Incidence of Sinusitis Postoperatively in Orthognathic Surgery: A Systematic Review and Meta-Analysis.

Maxillary osteotomies as a component of orthognathic surgery disrupt the normal anatomy and function of the sinus. The osteotomy with advancement of the inferior component of the sinus leaves a bony and mucosal opening in the sinus. Immediately after surgery, nasal drainage is impeded because of intranasal swelling. Acute and chronic maxillary sinusitis would be expected; however, its incidence as an expected complication is not well documented. A systematic review and meta-analysis was completed using PubMed to determine the incidence of sinusitis after maxillary orthognathic surgery. Studies were reviewed by two authors, and incidence data were extracted. Two hundred six articles were identified with 24 meeting the criteria for analysis. The incidence of sinusitis was based on 4213 participants who had undergone orthognathic surgery. Twenty-three studies reported a total number of sinusitis cases, and the results demonstrated a pooled incidence of 3.3% (95% confidence interval: 1.77, 6.06). One study did not report a total number of cases but reported chronic sinusitis survey-duration-based and Lund-Mackay scores. These scores, respectively, worsened from 7.6 to 14.8 and from 1.58 to 2.90 postoperatively. Despite the variability of maxillary surgery, the surgical technique, and the postoperative management, the incidence is low but sinusitis does occur. Prospective studies with validated questionnaires within the context of a specific protocol may further elucidate the causality of sinusitis. Further, patients with sinonasal symptoms postsurgery should be encouraged to consult with an otolaryngologist to ensure prompt treatment.

Alterations in Sphenoid Anatomy in Craniosynostosis: Implications for Fronto-Orbital Advancement.

OBJECTIVE: Fronto-orbital advancement involves removal of the fronto-orbital bandeau. Visualization of the saw blade is lost as it passes through the fronto-orbital-sphenoid junction (FOSJ), placing the temporal lobe at risk of injury. We aim to provide a 3D analysis of the space surrounding this osteotomy to differentiate various types of craniosynostoses. DESIGN: Retrospective cohort. SETTING: Institutional. PATIENTS: Thirty patients with isolated unicoronal synostosis, nonsyndromic bicoronal synostosis, metopic synostosis, Apert syndrome, Crouzon syndrome, and Muenke syndrome. INTERVENTIONS: CT scans conducted between 2 months to 2 years of age were 3D reconstructed to compare craniometrics against normal controls. MAIN OUTCOME MEASURE(S): Craniometrics. RESULTS: The mean bone thickness of the FOSJ at the level of the supraorbital rim was significantly small for the Apert, unicoronal and bicoronal groups. The mean vertical height of the middle cranial fossa from the lesser sphenoid wing was significantly greater in the unicoronal group. The mean vertical height of the tip of the temporal lobe from the lateral sphenoid ridge was greater in the unicoronal, isolated bicoronal, and Apert groups. The mean corneal protrusion beyond the lateral orbital rim was significantly greater in the Apert and unicoronal groups. The mean horizontal depth of the orbit was smallest in the Apert group. The mean vertical distance between the dacryon and the foramen cecum, and the mean volume of temporal lobe beneath the sphenoid shelf were the largest in the Apert group. CONCLUSIONS: Patients with Apert syndrome have the most unfavorable morphology of the anterior and middle cranial fossae.

Optimizing Facial Esthetic Outcomes: Adding Distraction Osteogenesis to Your Classic Orthognathic Surgery Armamentarium.

Classical orthognathic procedures have long been known to improve the facial esthetic contours and proportions of face by restoring the skeletal foundation, on which the soft-tissue drapes. Distraction osteogenesis was introduced to solve complex skeletal abnormalities in patients with craniofacial conditions that could not be solved by classical orthognathic surgery techniques. The gradual expansion in this group of patients showed not only greater skeletal stability, but the expansion at various tissue planes improved the facial appearance. In this report we review our experience in 22 cases with dentofacial skeletal abnormities for whom we believe achieved aesthetic outcomes could not habe been with classical orthognathic techniques alone. In addition, distraction at the interdental regions allowed for "tailoring" of the osteotomies and for simultaneous expansion at the occlusal level.

Patient-specific Composite Anatomic Models: Improving the Foundation for Craniosynostosis Repair.

Preoperative surgical planning incorporating computer-aided design and manufacturing is increasingly being utilized today within the fields of craniomaxillofacial, orthopedic, and neurosurgery. Application of these techniques for craniosynostosis reconstruction can include patient-specific anatomic reference models, "normal" reference models or patient-specific cutting/marking guides based on the presurgical plan. The major challenge remains the lack of tangible means to transfer the preoperative plan to the operating table. We propose a simple solution to utilize a digitally designed, 3D-printed "composite model" as a structural template for cranial vault reconstruction. The composite model is generated by merging the abnormal patient cranial anatomy with the "dural surface topography" of an age-matched, sex-matched, and ethnicity-matched normative skull model. We illustrate the applicability of this approach in 2 divergent cases: 22-month-old African American male with sagittal synostosis and 5-month-old White male with metopic synostosis. The aim of this technical report is to describe our application of this computer-aided design and modeling workflow for the creation of practical 3D-printed skulls that can serve as intraoperative frameworks for the correction of craniosynostosis. With success in our first 2 cases, we believe this approach of a composite model is another step in reducing our reliance on subjective guesswork, and the fundamental aspect of the workflow has a wider application within the field of craniofacial surgery for both clinical patient care and education.

Virtual Reality Planning in Reconstructive Surgery for Orbital Prosthetic Rehabilitation Using ImmersiveTouch Platform: Preliminary Report.

BACKGROUND/PURPOSE: Virtual reality (VR) is emerging as an effective and intuitive surgical planning and 3D visualization tool. Digital surgical planning is the gold standard for planning the placement of implants in maxillofacial prosthetics, but the field lacks a platform exclusively designed to perform the task. Virtual reality planning (VRP) specific for maxillofacial prosthetics offers the clinician improved control of the presurgical planning and the potential to limit the need to adapt other advanced segmentation software. Furthermore, the virtual plan can be directly translated to the patient through custom 3D printed (3DP) surgical guides and visual aids. To the best of our knowledge, this article outlines the development of the world's first virtual reality planning platform and workflow for pre-operatory planning within a VR environment for clinical use specific to facial prosthetics and anaplastology. METHOD: The workflow was applied to managing 2 patients presenting with unilateral total exenteration and severe contracture enucleation, respectively (n=2). A cone-beam CT was acquired for each patient, and their data set was directly imported into the ImmersiveView Surgical Plan VR environment (ImmersiveTouch Inc, Chicago, IL). The clinicians virtually selected appropriately sized craniofacial implants and placed the implants in the desired orientation. Various measurement tools are available to aid in clinical decision-making. The ideal location of craniofacial implants was set according to an orbital and auricular prosthetic reconstruction. The resultant VR plan was exported for 3DP. The patients were evaluated preoperatively and postoperatively using the proposed VRP treatment. The workflow's data accuracy was validated postoperatively by comparing posterative CT data and the proposed VRP. Analysis was performed using Mimics software (Materialise, Leuven, Belgium). RESULT: It takes, on average, 10 minutes to place 4 implants in the virtual reality space. The 3DP files resulting from VRP take ~2 hours to print and are constructed with a biocompatible resin appropriate for clinical use as surgical guides. Our user-friendly VRP workflow allows for an accurate simulation of surgical and nonsurgical procedures with an average displacement in XYZ of 0.6 mm and an SD of 0.3 mm. In addition, VRP is an excellent tool to simulate the craniofacial placement procedure and improves unsupervised self-learning teaching. CONCLUSION: VRP is an exciting tool for training clinicians and students in complex surgical procedures. This study shows the promising applicability and efficiency of VR in clinical planning and management of facial rehabilitation. Patients allowed to interact with VR have been engaged, which would aid their treatment acceptance and patient education. A valuable advantage of surgical simulation is the reduced costs associated with renting instruments, buying implant dummies, and surgical hardware. The authors will explore VR to plan and treat surgical and nonsurgical reconstructive procedures and improve soft tissue manipulation. This study outlines the development of an original platform and workflow for segmentation, preoperative planning, and digital design within a VR environment and the clinical use in reconstructive surgery and anaplastology.

Parental Perception of Oral Health and Oral Health Status of Pediatric Patients Attending an Urban Craniofacial Center.

OBJECTIVE: The objectives of this study were to assess the oral health status and parental perception of oral health needs of pediatric patients in an urban Craniofacial Center. DESIGN: This research utilized a prospective cross-sectional matched study design. The data was collected prospectively via clinical oral examinations measuring dental caries experience and gingival health status. Parental perception of oral health was assessed through a validated questionnaire. SETTING: The study was conducted at a Pediatric Dentistry Department and Craniofacial Center (CFC) in a large urban American city. PATIENTS/PARTICIPANTS: Participants were recruited and enrolled from a CFC and Pediatric Dental Clinic. MAIN OUTCOME MEASURE(S): The outcome measures were the oral health status and parental perception thereof. RESULTS: CFC patients' caries experience in primary teeth was significantly lower than that of a healthy matched cohort, but statistically similar in permanent teeth. CFC patients had significantly higher unmet dental treatment needs. CFC patients had poor oral hygiene and were shown to have significantly higher plaque levels and worse gingival health than that of a healthy matched cohort. Parental perception of oral health did not show a statistically significantly difference between the two groups. CONCLUSIONS: Patients in our study in an urban CFC were found to have a high unmet dental and poor oral hygiene. Despite the poor oral health status, parents of children with craniofacial anomalies did perceive their oral health as different from a matched cohort of patients without these conditions.

Phenotypic and genotypic characterization of multi-drug resistant, biofilm forming, human invasive strain of Salmonella Typhimurium SMC25 isolated from poultry meat in India.

Emergence of highly virulent and multi-drug resistant (MDR) strains of Salmonella in food products significantly impacts public health and demands continuous monitoring for their presence in the food chain. The ability of Salmonella to form biofilms under harsh environmental conditions accompanied by MDR serotypes underscores an important food safety threat. This study aimed to isolate, identify and characterize MDR, biofilm-forming Salmonella from local Indian dairy and meat products (n = 60). All of the 24 isolates of Salmonella produced biofilm and were categorized as strong (16.6%), moderate (58.3%), and weak (25%) biofilm producers. Multiple antimicrobial resistance (MAR) index of all the Salmonella isolates was ≥0.2. The strongest biofilm forming poultry meat isolate, Salmonella SMC25 demonstrated intermediate to complete resistance to 14 of 22 different antibiotics tested. Epifluorescence microscopy showed that biofilm formation initiated as early as 4 h, reaching zenith within 96 h and much denser and robust biofilm is formed on rough stainless steel (SS316) surface compared to smooth glass surface. The results corroborated with increased temporal production of exopolysaccharides (EPS), high cell surface hydrophobicity and upregulation of marker genes vital to biofilm-formation in Salmonella. Significantly, SMC25 was found to adhere and invade mammalian cell lines Caco2 and HepG2, thus posing a serious food safety threat. This study is important in comprehending the prevalence of multidrug resistant, biofilm-forming, invasive strains of foodborne Salmonella in Indian food products and is important for effective risk assessment besides ensuring better food safety and public health.

Discussion on Ultrasound Diagnosis of Prenatal Cleft Lip: How does Its Accuracy Affects the Family? Prenatal Counseling for Clefts: The University of Illinois at Chicago, Craniofacial Center's Protocols and Experience.

ABSTRACT: Prenatal diagnosis of cleft lip and palate as well as other craniofacial differences is now possible with a significant level of accuracy due to sonographic and other evaluations. Thus, prospective parents have the opportunity to be informed ahead of time about these conditions making them better prepared to deal with their child after birth. The role of the plastic surgeon and other craniofacial team members in prenatal consultations is becoming increasingly important and well accepted. Therefore, any additional publication reviewing the topic from different angles and specifically from the parents' perspective is a welcome addition to our understanding of the parents' points of view and enables the team to most effectively assist them as they cope with the new diagnosis.This review describes details about our Craniofacial Center's efforts over 24 years. Our focus has always been on providing support through face-to-face multidisciplinary consultations with prospective parents as well as offering education to the public and referring sources, such as obstetricians and sonographers through direct communications, newsletters, and our website for timely referrals. As an additional service, the authors have organized a group of volunteer parents of children who are patients of the Center to share their short long-term experiences.

Skeletal and Dental Habilitation of Residual Alveolar and Maxillary Clefts.

ABSTRACT: Management of residual clefts of the alveolus and maxilla requires the coordinated effort of multiple members of the craniofacial team including surgeon, orthodontist, and when teeth are hypoplastic or absent, the prosthodontist to achieve complete habilitation. Such cooperation among specialists begins early in the patient's life and continues through completion of care.Although numerous publications on this topic exist, few present definitive multidisciplinary reconstructive outcomes with longterm results. In this review paper, the authors present our comprehensive, multidisciplinary protocols, experience, and techniques as they have evolved with over 35 years of practice at our Craniofacial Center.Details of our updated protocols for each intervention and procedure, including our current thoughts on appropriate timing, follow up and advantages from the incorporation of current technologies are discussed. Close cooperation among specialists at all stages of care, the use of evolving technology, and adherence to, and modification where indicated, of time honored team protocols enables us to consistently achieve successful functional and esthetic outcomes, while minimizing complications.

Calcium-induced dissociation of CIB1 from ASK1 regulates agonist-induced activation of the p38 MAPK pathway in platelets.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that regulates activation of the c-Jun N-terminal kinase (JNK)- and p38-stress response pathways leading to apoptosis in nucleated cells. We have previously shown that ASK1 is expressed in platelets and regulates agonist-induced platelet activation and thrombosis. However, the mechanism by which platelet agonists cause activation of ASK1 is unknown. Here, we show that in platelets agonist-induced activation of p38 is exclusively dependent on ASK1. Both thrombin and collagen were able to activate ASK1/p38. Activation of ASK1/p38 was strongly dependent on thromboxane A2 (TxA2) and ADP. Agonist-induced ASK1 activation is blocked by inhibition of phospholipase C (PLC) ß/γ activity or by chelating intracellular Ca2+. Furthermore, treatment of platelets with thapsigargin or Ca2+ ionophore robustly induced ASK1/p38 activation. In addition, calcium and integrin-binding protein 1 (CIB1), a Ca2+-dependent negative regulator of ASK1, associates with ASK1 in resting platelets and is dissociated upon platelet activation by thrombin. Dissociation of CIB1 corresponds with ASK1 binding to tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) and the autophosphorylation of ASK1 Thr838 within the catalytic domain results in full activation of ASK1. Furthermore, genetic ablation of Cib1 in mice augments agonist-induced Ask1/p38 activation. Together our results suggest that in resting platelets ASK1 is bound to CIB1 at low Ca2+ concentrations. Agonist-induced platelet activation causes an increase in intracellular Ca2+ concentration that leads to the dissociation of CIB1 from ASK1, allowing for proper dimerization through ASK1 N-terminal coiled-coil (NCC) domains.

Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation.

Mitogen-activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists. Disruption of Ask1 (Ask1-/- ) resulted in a marked functional defect in platelets. Ask1-/- platelets showed an impaired agonist-induced integrin αIIbß3 activation and platelet aggregation. Although there was no difference in Ca2+ rise, platelet granule secretion and thromboxane A2 (TxA2) generation were significantly attenuated in Ask1-/- platelets. The defective granule secretion observed in Ask1-/- platelets was a consequence of impaired TxA2 generation. Biochemical studies showed that platelet agonists failed to activate p38 MAPK in Ask1-/- platelets. On the contrary, activation of c-Jun N-terminal kinases and extracellular signal-regulated kinase 1/2 MAPKs was augmented in Ask1-/- platelets. The defect in p38 MAPK results in failed phosphorylation of cPLA2 in Ask1-/- platelets and impaired platelet aggregate formation under flow. The absence of Ask1 renders mice defective in hemostasis as assessed by prolonged tail-bleeding times. Deletion of Ask1 also reduces thrombosis as assessed by delayed vessel occlusion of carotid artery after FeCl3-induced injury and protects against collagen/epinephrine-induced pulmonary thromboembolism. These results suggest that the platelet Ask1 plays an important role in regulation of hemostasis and thrombosis.

Virtual Surgical Planning and Three-Dimensional Printed Guide for Soft Tissue Correction in Facial Asymmetry.

Fat grafting has become a well-accepted surgical modality to correct soft tissue facial defects and asymmetries with overall good results. Several techniques have been reported over the last few years to assist in improving accurate evaluation of facial defects and in the preoperative planning of the reconstruction. Such techniques include among others, computer tomography, three-dimensional (3D) photogrammetry, high resolution ultrasound, and 3D laser scanning. There are advantages and disadvantages for each technique.With the rapid advance of 3D technologies that have become readily available to clinicians, new clinical applications continually emerge to guide and facilitate reconstructive procedures. The authors explored the possibility of fabricating a 3D printed surgical guide to define volume differences for soft tissue reconstruction in patients with facial asymmetry. The model was developed through the authors' virtual surgical simulation and planning system that consists of computer-assisted design (CAD) and 3D printing (3DP).Three-dimensional volumetric scans of patients' faces were analyzed with computer-aided design to quantify areas of facial asymmetry. Surgical guides with containers defining volumetric differences were fabricated using 3D printing to identify and quantify areas of soft tissue deficiency. The 3D printed patient-specific, guides were sterilized and used by the surgeon intraoperatively to accurately mark the areas of soft deficiency. Thus, facial symmetry was achieved by fat grafting the predetermined volume differences defined in the surgical guides. A postop mask was used by the surgeon at the end of the procedure and during follow-up clinic visit to verify and evaluate accurate fat grafting placement as well as to determine areas where to add volume if needed.This paper details the rational for the authors' approach, outlines the technical planning and fabrication process of these patient-specific custom surgical guides with quantified volumetric containers and their intraoperative use by the surgeon. Despite the authors' limited experience we conclude that the authors' technique offer surgeons a precise means for accurate volumetric reconstruction of facial asymmetry.

Delay in Cleft Lip and Palate Surgical Repair: An Institutional Review on Cleft Health Disparities in an Urban Population.

Access to specialized medical care is critical to decrease complications and minimize long-term morbidity, yet racial disparities in cleft surgery persist as time to initial reconstruction remains delayed among minority patients. Research has demonstrated an average 3-week delay in surgery for minority patients nationally. A retrospective chart review of patient demographics, visit timing, and surgical history was performed for patients who underwent primary cleft lip with or without palate (CL + P) reconstruction between 2002 and 2016 at an urban craniofacial center. Of the 89 children who underwent surgery, 87% were ethnic minorities (58% Hispanic, 25% African-American, 4% Asian/Other). Caucasian children were the earliest to receive CL (3.5 months) and CP (13-months) repair. Minority children trended toward a delay in CL repair, with surgery for African-Americans at 5-months (P = 0.06) and Hispanics at 4.8-months (P = 0.07). Time from first visit to CL surgery showed significant delays for minority, non-English speaking, and public insurance patients; however, for CP repair, male children were delayed from first visit to surgery compared to females (P = 0.03). While there was no statistical difference in age at CL or CP surgical repair among our racial/ethnic cohorts, there were significant racial/ethnic differences in timing spent in the preoperative period for CL. However, racial/ethnic differences decreased as the patients spent more time within the healthcare system. Thus, established, interdisciplinary cleft/craniofacial centers well versed in minority patients can minimize the complex social and cultural factors that contribute to delays in cleft care.

Quality by Design Approach for Developing Lipid-Based Nanoformulations of Gliclazide to Improve Oral Bioavailability and Anti-Diabetic Activity.

The aim of the current investigation was to generate a self-nanoemulsifying drug delivery system (SNEDDS) of gliclazide (GCZ) to address the poor solubility and bioavailability. Ternary phase diagram was created with Capmul MCM C8 NF (oil), Cremophor RH 40 (surfactant), and Transcutol HP (co-surfactant) to distinguish the self-emulsifying region. A D-optimal design was employed with three variables, such as oil, surfactant, and co-surfactant, for further optimization of liquid (L)-SNEDDS. GCZ-loaded L-SNEDDs were analyzed for globule size, polydispersity index (PDI), and solubility. In vitro dissolution of optimized L-SNEDDS exhibited (F5) faster drug release (97.84%) within 30 min as compared to plain drug (15.99%). The optimized L-SNEDDS was converted to solid (S)-SNEDDS as a self-nanoemulsifying powder (SNEP) and pellets by extrusion-spheronization. Optimized S-SNEDDS were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In vitro dissolution of SNEP (S3) and pellet were 90.54 and 73.76%, respectively, at 30 min. In vivo studies showed a twofold rise in bioavailability through SNEDDS with a significant decline in blood glucose levels compared to plain drug suspension suggesting a lipid-based system as an alternative approach for treating diabetes.

Development of a carotenoid enriched probiotic yogurt from fresh biomass of Spirulina and its characterization.

Incorporation of Spirulina in milk as thermally dried powder has the disadvantages of non-uniform distribution with undesirable odor and flavor. Through homogenization (200 ± 10 bar), complete dispersion of fresh Spirulina biomass (7% w/w) in milk was achieved and thereafter a carotenoid enriched probiotic yogurt was developed. Confocal microscopy revealed porous Spirulina-milk protein matrix integrated with smaller fat globules in the yogurt. Spirulina led to a 29.56% increase in Lactobacillus acidophilus count, a 20% reduction in fermentation time and a total probiotic count of 1.2 × 107 CFU mL-1. The protein, total chlorophyll, total carotenoid and ß-carotene content (on dry w/w basis) were 3.58 ± 0.08 g 100 g-1, 0.407 ± 0.018 mg g-1, 0.235 ± 0.016 mg g-1 and 13.28 ± 0.08 µg g-1, respectively. During storage (18 days at 6-8 °C), the L. acidophilus count reached 8.83 ± 0.11 log CFU mL-1 with 103.03% increase in the viability by day three and the yogurt retained 71.5% carotenoids. The probiotc Spirulina yogurt was found to be acceptable to consumers as evaluated by affective consumer test.

The Median Mandibular Symphysis Tessier 30 Cleft:: 3D Imaging Analysis and Review of the Literature.

Atypical craniofacial clefts of the upper facial region have been well documented; however, the mandibular clefts remain rare and reported as isolated case reports. We report a case of a median mandibular cleft within the context of a Tessier 0-14 axis that we have followed over a 5-year period without surgical/orthodontic intervention. The mandibular symphysis cleft remained open without evidence of the fusion, in contrast to ossification of the metopic dysraphism. Within this context, we present a review of the median mandibular cleft cases from 1819 to 2015.

Speech Production Skills in Children With Cleft Palate Who Were Internationally Adopted.

OBJECTIVE: The objective of this study was to investigate the impact of international adoption (IA), age at palatoplasty (PR age), and velopharyngeal sufficiency (VPS) on articulation outcomes. DESIGN: This was a cross-sectional, prospective, observational study. SETTING: Outpatient hospital clinic. PARTICIPANTS: Fifty-one IA and 65 not-adopted (NA) children between the ages of 3 and 9 with nonsyndromic cleft palate with or without cleft lip. MAIN OUTCOME MEASURE(S): The Goldman-Fristoe Test of Articulation-2nd Edition (GFTA-2) standard score and cleft-related articulation errors (CREs). RESULTS: Articulation impairment was observed for 40% to 76% of NA children and 71% to 92% IA children, depending on age. PR age mean IA = 2.07 (0.86) years; NA = 1.23 (0.71) years. Children who were IA had poorer performance on the GFTA-2 ( B = -13.82, P = .015). Children who were IA were not significantly more likely to make CRE; rather, age at the time of assessment ( B = -.10, P = .002) and VPS ( B = .24, P = .021) were associated with CRE. CONCLUSIONS: Children who were IA demonstrated poorer articulation skills. Although primary palatoplasty was accomplished later among children who were IA, age at assessment and VP status (not PR age) were significantly correlated with articulation outcomes. Implications for timing of surgical intervention are discussed.

Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I.

Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear.

Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII.

OBJECTIVE: The aim of this study was to quantify glycosaminoglycans (GAGs) in amniotic fluid (AF) from an MPS VII fetus compared with age-matched fetuses obtained from normal pregnancies. METHOD: Disaccharides were measured by liquid chromatography tandem mass spectrometry, compared to age-matched controls. Enzyme assay was performed in AF supernatant or cultured amniocytes. GUSB was analyzed by next generation sequencing using Ion Torrent Personal Genome Machine with a customized panel. RESULTS: No activity of ß-glucuronidase was detected in fetal cells. The pregnancy was spontaneously terminated in the third trimester. Genetic studies identified a homozygous mutation of p.N379D (c.1135A > G) in the GUSB gene. Liquid chromatography tandem mass spectrometry showed that chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate levels were markedly increased in the MPS VII AF, compared to those in age-matched control AF (dermatan sulfate, heparan sulfate, and chondroitin-6-sulfate more than 10 × than age-matched controls; chondroitin-4-sulfate and keratan sulfate more than 3 times higher). CONCLUSION: This is the first report of specific GAG analysis in AF from an MPS VII fetus, indicating that GAG elevation in AF occurs by 21 weeks of gestation and could be an additional tool for prenatal diagnosis of MPS VII and potentially other MPS types. © 2017 John Wiley & Sons, Ltd.

Activities of daily living in patients with Hunter syndrome: impact of enzyme replacement therapy and hematopoietic stem cell transplantation.

The aim of this study was to assess the activities of daily living (ADL) in patients with Hunter syndrome (mucopolysaccharidosis II; MPS II) using a newly designed ADL questionnaire. We applied the questionnaire to evaluate clinical phenotypes and therapeutic efficacies of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). We also explored early signs and symptoms to make early diagnosis feasible. We devised a new ADL questionnaire with three domains: "movement," "movement with cognition," and "cognition." Each domain has four subcategories rated on a 5-point scale based on level of assistance. We also scored signs and symptoms unique to MPS by 12 subcategories (five points per category), providing 60 points in total. The questionnaire was first administered to 138 healthy Japanese controls (0.33-50 years), and successively, to 74 Japanese patients with Hunter syndrome (4-49 years). The patient cohort consisted of 51 severe and 23 attenuated phenotypes; 20 patients treated with HSCT, 23 patients treated early with ERT (≤8 years), 25 patients treated late with ERT (>8 years), and 4 untreated patients. Among 18 severe phenotypic patients treated by HSCT, 10 were designated as early HSCT (≤5years), while 8 were designated as late HSCT (>5years). Scores from patients with severe phenotypes were lower than controls and attenuated phenotypes in all categories. Among patients with severe phenotypes, there was a trend that HSCT provides a higher ADL score than early ERT, and there was a significant difference in ADL scores between late ERT and HSCT groups. Early ERT and early HSCT provided a higher score than late ERT and late HSCT, respectively. In conclusion, we have evaluated the feasibility of a new questionnaire in control population and patients with Hunter syndrome, leading to a novel evaluation method for clinical phenotypes and therapeutic efficacy. Early treatment with HSCT provides a better consequence in ADL of patients.