Richard E. Kirschner

A Genome-Wide Association Study Identifies a Locus for Nonsyndromic Cleft Lip with or without Cleft Palate on 8q24

OBJECTIVE To identify, in a non-hypothesis manner, novel genetic factors associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P). STUDY DESIGN We performed a genome-wide association study in a pediatric cohort of European decent consisting of 111 NSCL/P cases and 5951 control subjects. All subjects were consecutively recruited from the Greater Philadelphia area from 2006 to 2009. High throughput genome-wide single nucleotide polymorphism genotyping was carried out with the Illumina Infinium II HumanHap550 BeadChip technology. RESULTS We observed association at the genome-wide significance level with SNP rs987525 at a locus on 8q24, which harbors no characterized genes to date (P = 9.18 x 10(-8); odds ratio = 2.09, 95% confidence interval = 1.59 to 2.76). While searching for a replication cohort, the same genetic determinant was established through a genome-wide association study of NSCL/P in Germany, so this previous report acts as a de novo replication for our independent observation outlined here. CONCLUSIONS These results strongly suggest that a locus on 8q24 is involved in the pathogenesis of NSCL/P.

Keloids and scars: a review of keloids and scars, their pathogenesis, risk factors, and management

Purpose of review The precise mechanisms of normal and abnormal scar formation have long remained a mystery despite the extensive literature regarding wound healing. Only recently have researchers begun to delineate the complex biochemical signaling pathways that regulate these processes. This article reviews basic wound healing, while focusing on medicines latest understanding of the development and treatment of keloids and hypertrophic scars. Recent findings The importance of the transforming growth factor-β signaling pathways and the related downstream effector molecules has proven to offer a new detailed view of scar biology. Regulation of scar metabolism with regards to collagen and wound matrix degradation is likewise showing promise in generating alternate therapies to treat abnormal scars. Summary Understanding the exact process of normal and abnormal scar formation will help define better ways to successfully manage and potentially prevent abnormal healing like hypertrophic scars and keloids.

Surgical Airway Management in Pierre Robin Sequence: Is There a Role for Tongue-Lip Adhesion?

OBJECTIVE The purpose of this study was to examine the efficacy of tongue-lip adhesion (TLA) in the management of clinically significant airway obstruction associated with Pierre Robin sequence. DESIGN The records of all children admitted to The Childrens Hospital of Philadelphia with a diagnosis of Pierre Robin sequence were reviewed. Charts were reviewed for birth data, diagnosis, preoperative airway management methods, and surgical intervention. Records of infants undergoing TLA were analyzed for timing of surgery, operative technique, postoperative complications, length of hospital stay, and treatment outcome. RESULTS Over the 28-year period 1971 to 1999, 107 patients (47 boys, 60 girls) meeting the criteria for Pierre Robin sequence were admitted for treatment. Of these, 74 (69.2%) were successfully managed by positioning alone. Surgical management of the airway was performed in the remaining 33 (30.8%) patients, 29 of whom underwent TLA and 4 of whom underwent tracheostomy. Dehiscence of the adhesion occurred in five patients (17.2%), two of whom subsequently required tracheostomy. Within the group of patients who underwent mucosal adhesion alone, the dehiscence rate was 41.6%. When the adhesion included muscular sutures, however, dehiscence was not observed in any patient. Of the 24 patients in whom primary TLA healed uneventfully, airway obstruction was successfully relieved in 20 (83.3%). Failure of a healed TLA to relieve the airway obstruction resulted in conversion to a tracheostomy in four patients. Six patients who underwent TLA (20.7%) ultimately required a tracheostomy; five of these patients (83.3%) were syndromic. Of patients requiring preoperative intubation, 42.9% ultimately required tracheostomy. CONCLUSION TLA successfully relieves airway obstruction that is unresponsive to positioning alone in the majority of patients with Pierre Robin sequence and should therefore play an important role in the management of these infants.

Metopic synostosis: Defining the temporal sequence of normal suture fusion and differentiating it from synostosis on the basis of computed tomography images.

Only the metopic suture normally fuses during early childhood; all other cranial sutures normally fuse much later in life. Despite this, metopic synostosis is one of the least common forms of craniosynostosis. The temporal sequence of normal physiologic metopic suture fusion remains undefined and controversial. Therefore, diagnosis of metopic synostosis on the basis of computed tomography images alone can prove misleading. The present study sought to determine the normal sequence of metopic suture fusion and characterize both endocranial and ectocranial suture morphology. An analysis of computed tomography scans of 76 trauma patients, ranging in age from 10 days to 18 months, provided normative craniofacial data that could be compared to similar data obtained from the preoperative computed tomography scans of 30 patients who had undergone surgical treatment for metopic synostosis. Metopic suture fusion was complete by 6 to 8 months in all nonsynostotic patients, with initiation of suture fusion evident as early as 3 months of age. Fusion was found to commence at the nasion, proceed superiorly in progressive fashion, and conclude at the anterior fontanelle. Although an endocranial ridge was not commonly seen in synostotic patients, an endocranial metopic notch was virtually diagnostic of premature suture fusion and was seen in 93 percent of synostotic patients. A metopic notch was not seen in any nonsynostotic patient. The morphologic and normative craniofacial data presented permit diagnosis of metopic synostosis based on computed tomography images obtained beyond the normal fusion period.

Cleft-palate repair by modified Furlow double-opposing Z-plasty: the Children's Hospital of Philadelphia experience.

Although the optimal technique of cleft-palate repair remains controversial, several small series have suggested that superior speech results may be obtained with the Furlow double-opposing Z-plasty. To examine speech outcome in a large series of Furlow palatoplasties performed at a single center, we retrospectively reviewed the records of 390 cleft-palate patients who underwent Furlow palatoplasty at The Childrens Hospital of Philadelphia from 1979 to 1992. Speech outcome at 5 years of age or greater was available for 181 nonsyndromic patients and was scored using the Pittsburgh Weighted Values for Speech Symptoms Associated with Velopharyngeal Incompetence. No or mild hypernasality was noted in 93.4 percent of patients, with 88.4 percent demonstrating no or inaudible nasal escape and 97.2 percent demonstrating no errors in articulation associated with velopharyngeal incompetence. Secondary pharyngeal flap surgery was required in just 7.2 percent of patients. Age at palatoplasty, cleft type, and experience of the operating surgeon had no significant effect on speech results, although there was a trend toward better outcome in those undergoing palatal repair before 6 months of age and toward poorer outcome in those with Veau class I and II clefts. Overall, Furlow palatoplasty yielded outstanding speech results, with rates of velopharyngeal dysfunction that seem to improve upon those reported for other techniques.

The Children's Hospital of Philadelphia modification of the Furlow double-opposing z-palatoplasty: Long-term speech and growth results

Of the 261 nonsyndromic patients we studied, over 90% had minimal or absent hypernasality, almost 86% had inconsistent or no nasal emission, and 95% had no articulation errors related to velar function. The patients with a Pittsburgh score indicating an incompetent velopharyngeal mechanism comprised only about 6% of the group. Ninety-four percent had a socially functional speech quality. Secondary surgery was done in 6.5% of patients and was done or was recommended in about 8% of patients. Patients with isolated cleft palate seemed to do less well, although their outcomes were not statistically different from those with complete unilateral and bilateral clefts. Relaxing incisions have kept our fistula rate to an acceptably low rate of 6.8%. No major soft palate dehiscences or hard palate flap losses have occurred. The speech outcomes we are achieving are improved over our historical results and compared with published reports using nondouble reversing z-palatoplasty techniques. Similar outcomes with the Furlow repair have been confirmed. Maxillary growth, occlusion, and the need for orthognathic surgery do not seem to be influenced by the CHOP modification of the Furlow double-opposing z-palatoplasty. These modifications facilitate a tension free-closure and a low fistula rate.

Repair of oronasal fistulae with acellular dermal matrices.

Background: The authors examined the efficacy of a novel technique for oronasal fistula repair using acellular dermal matrix grafts. In part I, an animal model was used to demonstrate proof-of-concept; in part II, the method was applied to oronasal fistula repair in the clinical setting. Methods: In part I, oronasal fistulas were created in Yorkshire piglets (n = 6) and allowed to mature for 2 weeks. In three animals, acellular dermal grafts were interposed between the oral and nasal mucosa traversing the palatal fistulas. Mucosal edges were not closed. Three weeks postoperatively, the palates were examined histologically. The fistulas of control piglets (n = 3) remained unrepaired and were examined 5 weeks after their creation. In part II, acellular dermal grafts were interposed between the oral and nasal mucosa in nine consecutive patients undergoing oronasal fistula repair. Complete closure of the oral and nasal mucosa was achieved in two patients. In the remainder, nasal closure was affected by interposition of the dermal matrices beneath a complete oral mucosal closure. Results: All animals that underwent fistula repair demonstrated successful healing with revascularization, complete reepithelialization, and cellular infiltration into the grafts. All control fistulas remained patent. Successful fistula closure was observed in all patients. In two patients, early oral mucosal dehiscence and exposure of the dermal graft was followed by complete healing. Conclusions: This study demonstrates successful closure of palatal fistulas in an animal model and in cleft palate patients using interposition grafts of acellular dermis. This novel method offers promise as a simple and effective technique for tension-free closure of oronasal fistulas.

Communication issues in 22q11.2 deletion syndrome: children at risk.

Purpose: The purpose of this investigation is to describe the communication profile of children with the 22q11.2 deletion syndrome from infancy through school age and to examine the influence of other medical aspects, such as palate anomalies, learning disorders, and cardiac defects of the syndrome to communication.Methods: Seventy-nine children were examined using standardized tests of speech and language and perceptual measures of resonance and voice.Results: Results show significant delay in emergence of speech and language milestones with delay/disorder in speech-language processes persisting into the school aged years, including those children diagnosed with nonverbal learning disabilities. Persistent articulation and resonance disorders were also present, presumed to be related in part to palatal anomalies. No correlation was found between cardiac status, learning disorders, palate anomalies and communication disorders.Conclusion: The need for early identification and management of communication skills is crucial in the care of children with the 22q11.2 deletion.

Congenital nasal anomalies: a classification scheme.

The purpose of this work was to develop a simple yet comprehensive classification scheme dedicated to congenital nasal anomalies. To date, no such classification system has been proposed and widely used. A 22-year retrospective review was performed. Two hundred sixty-one patients with congenital nasal anomalies were identified. From this extensive database, a systematic morphogenic classification system was devised. Congenital nasal deformities were classified into four categories. Type I, hypoplasia and atrophy, represents paucity, atrophy, or underdevelopments of skin, subcutaneous tissue, muscle, cartilage, and/or bone. Type II, hyperplasia and duplications, representing anomalies of excess tissue, ranging from duplications of parts to complete multiples, are categorized here. In the type III category, clefts, the comprehensive and widely utilized Tessier classification of craniofacial clefts is applied. Type IV deformities consist of neoplasms and vascular anomalies. Both benign and malignant neoplasms are found in this category.

Pediatric dog bite injuries: a 5-year review of the experience at the Children's Hospital of Philadelphia

Background: The objective of this study was to characterize the nature of dog bite injuries treated over a 5-year period at a large tertiary pediatric hospital and to identify relevant parameters for public education and injury prevention. Methods: Investigators performed a retrospective review of emergency room records of a single tertiary pediatric hospital. Records of all patients who were evaluated for dog bite injuries between April of 2001 and December of 2005 were reviewed. All demographic, patient, and injury details were recorded. Results: Five hundred fifty-one patients aged 5 months to 18 years were treated in the emergency department after suffering dog bite injuries during the study period. The majority of injuries (62.8 percent) were sustained by male children. Dog bite injuries were most prevalent during the months of June and July (24.1 percent). Grade school–aged children (6 to 12 years) constituted the majority of victims (51 percent), followed by preschoolers (2 to 5 years; 24.0 percent), teenagers (13 to 18 years; 20.5 percent), and infants (birth to 1 year; 4.5 percent). Injuries sustained by infants and preschoolers often involved the face (53.5 percent), whereas older children sustained injuries to the extremities (60.7 percent). More than 30 different offending breeds were documented in the medical records. The most common breeds included pit bull terriers (50.9 percent), Rottweilers (8.9 percent), and mixed breeds of the two aforementioned breeds (6 percent). Conclusions: Pediatric dog bites are preventable injuries, yet they persist as a prevalent public health problem. Evaluation of data from high-volume tertiary pediatric health care institutions identifies predictable patterns of injury with respect to patient age and gender, animal breed, provocation, and seasonality.