Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Differential Gene Expression and Pathway Analysis in Juvenile Nasopharyngeal Angiofibroma Using RNA Sequencing.

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascularized and locally aggressive tumor that typically presents in adolescent males. The molecular biology of this tumor remains understudied. We sought to identify differentially expressed genes in the JNA transcriptome through messenger RNA sequencing of primary fibroblasts from 2 tumor explants and tonsil tissue from tumor-free subjects. In total, 1088 significant, differentially expressed genes were identified with 749 upregulated and 339 downregulated. Pathway analysis identified a number of activated signaling pathways, most notably, the vascular endothelial growth factor (VEGF) pathway (adjusted overlap P = .03). VEGF-A showed a 4.4-fold upregulation in JNA samples. In addition, the angiogenic receptor, fibroblast growth factor receptor 2 (FGFR2), was not present in tumor-free samples but increased in JNA. We validate these findings with immunohistochemistry, demonstrating upregulation of VEGF and FGFR2 in patient sections. Inhibition of the VEGF or FGFR signaling axes may have therapeutic potential in the treatment of JNA.

Migrated esophageal foreign body presents as acute onset dysphagia years later: A case report.

Ingested esophageal foreign bodies are commonly seen in the pediatric population. Rarely do they perforate and migrate through neck fascial planes asymptomatically. We present a case of an otherwise healthy 11 year old with sudden onset dysphagia that based on MRI and CT findings was most consistent with an esophageal duplication cyst. However upon surgical exploration, a circular disk like foreign body was identified adjacent to the esophagus. Given the patient's age and no reports of purposeful ingestion, it is most likely the patient had ingested this disk foreign body in early childhood, leaving her asymptomatic for 8 years prior to presentation.

Wire grill brush bristle as an unusual foreign body: report of two pediatric cases.

Wire grill brushes are commonly used for cleaning grill grates. Accidental ingestion of a wire bristle from a grill-cleaning brush is a rarely reported foreign body, with only three prior case reports. Although scarce in the literature, we encountered two pediatric cases at the regional children's hospital within 1 year. By presenting these two cases, our goal was to raise awareness of this potentially hazardous foreign body. Additionally, we raise a consumer safety issue associated with the use of wire grill-cleaning brushes as there are currently no ingestion hazard warnings on these products. Laryngoscope,, 2011.

Emergence delirium and postoperative pain in children undergoing adenotonsillectomy: a comparison of propofol vs sevoflurane anesthesia.

BACKGROUND: Emergence delirium (ED) is a frequent postoperative complication in young children undergoing ENT procedures and it may be exacerbated by sevoflurane anesthesia whereas propofol maintenance has been suggested to decrease the incidence of ED. The aim of this randomized, prospective, double-blind study was to evaluate the effect of sevoflurane vs propofol anesthesia on the quality of recovery after adenotonsillectomy. METHODS: Forty-two patients were randomized to maintenance with either propofol or sevoflurane for adenotonsillectomy. At the conclusion of surgery, patients were extubated awake. ED and pain were assessed using the Pediatric Anesthesia Emergence Delirium (PAED) and the Children's Hospital of Eastern Ontario Scale (CHEOPS), respectively. Higher PAED scores (0-20) indicate greater severity of ED. Nursing and parental satisfaction, hospital length of stay, postoperative nausea and vomiting (PONV), anesthetic complications, and subsequent emergency room admissions were also assessed. RESULTS: Median PAED score was 14 in the propofol group and 17 in the sevoflurane group (NS). Propofol was associated with less pain medication required during recovery and a lower incidence of PONV (5.3% vs 36.8%, P < 0.05). Nursing and parental satisfaction as well as time spent in recovery room was similar for the two groups. CONCLUSION: Propofol anesthesia does not influence agitation after adenotonsillectomy, as measured by the PAED score. A PAED score of ≥ 10 was not useful in identifying patients with ED. However, propofol maintenance is associated with less need for pain medication in the recovery room and a lower incidence of PONV compared to sevoflurane anesthesia.

Incidence of and risk factors for airway complications following endotracheal intubation for bronchiolitis.

OBJECTIVE: To identify risk factors predisposing to postextubation complications and the incidence of subglottic stenosis following endotracheal intubation for bronchiolitis. STUDY DESIGN AND SETTING: A review of 144 consecutive infants and children intubated for bronchiolitis between 2000 and 2005 at a regional children's hospital. RESULTS: The mean age at diagnosis was 6.4 months. Follow-up data were available in 93 patients (64.6%), and average length of follow-up was 9.3 months. One hundred and three patients (71.5%) had positive RSV detection. Average duration of intubation was 5.5 days. Twenty-six patients (18.1%) required reintubation during the same admission. Children intubated for less than 3 days and those greater than 12 months of age were more likely to experience postextubation difficulties. Approximately 40% of patients experienced postextubation difficulties. Subglottic pathology was found on endoscopy in 6 patients (4%). There were no cases of long-term subglottic stenosis. CONCLUSION: Immediate postextubation complications are common after bronchiolitis, especially in patients intubated for less than 3 days and greater than 12 months of age. We found no evidence of long-term subglottic stenosis in this population.

Buccal mucosal urethroplasty in patients who had multiple previous procedures.

OBJECTIVES: To review the success rate of ventral onlay buccal mucosal grafts for anterior bulbar urethroplasty in patients who had undergone multiple procedures before repair. METHODS: We performed a retrospective review of one surgeon's experience performing 58 consecutive buccal mucosal urethroplasties on 57 patients from September 1999 to September 2004. The cause of the anterior urethral stricture was unknown in 33, trauma in 20, and urethritis in 4. Most of these patients had undergone multiple procedures before urethroplasty. An American Urological Association symptom score questionnaire was sent to all patients. RESULTS: The average patient age was 40.7 years (range 17 to 72). The average follow-up was 29.6 months (range 6 to 66). Of the 57 patients, 48 responded to the American Urological Association questionnaire (84%), and the average symptom and bother score was 4.8 and 1.3, respectively. Three patients had treatment failure, for a 94% success rate. CONCLUSIONS: The results of this study confirm the efficacy of buccal mucosal urethroplasty for anterior urethral strictures, especially in a tertiary referral setting in which a number of our patients had undergone repeat endoscopic procedures and multiple urethral dilations.

Endoscopic extended ventriculotomy for congenital saccular cysts of the larynx in infants.

OBJECTIVE: To report a new procedure that has been successful in endoscopically treating congenital saccular cysts of the larynx without the need for a tracheostomy or an external incision. DESIGN: Retrospective chart review of a case series involving 4 patients who underwent a single endoscopic procedure for the treatment of their congenital saccular cysts. SETTING: Two pediatric tertiary care referral centers. PATIENTS: Four pediatric patients aged 1 to 7 weeks. INTERVENTIONS: Three of 4 patients underwent endoscopic extended ventriculotomy for treatment of a congenital laryngeal saccular cyst. The remaining patient had wide unroofing of the cyst through the floor of the vallecula. MAIN OUTCOME MEASURES: The patients were followed up for breathing difficulties, dysphagia, and dysphonia. Routine flexible endoscopy was used to evaluate for recurrence of cysts. RESULTS: All 4 patients were successfully treated with a single endoscopic procedure. None has had a recurrence, and none required tracheostomy. One patient subsequently underwent conservative unilateral epiglottoplasty to remove redundant tissue caused by the cyst. Disease-free follow-up ranged from 2 to 6 years. CONCLUSIONS: The endoscopic extended ventriculotomy procedure allowed successful endoscopic management of congenital saccular cysts of the larynx in 3 of 4 patients. Previously described management strategies for these difficult lesions have involved multiple failed endoscopic procedures or an external approach to the lesion and frequently required tracheostomy. With this procedure, we have avoided both a tracheostomy and an external approach to the lesion, which has minimized morbidity. Use of modern instrumentation and surgical adjuncts such as mitomycin C, as well as the support of the laryngeal framework for the continued patency of the ventriculotomy, has led to successful single-stage management of congenital saccular cysts of the larynx.

A retrospective study of tonsillectomy in the under 2-year-old child: indications, perioperative management, and complications.

OBJECTIVE: To retrospectively review the experience with tonsillectomy in the under 2-year-old child at an urban children's hospital. METHODS: The medical records of 94 patients under 2 years old undergoing tonsillectomy between May 1, 1995, and May 31, 2000, were reviewed. The methods of tonsil and adenoid excision were noted, as was the use of perioperative steroids, antibiotics, and antiemetics. Outcome measures studied included the duration of postoperative inpatient observation, complications, time to first oral intake, prevalence of postoperative vomiting, type and duration of respiratory support, and improvement relative to operative indications. RESULTS: Eighty-two patients (87%) underwent tonsillectomy and adenoidectomy (T&A). Twelve patients (13%) underwent tonsillectomy without adenoidectomy. Patient ages ranged from 12 to 23 months (mean 19.6+/-3.1). Indications included obstructive sleep apnea (OSA) in 51 patients (54%), chronic or recurrent tonsillitis in 30 (32%), both OSA and infection in 11 (12%), and acute tonsillitis with airway obstruction in two (2%). Comorbid conditions were numerous. Preoperative polysomnograms were obtained for eight patients (8%). Hospital stays ranged from 4 h to 16 days. Complications included hemorrhage in four patients (4%) and pneumonia in two (2%). Oxygen was required after discharge from the recovery room in 27 patients (29%), with seven more (7%) requiring either reintubation, continuous positive airway pressure, or nasopharyngeal airways. Of the 88 patients on oral diets, only five (5%) took longer than 24 h to resume oral intake. Two patients (2%) experienced significant emesis after surgery. Four patients (4%) required treatment for dehydration after discharge. CONCLUSIONS: Tonsillectomy is a procedure with low morbidity in the otherwise healthy child under 2 years of age. However, we advocate routine postoperative overnight inpatient observation in this age group. We found that young children with comorbid conditions had a higher incidence of complications and required special postoperative management strategies.

Vagus nerve stimulator implantation in children.

BACKGROUND: Vagus nerve stimulation was approved in 1997 as an adjunctive treatment of partial-onset seizures refractory to medical therapy. Subsequent to the initial clinical trials, few studies have been published specifically addressing perioperative management issues. OBJECTIVES: To review the operative technique and perioperative management of patients undergoing vagus nerve stimulator implantation and to analyze complications and their management. DESIGN: Retrospective medical record review and survey of patients who underwent implantation. SETTING: A tertiary care pediatric hospital in Kansas City, Mo. PATIENTS: One hundred two patients aged 21 months to 40 years. INTERVENTION: Vagus nerve stimulator implantation and lead placement. MAIN OUTCOME MEASURES: The surgical technique of vagus nerve stimulator implantation is presented in detail. Perioperative complications are enumerated, and strategies for their management are described. A subjective patient survey addresses some quality-of-life issues and the effect on swallowing and voice. RESULTS: One hundred two patients successfully underwent vagus nerve stimulator implantation. Three patients experienced infection of the chest wound holding the generator and required explantation. These 3 patients underwent reimplantation within 2 months after the infection had cleared. Most patients experience some degree of hoarseness when the generator is activated, but this symptom usually does not significantly affect the ability to communicate. Responses to questions regarding quality of life are positive. CONCLUSIONS: Vagus nerve stimulator implantation has a low incidence of serious complications. Quality of life seems to be improved for most patients. Modifications to the surgical procedure must be considered when performing the implantation on a young patient.