commitment during craniofacial intramembranous ossification, suggesting that exogenous JAG1 delivery is a potential craniofacial bone-regenerative approach. In this study, we found that JAG1 delivery using synthetic hydrogels containing O9-1 cells, a CNC cell line, into critical-sized calvarial defects in C57BL/6 mice provided robust bone-regeneration. Since JAG1 signals through canonical (Hes1/Hey1) and non-canonical (JAK2) NOTCH pathways in CNC cells, we used RNAseq to analyze transcriptional pathways activated in CNC cells treated with JAG1 ± DAPT, a NOTCH-canonical pathway inhibitor. JAG1 upregulated expression of multiple NOTCH canonical pathway genes (Hes1), which were downregulated in the presence of DAPT. JAG1 also induced bone chemokines (Cxcl1), regulators of cytoskeletal organization and cell migration (Rhou), signaling targets (STAT5), promoters of early osteoblast cell proliferation (Prl2c2, Smurf1 and Esrra), and, inhibitors of osteoclasts (Id1). In the presence of DAPT, expression levels of Hes1 and Cxcl1 were decreased, whereas, Prl2c2, Smurf1, Esrra, Rhou and Id1 remain elevated, suggesting that JAG1 induces osteoblast proliferation through these non-canonical genes. Pathway analysis of JAG1 + DAPT-treated CNC cells revealed significant upregulation of multiple non-canonical pathways, including the cell cycle, tubulin pathway, regulators of Runx2 initiation and phosphorylation of STAT5 pathway. In total, our data show that JAG1 upregulates multiple pathways involved in osteogenesis, independent of the NOTCH canonical pathway. Moreover, our findings suggest that JAG1 delivery using a synthetic hydrogel, is a bone-regenerative approach with powerful translational potential., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To provide recommendations to otolaryngologists, pulmonologists, and allied clinicians for tracheostomy decannulation in pediatric patients., Methods: An iterative questionnaire was used to establish expert recommendations by the members of the International Pediatric Otolaryngology Group., Results: Twenty-six members completed the survey. Recommendations address patient criteria for decannulation readiness, airway evaluation prior to decannulation, decannulation protocol, and follow-up after both successful and failed decannulation., Conclusion: Tracheostomy decannulation recommendations are aimed at improving patient-centered care, quality and safety in children with tracheostomies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To describe the implementation of telemedicine in a pediatric otolaryngology practice during the coronavirus disease 2019 (COVID-19) global pandemic., Methods: A descriptive paper documenting the development and application of telemedicine in a tertiary academic pediatric otolaryngology practice., Results: A total of 51 established patients were seen via telemedicine within the first 2 weeks of telemedicine implementation. Seven (7) patients were no shows to the appointment. The median patient age was 5 years old, with 55% male patients. Common diagnoses for the visits included sleep disordered breathing/obstructive sleep apnea (25%) and hearing loss (19.64%). Over half (50.98%) of visits were billed at level 4 visit code., Discussion: The majority (88%) of visits during the first 2 weeks of telemedicine implementation in our practice were completed successfully. Reasons that patients did not schedule telemedicine appointments included preference for in person appointments, and lack of adequate device at home to complete telemedicine visit. Limitations to our telemedicine practice included offering telemedicine only to patients who had home internet service, were established patients, and English-speaking. Trainees were not involved in this initial implementation of telemedicine., Conclusions: COVID-19 has driven the rapid adoption of telemedicine in outpatient medicine. Our group was able to institute an effective telemedicine practice during this time., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To develop an expert-based consensus of recommendations for the diagnosis and management of pediatric obstructive sleep apnea., Methods: A two-iterative Delphi method questionnaire was used to formulate expert recommendations by the members of the International Pediatric Otolaryngology Group (IPOG)., Results: Twenty-six members completed the survey. Consensus recommendations (>90% agreement) are formulated for 15 different items related to the clinical evaluation, diagnosis, treatment, postoperative management and follow-up of children with OSA., Conclusion: The recommendations formulated in this IPOG consensus statement may be used along with existing clinical practice guidelines to improve the quality of care and to reduce variation in care for children with OSA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting., Methods: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice., Results: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale., Discussion: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response during oral cavity wound healing and ONF formation. Immunophenotyping of the inflammatory infiltrate following hard palate injury showed delayed recruitment of non-classical LY6C lo monocytes and failure to resolve inflammation. To induce a pro-regenerative inflammatory response, delivery of FTY720 nanofiber scaffolds following hard palate mucosal injury promoted complete ONF healing and was associated with increased LY6C lo monocytes and pro-regenerative M2 macrophages. Alteration in gene expression with FTY720 delivery included increased Sox2 expression, reduction in pro-inflammatory IL-1, IL-4 and IL-6 and increased pro-regenerative IL-10 expression. Increased keratinocyte proliferation during ONF healing was observed at day 5 following FTY720 delivery. Our results show that local delivery of FTY720 from nanofiber scaffolds in the oral cavity enhances healing of ONF, occurring through multiple immunomodulatory mechanisms. STATEMENT OF SIGNIFICANCE: Wound healing complications occur in up to 60% of patients undergoing cleft palate repair where an oronasal fistula (ONF) develops, allowing food and air to escape from the nose. Using a mouse model of palate mucosal injury, we explored the role of immune cell infiltration during ONF formation. Delivery of FTY720, an immunomodulatory drug, using a nanofiber scaffold into the ONF was able to attract anti-inflammatory immune cells following injury that enhanced the reepithelization process. ONF healing at day 5 following FTY720 delivery was associated with altered inflammatory and epithelial transcriptional gene expression, increased anti-inflammatory immune cell infiltration, and increased proliferation. These findings demonstrate the potential efficacy of immunoregenerative therapies to improve oral cavity wound healing., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Sensorineural hearing loss (SNHL) has been reported to occur at increased frequency in the pediatric sickle cell disease (SCD) population, likely secondary to ototoxic medication regimens and repeat sickling events that lead to end organ damage. Risk and protective factors of SNHL in this population are not fully characterized. The objective of this study was to describe audiology results in children with SCD and the prevalence and sequelae of SNHL., Methods: A comprehensive clinical database of 2600 pediatric SCD patients treated at 1 institution from 2010-16 was retrospectively reviewed to identify all patients who were referred for audiologic testing. Audiologic test results, patient characteristics, and SCD treatments were reviewed., Results: 181 SCD children (97 male, 153 HbSS) underwent audiologic testing, with 276 total audiology encounters, ranging 1-9 per patient. Mean age at first audiogram was 8.9 ± 5.2 years. 29.8% had prior cerebrovascular infarct and an additional 25.4% had prior abnormal transcranial Doppler screens documented at time of first audiogram. Overall, 13.3% had documented hearing loss, with 6.6% SNHL. Mean pure tone average (PTA) among patients with SNHL ranged from mild to profound hearing loss (Right: 43.3 ± 28.9, Left: 40.8 ± 29.7), sloping to more severe hearing loss at higher frequencies., Conclusions: Hearing loss was identified in a significant subset of children with SCD and the hearing loss ranged from normal to profound. Though the overall prevalence of SNHL in SCD patients was low, baseline audiology screening should be considered., (Copyright © 2018. Published by Elsevier B.V.)

Background: Pediatric surgical risk assessment tools use patient- and procedure-specific variables to predict postoperative complications. These tools assist clinicians in preoperative counseling and surgical decision-making. The objective of this systematic literature review was to compile and compare existing pediatric surgical risk tools that are broadly applicable across pediatric surgical specialties., Methods: A systematic literature review was performed following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Relevant publications were identified and screened based on predefined eligibility criteria: (1) a preoperative risk assessment tool predicting postoperative complications or mortality, (2) applicable across various surgical specialties, and (3) pertinent to the pediatric population. Studies with specialty- or procedure-specific risk scores and validation studies were excluded. Included articles were assessed for quality and risk of bias by using the Newcastle-Ottawa Scale., Results: Four studies met inclusion criteria. Risk factors were evaluated across the models as proxies for operative suitability of patients before surgery. Risk factors common to all studies were the presence of cardiovascular or neurological diseases and history of prematurity. Three of the four included studies defined most risk factors in binary terms, whereas one study used a scale of severity of organ system disease when defining preoperative risk. Generated risk score models provided good to strong concordance with inpatient mortality or postoperative complications, with c-statistic values ranging from 0.77 to 0.98., Conclusions: Each study reported an assessment of a novel, generally applicable pediatric surgical risk assessment tool for risk-stratifying children preoperatively for complications that rise after surgery. More studies are needed to assess generalizability in all populations and procedures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

During craniofacial development, cranial neural crest (CNC) cells migrate into the developing face and form bone through intramembranous ossification. Loss of JAGGED1 (JAG1) signaling in the CNC cells is associated with maxillary hypoplasia or maxillary bone deficiency (MBD) in mice and recapitulates the MBD seen in humans with Alagille syndrome. JAGGED1, a membrane-bound NOTCH ligand, is required for normal craniofacial development, and Jagged1 mutations in humans are known to cause Alagille Syndrome, which is associated with cardiac, biliary, and bone phenotypes and these children experience increased bony fractures. Previously, we demonstrated deficient maxillary osteogenesis in Wnt1-cre;Jagged1 f/f (Jag1CKO) mice by conditional deletion of Jagged1 in maxillary CNC cells. In this study, we investigated the JAG1 signaling pathways in a CNC cell line. Treatment with JAG1 induced osteoblast differentiation and maturation markers, Runx2 and Ocn, respectively, Alkaline Phosphatase (ALP) production, as well as classic NOTCH1 targets, Hes1 and Hey1. While JAG1-induced Hes1 and Hey1 expression levels were predictably decreased after DAPT (NOTCH inhibitor) treatment, JAG1-induced Runx2 and Ocn levels were surprisingly constant in the presence of DAPT, indicating that JAG1 effects in the CNC cells are independent of the canonical NOTCH pathway. JAG1 treatment of CNC cells increased Janus Kinase 2 (JAK2) phosphorylation, which was refractory to DAPT treatment, highlighting the importance of the non-canonical NOTCH pathway during CNC cells osteoblast commitment. Pharmacologic inhibition of JAK2 phosphorylation, with and without DAPT treatment, upon JAG1 induction reduced ALP production and, Runx2 and Ocn gene expression. Collectively, these data suggest that JAK2 is an essential component downstream of a non-canonical JAG1-NOTCH1 pathway through which JAG1 stimulates expression of osteoblast-specific gene targets in CNC cells that contribute to osteoblast differentiation and bone mineralization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cleft lip and palate are common craniofacial deformities. The etiology underlying these deformities is complex and multifactorial and they can occur as part of one of many chromosomal syndromes, Mendelian single gene disorders, teratogenic effects, and as yet uncharacterized syndromes. Our paper will provide an overview of the multiple genes and molecular pathways that have been implicated in palatal fusion. We believe that understanding the molecular mechanisms of cleft formation can help clinicians anticipate which patients may have difficulties healing and in the future allow them to make surgical and medical treatment decisions based on genetic information.

Introduction: Obstructive sleep apnea (OSA) is prevalent and may be more severe in children with Sickle Cell Disease (SCD) compared to the general pediatric population., Objectives: The objective of this study was to describe the therapeutic effects and complications of tonsillectomy and adenoidectomy (T&A) for treatment of OSA in children with SCD., Methods: A comprehensive database of pediatric SCD patients was reviewed to identify all patients who underwent T&A between 2010 and 2016. An IRB-approved, retrospective review of laboratory values, perioperative course, pre- and post-T&A hospital utilization, and polysomnography was conducted., Results: There were 132 SCD children (108 HbSS) who underwent T&A. Mean age was 7.6 ± 4.6 years. The mean baseline hemoglobin of these patients was 9.3 ± 1.4 g/dL; 72.7% of patients had pre-operative transfusion, such that the mean Hb at time of T&A was 11.4 ± 1.0 g/dL. The average admission length surrounding T&A was 3.5 ± 1.2 days. Complications were documented in 11.4% of operative cases. Polysomnography was available in 104 pre-T&A and 45 post-T&A. The Apnea-Hypopnea Index decreased on post-T&A polysomnogram (7.6 ± 8.7 vs. 1.3 ± 1.9, p = 0.0001). The O2 nadir improved on post-T&A polysomnogram (81.2 ± 10.8 vs. 89.3 ± 7, p = 0.0003). Emergency room visits (mean events per year) decreased post-operatively (2.6 ± 2.8 vs. 1.8 ± 2.2, p = 0.0002)., Conclusions: T&A can be a safe and effective option to treat OSA in pediatric patients with SCD and was significantly associated with reduced AHI and fewer ER visits post-operatively., (Copyright © 2018. Published by Elsevier B.V.)

Despite humanitarian otolaryngology groups traveling in record numbers to resource-limited areas treating pediatric otolaryngology disease processes and training local providers, there remains a large burden of unmet needs. There is a meager amount of published information that comes from the developing world from an otolaryngology standpoint. As would be expected, the little information that does comes involves some of the most common pediatric otolaryngology diseases and surgical burdens including childhood hearing loss, otitis media, adenotonsillectomies, airway obstructions requiring tracheostomies, foreign body aspirations, and craniomaxillofacial surgeries, including cleft lip and palate., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This article focuses on the embryologic development and growth of the temporomandibular joint (TMJ) and touches on the development and growth of surrounding structures. Aberrations in structures surrounding the TMJ can affect its development as well. The normal adult anatomy of the TMJ is described as well as common malformations. The clinical ramifications of a malformed TMJ are also discussed in order to understand future necessary consultants involved in the care of these patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Long-term immunosuppressants form an integral part of therapy for post-transplantation patients. Immunosuppressants may also have an anticoagulant effect, and little is known about their effects on bleeding risk after adenotonsillectomy. Our objective was to investigate whether there is an increased observed rate of post-tonsillectomy hemorrhage in a population of pediatric patients on long-term immunosuppressants after solid organ transplantation, compared to healthy controls., Methods: This was a retrospective chart review of pediatric patients with a history of renal or heart transplant undergoing adenotonsillectomy at our institution between 2000 and 2014. All patients underwent tonsillectomy with monopolar electrocautery. Retrieved data included perioperative medications, occurrence of post-operative bleeding and associated treatment. For comparison, we obtained a population of age-matched controls with no history of immunosuppression who underwent the same procedure., Results: A total of 34 patients meeting criteria were identified, of which 3 (8.82%) suffered a postoperative bleed. Forty-seven controls were obtained, with a total of 2 (4.26%) postoperative hemorrhages (p = 0.65). Two of the post-transplantation patients who bled postoperatively required cauterization in the operating room. None of the controls required surgical treatment. The incidences of postoperative bleeding requiring surgical treatment were 5.88% and 0%, respectively (p = 0.17)., Conclusion: We failed to demonstrate an increased risk of bleeding after undergoing adenotonsillectomy in our cohort of post-transplantation pediatric patients on chronic immunosuppression. Future research, likely requiring a multi-institutional effort, could stratify by immunosuppressive agent to elucidate bleeding risk with specific medications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives/hypothesis: Superior pediatric orbital subperiosteal abscesses (SPAs) are less common than medial ones, and clinical features specific to patients with superior SPAs have not been well defined. Clinical characteristics between patients with superior and medial SPAs are compared to determine whether superior location is a risk factor for surgical intervention., Study Design: Retrospective cohort study., Methods: The target population consisted of patients diagnosed with an SPA and seen by the pediatric otolaryngology service at a tertiary children's hospital between January 2010 and October 2014. Imaging characteristics including proptosis, hypoglobus, intraorbital air, and abscess volume as well as treatment interventions were reviewed., Results: Forty patients between 5 and 17 years of age treated for an orbital SPA were identified. Thirteen patients were identified as having superior SPAs; 27 had medial SPAs. The average ages in the two groups were 10.92 and 9.26 years, respectively. The odds ratio for surgical treatment per each increasing year of age was 1.5 (P = .004). The proportion of patients requiring surgery was significantly different between the groups (12/13 superior vs. 13/27 medial, P = .01). The predominant organism group cultured in surgical patients was Streptococcus anginosus (8/24, 29.17%). Superior SPA patients had significantly more proptosis, hypoglobus, and abscess volume on computed tomography scan., Conclusions: Patients with superior SPAs may present with more advanced disease, leading to a higher rate of characteristics such as proptosis, hypoglobus, and intraorbital air, factors that would predispose to surgical drainage. We found that abscess volume was the most predictive of surgery., Level of Evidence: 4 Laryngoscope, 127:735-740, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Repair of the cleft palate intends to establish the division between the oral and nasal cavity, thereby improving feeding, speech, and eustachian tube dysfunction all while minimizing the negative impact on maxillary growth. Before palate repair candidacy, timing and surgical method of repair is dependent on comorbid conditions, particularly cardiac disease, mandibular length, and palate width. Additionally, management of the alveolar cleft and the indications for gingivoperiosteoplasty versus secondary alveolar bone grafting is a controversial topic that weighs the risks and benefits of potentially sparing the patient an additional surgery against iatrogenic restriction of facial growth and malocclusion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to identify prognostic factors associated with improved speech outcomes following surgical correction for velopharyngeal insufficiency (VPI) in pediatric patients with 22q11.2 deletion syndrome (22q11DS)., Methods: Eighteen patients were identified via retrospective chart review of patients with 22q11DS between 2005 and 2014. Patient characteristics, medical histories, associated comorbidities, surgical procedures, and pre- and postoperative perceptual hypernasality (subjectively rated 1-5 with 5 being the most severe) were gathered for each patient., Results: 12 patients (67%) experienced improvement in hypernasality following corrective surgery for VPI. Higher severity of hypernasality preoperatively was found to be indicative of a lower chance of improvement with VPI surgery. Of 8 patients with a preoperative hypernasality score of 5, 3 (38%) showed improvement in hypernasality postoperatively, while 9 out of 10 (90%) of patients with a preoperative hypernasality score less than 5 showed postoperative improvement. Females were also found to have worse speech outcomes compared to males., Conclusion: 22q11DS patients presenting with severely hypernasal speech preoperatively are less likely to show improvement in hypernasality following corrective surgery for VPI. Those patients with moderate hypernasality are most likely to benefit from surgery., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: The purpose of this study was to determine the prevalence and characterize the types of hearing loss in pediatric patients with 22q11.2 deletion syndrome (22q11DS)., Methods: Fifty-eight patients were identified via retrospective chart review performed of patients with 22q11DS between 1996 and 2014. Patient demographics, pertinent family history, associated comorbidities, and degree and type of hearing loss were gathered for each patient. A literature review of the National Library of Medicine's database with a focus on hearing loss and 22q11DS was performed., Results: 22 patients (38%) were found to have hearing impairment: 68% with conductive hearing loss, 14% with sensorineural hearing loss, and 18% with mixed hearing loss. Patients with hearing loss regardless of type had a higher prevalence of developmental delay (55%), cleft palate (23%), articulation disorders (77%), and a greater need for tympanostomy tubes (73%) compared to patients with normal hearing. Temporal bone computed tomography scans of 5 patients revealed a variety of abnormalities in the middle and/or inner ears., Conclusion: Hearing impairment occurs in up to 38% of 22q11DS patients of both conductive and sensorineural types, with the conductive type being the most common. These patients have a greater need for tympanostomy tubes and a higher prevalence of developmental delay and speech articulation disorders. Early hearing screening and treatment is warranted in this population., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To describe the presence of laryngeal eosinophils and associated symptomatology in patients with aerodigestive dysfunction., Study Design: Case series with chart review., Setting: Single tertiary pediatric referral center., Subjects: Eighty-one consecutive pediatric patients referred to a multidisciplinary aerodigestive clinic with upper airway concerns., Methods: Microlaryngoscopy and posterior arytenoid biopsy, flexible bronchoscopy, esophagogastroduodenoscopy and esophageal biopsy, and impedance probe testing were performed as indicated by clinical symptoms. Positive versus negative posterior arytenoid biopsy for eosinophils and the presence or absence of concomitant histopathological laryngitis and/or esophagitis were measured., Results: Nine of 81 (11%) patients had positive laryngeal biopsy for eosinophils (range, 1-29 eosinophils/high-powered field [HPF]). Three of these 9 patients also had concurrent biopsy-proven eosinophilic esophagitis, while 8 of 81 total patients had biopsy-proven eosinophilic esophagitis. The frequency of biopsy-proven eosinophilic esophagitis was higher in patients with posterior arytenoid eosinophils versus patients without laryngeal eosinophils (33% versus 6.9%, P = .0408)., Conclusions: Eosinophilic inflammation in the larynx has not been described in children with complex aerodigestive complaints. Posterior arytenoid eosinophils may serve as a marker of chronic laryngeal inflammation in children with aerodigestive dysfunction, although their exact role in this inflammation remains unclear. In our population, >15 eosinophils/HPF within posterior arytenoid biopsies was associated with concomitant eosinophilic esophagitis., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study, we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development., (© 2015 Wiley Periodicals, Inc.)

Background: The reparative mechanism that operates following post-natal cutaneous injury is a fundamental survival function that requires a well-orchestrated series of molecular and cellular events. At the end, the body will have closed the hole using processes like cellular proliferation, migration, differentiation and fusion., Results: These processes are similar to those occurring during embryogenesis and tissue morphogenesis. Palatogenesis, the formation of the palate from two independent palatal shelves growing towards each other and fusing, intuitively, shares many similarities with the closure of a cutaneous wound from the two migrating epithelial fronts., Conclusions: In this review, we summarize the current information on cutaneous development, wound healing, palatogenesis and orofacial clefting and propose that orofacial clefting and wound healing are conserved processes that share common pathways and gene regulatory networks., (© 2014 Wiley Periodicals, Inc.)

Background: Cleft palate occurs in up to 1:1,000 live births and is associated with mutations in multiple genes. Palatogenesis involves a complex choreography of palatal shelf elongation, elevation, and fusion. Transforming growth factor β (TGFβ) and bone morphogenetic protein 2 (BMP2) canonical signaling is required during each stage of palate development. The type III TGFβ receptor (TGFβR3) binds all three TGFβ ligands and BMP2, but its contribution to palatogenesis is unknown., Results: The role of TGFβR3 during palate formation was found to be during palatal shelf elongation and elevation. Tgfbr3(-) (/) (-) embryos displayed reduced palatal shelf width and height, changes in proliferation and apoptosis, and reduced vascular and osteoblast differentiation. Abnormal vascular plexus organization as well as aberrant expression of arterial (Notch1, Alk1), venous (EphB4), and lymphatic (Lyve1) markers was also observed. Decreased osteoblast differentiation factors (Runx2, alk phos, osteocalcin, col1A1, and col1A2) demonstrated poor mesenchymal cell commitment to the osteoblast lineage within the maxilla and palatal shelves in Tgfbr3(-) (/) (-) embryos. Additionally, in vitro bone mineralization induced by osteogenic medium (OM+BMP2) was insufficient in Tgfbr3(-) (/) (-) palatal mesenchyme, but mineralization was rescued by overexpression of TGFβR3., Conclusions: These data reveal a critical, previously unrecognized role for TGFβR3 in vascular and osteoblast development during palatogenesis., (© 2014 Wiley Periodicals, Inc.)

The differential diagnosis in pediatric lymphadenopathy includes bacterial, viral, fungal, and idiopathic causes. A systematic approach to patient evaluation is necessary because the differential diagnosis, presentation, and work up must consider infectious, immunologic, neoplastic, and idiopathic disorders. A thorough history and examination are vital to determining the diagnosis and ruling out a malignant process., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cleft lip with or without cleft palate is the most common congenital malformation of the head and neck. Orofacial clefting could significantly affect the quality of life of the child and requires multiple steps of care to obtain an optimal outcome. Each patient should be evaluated for congenital anomalies, developmental delay, neurologic disorders, and psychosocial concerns. A multidisciplinary team is necessary to ensure that every aspect of the child's care is appropriately treated and coordination between providers is achieved. This article discusses the assessment and treatment recommendations for children born with cleft lip and/or cleft palate., (Copyright © 2014 Elsevier Inc. All rights reserved.)