Intellectual Functioning of Children With Isolated PRS, PRS-Plus, and Syndromic PRS.

OBJECTIVE: Describe the intelligence quotient (IQ) of children with Pierre Robin sequence (PRS). DESIGN: Prospective cohort study. SETTING: Neurodevelopmental follow-up clinic within a hospital. PATIENTS: Children with PRS (n = 45) who had been in the Neonatal Intensive Care Unit (NICU) were classified by a geneticist into 3 subgroups of isolated PRS (n = 20), PRS-plus additional medical features (n = 8), and syndromic PRS (n = 17) based on medical record review and genetic testing. MAIN OUTCOME MEASURE: Children with PRS completed IQ testing at 5 or 8 years of age with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) or Fourth Edition (WPPSI-IV) or the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) or Fifth Edition (WISC-V). RESULTS: IQ scores were more than 1 to 2 standard deviations below the mean for 36% of the overall sample, which was significantly greater compared to test norms (binomial test P = .001). There was a significant association between PRS subtype and IQ (Fisher's exact P = .026). While only 20% of children with isolated PRS were within 1 standard deviation below average and 35% of children with syndromic PRS were below 1 to 2 standard deviations, 75% of PRS-plus children scored lower than 1 to 2 standard deviations below the mean. CONCLUSION: PRS subgroups can help identify children at risk for cognitive delay. The majority of children with PRS-plus had low intellectual functioning, in contrast to the third of children with syndromic PRS who had low IQ and the majority of children with isolated PRS who had average or higher IQ.

A Standard Set of Outcome Measures for the Comprehensive Appraisal of Cleft Care.

Care of the patient with cleft lip and/or palate remains complex. Prior attempts at aggregating data to study the effectiveness of specific interventions or overall treatment protocols have been hindered by a lack of data standards. There exists a critical need to better define the outcomes-particularly those that matter most to patients and their families-and to standardize the methods by which these outcomes will be measured. This report summarizes the recommendations of an international, multidisciplinary working group with regard to which outcomes a typical cleft team could track, how those outcomes could be measured and recorded, and what strategies may be employed to sustainably implement a system for prospective data collection. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of cleft care that intercenter comparisons can become possible. This is important for quality-improvement endeavors, comparative effectiveness research, and value-based health-care reform.

A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome.

Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic "question-mark" ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in PLCB4 and a shared mutation in GNAI3 in two unrelated probands. In confirmatory studies, three additional novel PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream DLX5 and DLX6 expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.

Anesthetic implications of infants with mandibular hypoplasia treated with mandibular distraction osteogenesis.

OBJECTIVES: To document the incidence of difficult intubation following mandibular distraction osteogenesis (MDO) in children with severe mandibular hypoplasia. BACKGROUND: Syndromes associated with significant mandibular hypoplasia, especially Pierre Robin sequence, provide a challenge in airway management both in and out of the operating room. Mandibular advancement using mandibular distraction osteogenesis devices has been used in infants in an attempt to reduce the incidence of acute life-threatening airway obstruction. Whether MDO also reduces the incidence of difficult intubation has not been adequately described. METHODS: A retrospective chart review of 51 infants with upper airway obstruction secondary to mandibular hypoplasia who required MDO between January 2002 and 2012. The primary outcome was the incidence of difficult or failed intubation. Secondary outcomes were the relationship between syndrome type and the incidence of difficult intubation. RESULTS: Fifty-one PRS infants were identified. Twenty-eight patients had isolated PRS, six had syndromic PRS, seven had Treacher Collins syndrome, and 10 had another coexisting syndrome. Prior to mandibular distraction osteogenesis (MDO), the incidence of difficult intubation was 71%, with the highest incidence in patients with Treacher Collins syndrome (100%), sPRS syndrome (100%), and PRS (65%). Following MDO, the incidence of difficult intubation was 8.3%. The difference was statistically significant for all patients (Kruskal-Wallis rank test P = 0.0001) those with isolated PRS (P = 0.0001), syndromic PRS (P = 0.0023), and other syndromes (P = 0.0002), but not for Treacher Collins syndrome (P = 0.21). Three patients had pre existing tracheostomies. CONCLUSIONS: In a select group of infants with severe upper airway obstruction who have failed nonsurgical airway interventions, mandibular distraction osteogenesis reduces the incidence of difficult mask ventilation and difficult intubation. We were not able to compare the improvement in airway management to a comparable group of PRS infants who did not undergo surgical intervention. The improvement in laryngeal view was most marked for infants with isolated PRS but no significant benefit was demonstrated in infants with TCS.

Obstructive sleep apnea successfully treated by mandibular distraction osteogenesis in a rare skeletal dysplasia.

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked skeletal dysplasia characterized by linear striations of the long bones, osteosclerosis of the cranium, and extraskeletal anomalies. We report a female infant with OSCS diagnosed radiographically with molecular confirmation in the first year of life. The patient presented at 5 months with severe obstructive sleep apnea, which had progressed rapidly after the neonatal period and which responded favorably to mandibular distraction osteogenesis. This procedure has not previously been reported in association with OSCS, which is a rare cause of Pierre Robin sequence with dysmorphic features.

Tonsilloliths appearing as multiple opacities on panoramic imaging: case report.

Tonsilloliths are dystrophic calcifications that can form in tonsillar crypts. They can be asymptomatic or a component of tonsillitis. This article presents a case of tonsilloliths that appeared on a panoramic image as multiple opacities.

Nasal reconstruction for maxillonasal dysplasia.

BACKGROUND: Maxillonasal dysplasia, Binder type (Binder syndrome and nasomaxillary hypoplasia), is a spectrum of deficient nasomaxillary osteocartilaginous framework, deficient nasal soft tissues, and a short columella. The correction of these deformities is challenging, and results are often disappointing. Tissue expansion with multiple bone grafts for nasal augmentation from childhood has been advocated as a means to address the constricted soft tissues. However, bone grafts in children have been associated with unpredictable growth and resorption. Agreeing with the principle of serial nasal augmentation that commences in childhood, we used alloplastic material for tissue expansion followed by definitive reconstructive rhinoplasty at the completion of growth and orthognathic surgery as required. Definitive rhinoplasty mainly used a 1-piece costochondral graft cantilevered to the frontal bone. MATERIALS AND METHODS: Thirty-one patients over a period of 27 years were reviewed. The patients were divided into 2 groups based on the age of presentation, namely, prepubertal and postpubertal. The prepubertal group underwent serial tissue expansion of the constricted nasal envelope with customized silicone implants and final reconstruction by costochondral rhinoplasty at the end of puberty. The postpubertal group underwent 1-stage costochondral rhinoplasty. The definitive rhinoplasty used a cantilevered 1-piece costochondral graft retaining the dorsal periosteum that was dowelled into the frontal sinus wall. RESULTS: In the prepubertal group (n = 20), 41 silicone implants were placed in the childhood years for tissue expansion of the nasal envelope. One patient developed implant infection, and another required replacement after extrusion. Long-term follow-up showed minimal resorption of the costochondral graft in the pre-expanded prepubertal group and minimal to moderate graft resorption in the postpubertal group. CONCLUSIONS: Successful treatment of maxillonasal dysplasia is dependent on the following: an understanding of the underlying pathologic anatomy, namely, that of the constricted nasal tissues, serial tissue expansion of the nasal envelope in childhood, and definitive costochondral rhinoplasty at the end of growth. Early tissue expansion with the placement of alloplastic silicone implants effectively stretches the constricted nasal soft tissues in Binder syndrome to limit graft resorption after definitive nasal reconstruction with costochondral rib grafts. There is a possible role for similar tissue expansion in the postpubertal patient with alloplastic material before costochondral grafting if the soft tissues are inadequate. Long-term resorption of cantilevered, 1-piece, periosteum-covered costochondral grafts was minimal.

Simple bone cyst of the mandibular condyle.

Simple bone cysts (SBCs) are benign lesions often found in the long bones of children between their first and second decades. They occasionally occur in the mandible but rarely in the mandibular condyle. A case of a 7-year-old female child with an increasing enlargement of the left mandibular condyle is presented. A 2 cm × 3 cm lytic lesion was explored and curetted through an intraoral vestibular incision and proved to be an SBC. Postoperative recovery was uncomplicated with remodeling of the condylar observed at 3 years follow-up.

Infant Mandibular Distraction for Upper Airway Obstruction: A Clinical Audit.

BACKGROUND: Mandibular distraction osteogenesis (MDO) is an effective method of treating upper airway obstruction (UAO) in micrognathic infants. The short-term outcomes include relief of UAO, avoidance of tracheostomy, and prompt discharge from hospital. However, it is a significant surgical procedure with potential associated morbidities. This study describes a cohort of infants managed using MDO over a twelve-year period. METHODS: A retrospective chart review was undertaken for children who had MDO before the age of 5 years between 2000 and 2012. This was followed by a clinical review of the same cohort specifically looking for dental anomalies, nerve injuries, and scar cosmesis. RESULTS: Seventy-three children underwent MDO at a mean age of 2 months [interquartile range (IQR), 1.7-4.2] for nonsyndromic infants and 3.3 months (IQR, 2.1-7.4) for those with syndromes. Infants were discharged from hospital, on average, 15 days after procedure. After MDO, of the 9 who were previously tracheostomy dependent, 5 (56%) were decannulated within 12 months and none of the nontracheostomy-dependent children required further airway assistance. The majority of children required supplemental feeding preoperatively but, 12 months postoperatively, 97% of the nonsyndromic infants fed orally. Thirty-nine children (53%) were reviewed clinically [median age, 5.1 y (IQR, 3.9-6.5)] with 18 being syndromic. Many of the mandibular first permanent and second primary molars had developmental defects, but there was a low rate of neurosensory deficit and good scar cosmesis. CONCLUSIONS: This study contributes further to the evidence base underpinning the management of micrognathic infants with UAO.

Cysts of the jaws and advances in the diagnosis and management of nevoid Basal cell carcinoma syndrome.

Cysts of the jaws are a relatively commonly encountered pathologic condition, and a full spectrum of these lesions may present in pediatric patients. Most cystic lesions are of odontogenic origin, as seen in adult patients, and a range of surgical approaches are available for their management. These approaches are based on the clinical and radiologic features and the behavioral and histologic characteristics of each cyst. Advances in imaging techniques and laboratory investigations, such as immunocytochemistry and genetic analysis, will continue to facilitate improved diagnoses, patient management, and clinical outcomes.

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.

Internal mandibular distraction to relieve airway obstruction in infants and young children with micrognathia.

Micrognathia may cause upper airway obstruction requiring complex medical interventions and sometimes tracheostomy. The role of distraction techniques to lengthen the mandible is yet to be clarified. The aim of this paper is to present a series of five cases in which mandibular lengthening by osteotomy and internal distraction was used to relieve airway obstruction. Five patients whose ages ranged from 4-39 months (mean, 15 months) were managed at our center with internal distraction osteogenesis to relieve airway obstruction. Three patients had a tracheostomy, and two patients had refractory airway obstruction prior to distraction. Following osteotomy and insertion of internal distraction devices, the mandible was distracted a mean of 17 mm (range, 15-25 mm). The distraction devices were removed at the end of a consolidation period ranging from 3-10 weeks. Two of 3 patients with a tracheostomy were decannulated, while the third patient with tracheostomy is awaiting choanal atresia repair before being decannulated. The two patients who were not managed with a tracheostomy but who had persistent upper airway obstruction have not required further airway intervention after mandibular distraction. In conclusion, mandibular lengthening by distraction osteogenesis can relieve airway obstruction in infants and small children. This is a promising new technique that may avoid the need for tracheostomy in some infants with micrognathia, and facilitate early decannulation in those who have a tracheostomy.

Hemifacial microsomia: use of the OMENS-Plus classification at the Royal Children's Hospital of Melbourne.

Hemifacial microsomia is the most common facial congenital disability after cleft lip and palate, but as yet its pathogenesis remains unknown. Clinical classification systems have evolved over the last 30 years from those classifying only single components of the disorder, to those classifying according to the combination of deformities, to the most recent systems that grade each anatomical component separately, such as the Orbit, Mandible, Ear, Nerve, and Soft tissue (OMENS) system. The aim of the present study was to review the classification of patients with hemifacial microsomia treated by the Melbourne Craniofacial Unit at the Royal Children's Hospital using the OMENS-Plus system of classification and to correlate the findings with data from other centers. Records of patients treated by the craniofacial unit were reviewed and included in the study if adequate clinical records, photographs, and radiographs (anteroposterior, lateral, basal cephalometry, panoramic views) were available. The data were entered into a database file developed for this purpose. Seventy-one patients were identified from the hospital database, of which six were excluded because of incomplete data. Of the 65 patients, there were 31 (48 percent) with right-sided microsomia, 25 (38 percent) with left-sided microsomia, and nine (14 percent) with bilateral microsomia, with an overall male-to-female ratio of 1.2:1. The majority of patients had a normal orbit (77 percent), mildly hypoplastic mandibular ramus-condyle with functioning temporomandibular joint (57 percent with type M1 or M2a), normal facial nerve (76 percent), and mild soft-tissue hypoplasia (73 percent). There was a similar proportion of patients with mild ear anomalies (53 percent with grade 0 or 1) compared with those with more severe anomalies (47 percent with grade 2 or 3). Correlative analysis demonstrated a slight but positive correlation between the severity gradings of the five individual components. The correlation was lowest between the grading of the nerve and ear and that of the mandible and nerve. The data demonstrate the phenotypic variability of hemifacial microsomia and suggest a degree of relationship among the components of hemifacial microsomia. The OMENS-Plus system has provided a major advancement in the classification of hemifacial microsomia. The authors suggest refinements to the grading of the orbit and nerve components.

Stability of combined Le Fort I maxillary advancement and mandibular reduction.

BACKGROUND: There have been reports that correction of severe Class III abnormality by single jaw surgery may invite relapse in the long-term. The purpose of this study was to retrospectively evaluate the stability of combined Le Fort I maxillary advancement and bilateral sagittal split osteotomies for mandibular reduction. METHODS: Thirty patients with a skeletal Class III malocclusion underwent bimaxillary surgery using rigid fixation and interpositional bone grafting of the maxilla. The average age was 24.4 years, and the mean follow-up period was 20 months (Range: 12-63 months). Post-operative changes were measured on lateral cephalometric radiographs using an anatomical best-fit technique. RESULTS: The maxilla was advanced, on average, 6.1 mm (SD: 1.8 mm) and repositioned superiorly at PNS 1.9 mm (SD: 2.1 mm). The mandible was repositioned posteriorly 5.6 mm ISD: 4.2 mm) at menton, which also auto-rotated superiorly. At follow-up, the maxilla relapsed horizontally 0.6 mm (SD: 1.1 mm, p < 0.01) with no significant vertical change. The maxillary central incisors were proclined and the interincisal angle was reduced. Menton relapsed anteriorly 1.4 mm (SD: 2.7 mm, p < 0.01), and gonion rotated superiorly 1.5 mm (SD: 2.3 mm, p < 0.001). In 67 per cent of cases menton moved anteriorly less than 2.5 mm. The overjet and overbite did not change significantly. CONCLUSIONS: The data show that 12-months post-operatively, maxillary advancement combined with mandibular setback was relatively stable in the horizontal and vertical planes.

The role of distraction osteogenesis in the management of craniofacial syndromes.

In patients with craniofacial syndromes, the skeletal discrepancy is often severe, and the ability to achieve the desired movement by immediate surgical repositioning is difficult because of restrictions of the soft-tissue envelope. The technique of distraction osteogenesis has provided an additional option for managing congenital and acquired craniofacial deformities. The use of distraction osteogenesis is, however, still within its infancy as a treatment modality. It is unlikely that the procedure will obviate the need for definitive orthognathic surgery at skeletal maturity in most patients with craniofacial anomalies. The role of distraction osteogenesis in craniofacial surgery will continue to evolve rapidly with increasing experience and technological advancement. Because distraction osteogenesis in the facial skeleton is a relatively new approach, analysis of the contemporary literature is imperative, and future long-term studies on the effects and outcome of distraction are essential.

A mouse splice-site mutant and individuals with atypical chromosome 22q11.2 deletions demonstrate the crucial role for crkl in craniofacial and pharyngeal development.

The 22q11.2 deletion syndrome (22q11DS) is thought to be a contiguous gene syndrome caused by haploinsufficiency for a variable number of genes with overlapping function during the development of the craniofacial, pharyngeal and cardiac structures. The complexity of genetic and developmental anomalies resulting in 22q11DS has made attributing causation to specific genes difficult. The CRKL gene resides within the common 3-Mb region, most frequently affected in 22q11DS, and has been shown to play an essential role in the development of tissues affected in 22q11DS. Here, we report the characterisation of a mouse strain we named 'snoopy', harbouring a novel Crkl splice-site mutation that results in a loss of Crkl expression. The snoopy strain exhibits a variable phenotype that includes micrognathia, pharyngeal occlusion, aglossia and holoprosencephaly, and altered retinoic acid and endothelin signalling. Together, these features are reminiscent of malformations occurring in auriculocondylar syndrome and agnathia-otocephaly complex, 2 conditions not previously associated with the CRKL function. Comparison of the features of a cohort of patients harbouring small 22q11.2 deletions centred over the CRKL gene, but sparing TBX1, highlights the role of CRKL in contributing to the craniofacial features of 22q11DS. These analyses demonstrate the central role of Crkl in regulating signalling events in the developing oropharyngeal complex and its potential to contribute to dysmorphology.

The role of distraction osteogenesis in the management of craniofacial syndromes.

Distraction osteogenesis (DO) has been established as a useful technique in the correction of skeletal anomalies of the long bones for several decades. However, the use of DO in the management of craniofacial deformities has been evolving over the past 20 years, with initial experience in the mandible, followed by the mid-face and subsequently, the cranium. This review aims to provide an overview of the current role of DO in the treatment of patients with craniofacial anomalies.

Repair of critical size defects in the rabbit calvarium with the use of a novel scaffold material.

A number of materials have been implanted into skull defects to determine if improved healing outcomes can be achieved. In some instances, packing or implanting bone-inducing alloplasts into a standardized skull defect results in better healing than an untreated defect. AlloDerm is a skin derived acellular collagen membrane and has characteristics that are known to be effective in promoting bone growth. It has not been previously investigated for use in cranial bone healing. The aim of the investigation was to determine if implanting this novel scaffold into skull defects will improve the quality of bone repair. Six rabbits received AlloDerm grafts into critical-sized calvarial defects. The rabbits were sacrificed at two months and the specimens examined histologically and radiographically. At the time of sacrifice, it was found that while bony growth had commenced at the margins of the defect and as isolated islands within the graft, there did not appear to be a major benefit in using the material described.