Faculty Bibliography

BACKGROUND:Nonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored. METHODS:The authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information. RESULTS:The authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI) >0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4). CONCLUSIONS:These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE/METHODS:Risk, III.

OBJECTIVES/OBJECTIVE:Cleft lip repair has traditionally been performed as an inpatient procedure. There has been an interest toward outpatient cleft lip repair to reduce healthcare costs and avoid unnecessary hospital stay. We report surgical outcomes following implementation of an ambulatory cleft lip repair protocol and hypothesize that an ambulatory repair results in comparable safety outcomes to inpatient repair. DESIGN/SETTING/METHODS:This is a single-institution, retrospective study. PATIENTS/PARTICIPANTS/METHODS:Patients undergoing primary unilateral (UCL) and bilateral (BCL) cleft lip repair from 2012 to 2021 with a minimum 30-day follow-up. A total of 226 patients with UCL and 58 patients with BCL were included. INTERVENTION/METHODS:Ambulatory surgery protocol in 2016. OUTCOME MEASURES/METHODS:Variables include demographics and surgical data including 30-day readmission, 30-day reoperation, and postoperative complications. RESULTS:There were no differences in rates of 30-day readmission, reoperation, wound complications, or postoperative complications between the pre- and post-protocol groups. Following ambulatory protocol implementation, 80% of the UCL group and 56% of the BCL group received ambulatory surgery. Average length of stay dropped from 24 h pre-protocol to 8 h post-protocol. The 20% of the UCL group and 44% of the BCL group chosen for overnight stay had a significantly higher proportion of congenital abnormalities and higher American Society of Anesthesiology (ASA) class. Reasons for overnight stay included cardiac/airway monitoring, prematurity, and monitoring of comorbidities. There were no differences in surgical outcomes between the ambulatory and overnight stay groups. CONCLUSIONS:An ambulatory cleft lip repair protocol can significantly reduce average length of stay without adversely affecting surgical outcomes.

Background/Purpose: Gingivoperiosteoplasty (GPP) is a procedure performed at the time of primary cleft lip or palate repair in which the alveolus is repaired without the need for bone graft. Although the success of GPP is reported up to 70%, the associated disparities with regards to access or receipt of GPP has not been studied. This study reports on patient access to GPP reconstruction. Methods/Description: The American College of Surgeons National Surgical Quality Improvement Program Pediatric (ACS NSQIP Peds) was queried from 2014 to 2019. Patients were selected using the Current Procedural Terminology (CPT) codes (Table 1). Patient race, gender, age at time of surgery, 30 day readmission, comorbidities and complications were recorded. Postoperative complications included surgical site infections (SSI), dehiscence and transfusion. Receipt of GPP was analyzed using binary logistic regression to control for variables that could potentially affect access to/ receipt of GPP. For multivariable analysis, Bonferroni correction was used.
Result(s): 23408 patients with a cleft were included in our analysis. 12590 were White, 1732 were Black/African American, 3914 were Hispanic, 2267 were Asian/other Pacific Islander, and 2905 did not have a reported Race. Amongst this cohort, 709 patients underwent GPP (2.25%). Patients who did not report/of unknown Race were less likely to undergo GPP (p = 0.001), while there was no statistically significant difference amongst access to GPP for Black/African American, Hispanic, or Asian/ other Pacific Islander patients. The average age of all patients was 2411 days. White patients had primary cleft repair at a younger age (p = 0.000) than non-White patients. There was no difference in gender or co-morbidities (cardiac risk factors and congenital/chronic lung disease, respectively) amongst all Races (p = 0.291, p = 0.276, p = 0.547). There was no statistically significant difference in unplanned 30-day readmission and 30-day postoperative complication (p = 0.326, 0.934, respectively). Patients with ASA class 3 or 4 and minor or major cardiac risk factors had a statistically significant higher chance of 30-day readmission (p = 0.000, 0.000, 0.000, 0.001, respectively).
Conclusion(s): Amongst reported Races there was no statistically significant difference with regards to access/receipt of GPP, but patients without a reported Race were less likely to undergo GPP. Undergoing GPP did not appear to increase the likelihood of 30-day readmission or postoperative complication. We did find that White patients received cleft lip/palate repair at a statistically significant younger age and Hispanic patients at a later age, which is similar to previous studies. Although there was no difference in access to GPP amongst Races, further studies to evaluate disparities in outcomes for children undergoing GPP needs to be elucidated

Background/Purpose: Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. Methods/Description: We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n=138) or familial (n=8) CFM.
Result(s): We identify a highly significant burden of loss of function variants in SF3B2 (P=3.8 x 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease.
Conclusion(s): The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases

Background/Purpose: Nasoalveolar molding (NAM) in combination with primary gingivoperiosteoplasty (GPP) may obviate the need for a secondary alveolar bone graft. While the long-term facial growth following GPP has been well documented, no study has evaluated the transverse growth of the cleft-maxilla following NAM and GPP. Here we report the effects of NAM and GPP on the maxillary transverse dimension in patients with complete unilateral cleft lip and palate (UCLP). Methods/Description: A retrospective single-institution review of nonsyndromic patients with complete unilateral cleft lip and palate born between 2005 and 2010 was completed. Patients were divided into four groups based on their interventions: 1) NAM-GPP with adequate bone formation 2) NAM-GPP without adequate bone formation (requiring ABG) 3) NAM-no GPP (requiring ABG), and 4) No NAM-no GPP control (patients who received primary surgeries outside of our institution). Cone-beam computed tomographic scans (CBCTs) taken at the early-mixed dentition stage, prior to orthodontic intervention, were used to assess the anterior and posterior maxillary transverse dimensions. The transverse discrepancy at the affected and non-affected sides was measured at the level of the primary canines (anterior dimension) and the permanent first molars (posterior dimension) to the maxillary midline. Wilcoxon signed-rank tests were used to compare the transverse dimension of the affected versus non-affected sides within each group. Mann-Whitney U tests were used to compare each NAM group with the no NAM-no GPP control group.
Result(s): A total of 85 patients were included in this study (mean age = 8.7). Male patients (50.6%) and the left side (64.7%) were most affected. Of the 85 patients, 26 (30.6%) underwent NAM-GPP with adequate bone formation, 22 (25.9%) underwent NAM-GPP but required ABG, 16 (18.8%) underwent NAM without GPP, and 21 (24.7%) underwent no NAM-no GPP. Median values were significantly different in the anterior maxilla between the affected and nonaffected sides across all four groups (p = 0.001). The transverse dimension at the affected side also revealed a significant difference in both the NAM-GPP (with adequate bone formation) and the NAM-GPP (requiring ABG) groups compared to the no NAM-no GPP group (p= 0.022 and p= 0.001, respectively). There was no significant difference between the NAM-no GPP group compared to the control (p = 0.059). Distances to the molars of the affected and nonaffected sides were not statistically significant within or across any of the groups (p > 0.05).
Conclusion(s): In patients with UCLP, the maxillary primary canine transverse dimension on the affected side is significantly reduced in patients undergoing NAM and GPP compared to the control. However, the position of the maxillary first molars appear to be unaffected by NAM and GPP

Background/Purpose: After LeFort I advancement surgery, soft tissue changes are unpredictable, especially in patients with orofacial clefts, as scar tissue from primary repair can alter soft tissue responses. Therefore, this study aimed to measure and evaluate soft tissue response following LeFort I advancement in skeletally matured patients with complete cleft lip and palate (CLP). Methods/Description: The cohort of 26 patients with non-syndromic CLP who underwent Le Fort I osteotomy between 2013 and 2019 and met the inclusion criteria. Patients were included if they had lateral cephalograms or CBCT at pre-operative (T1), immediately post-operative (T2), and one-year follow-up (T3). Patients who underwent nose/lip revision surgery before T3 were excluded. Four skeletal and dental hard-tissue (ANS, point A; A-point, upper incisor most labial; U1-most, upper incisor edge; U1-tip) and 5 softtissue (tip of nose or pronasale; Prn, subnasale; Sn, superior labial sulcus; SLS, upper lip anterior or labrale superius; LS, and stomion superius; SIMS) landmarks were digitized and measured. For the outcome analyses, 5 ratios of soft- to hard-tissue changes (Prn/ANS, Sn/A-point, SLS/A-point, LS/U1-most, and SIMS/ U1-tip) were calculated for each group, and associations between hard-and-soft tissue counterparts were assessed using Pearson correlation coefficient (r).
Result(s): Sixteen patients had UCLP, and 10 patients had BCLP. At one-year follow-up (T1-T3), the mean advancement in UCLP and BCLP groups at ANS were 4.4+/-3 and 4.7+/-3.9 mm, from point A were 6.6+/-2.5, 8.8+/- 2.6 mm, respectively. The mean horizontal changes of the corresponding soft tissue anatomy, Prn, were 2.7 +/-1.7, 4.6+/-3.5 mm, from Sn, were 3.9+/-1.9, 6.2+/-2.4. mm, and from SLS were 5.2+/-2.5, 7.4+/-2.8 mm. The mean advancement in at upper incisor most labial were 7.2+/-2.7 and 8.4+/-2.4 mm, and from the upper incisal edge were 7.5+/-2.9 and 8.4+/-2.7. mm. The mean horizontal changes of the soft tissue counterpart, LS, were 5.6+/-2.9, 7.9+/- 3.7 mm, and SIMS were 6.0+/-3.2, 7.3+/- 2.7 mm. All skeletal, dental, and soft tissue advancements from T1-T3 were significant (P< 0.01) except for Sn and LS in both groups and SIMS in UCLP group. For ratio and correlation analyses in UCLP and BCLP groups, Prn/AND were 0.48 (r=0.40) and (r=0.00), Sn/A-point were 0.58 (r=0.79) and 0.70 (r=0.77), SLS/A-point were 0.79 (r=0.82) and 0.85 (r=0.80), LS/U1-most were 0.74 (r=0.92) and 0.96 (r=0.74), and SIMS/U1-tip were 0.78 (r=0.75) and 0.82(r=0.67), respectively. All associations except for Prn/ANS were statistically significant (P< 0.01).
Conclusion(s): This study demonstrated a linear relationship between soft- and hard-tissue changes in the maxillary landmarks following LeFort I advancement in patients with complete cleft lip and palate (UCLP and BCLP)

PURPOSE/OBJECTIVE:The purpose of this study was to measure the association between the magnitude of advancement and dental and skeletal relapse in patients with cleft lip and palate (CLP). METHODS:A single-institution retrospective cohort study of skeletally matured patients with CLP who underwent isolated Le Fort I advancement surgery between 2013 and 2019 was studied. Patients were included if they had lateral cephalograms or cone-beam computed tomography (CBCT) at preoperative (T1), immediately postoperative (T2), and 1-year follow-up (T3). Lateral cephalometric landmarks were digitized and measured. The sample was divided on the basis of the magnitude of skeletal advancement: minor (<5 mm), moderate (≥5 but <10 mm), and major (≥10 mm) advancement groups. The mean advancement and relapse were compared between groups using 1-way ANOVA. Correlation between the amount of surgical advancement and relapse was evaluated. RESULTS:Forty-nine patients with nonsyndromic CLP with hypoplastic maxilla met inclusion criteria and the sample consisted of 36 males and 13 females with the mean age of 19.5 years. In the minor, moderate, and major advancement groups, the mean advancement at point A was +4.1 ± 0.4, + 7.5 ± 1.4, and +11.3 ± 1.3 mm, respectively. At 1-year follow-up, the mean relapse at point A was -1.3 ± 1.2, -1.1 ± 1.2, and -1.7 ± 1.5 mm, respectively. There was no significant difference in the relapse amount between all surgical groups. No correlation between the magnitude of advancement and relapse was found. CONCLUSIONS:This study demonstrated no statistically significant difference in skeletal stability between a minor (<5 mm), moderate (≥5 but <10 mm), and major (≥10 mm) Le Fort I advancement groups in patients with clefts. Regardless of the degree of advancement, mild skeletal relapse was observed in all 3 groups.

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10^-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.

The Le Fort III advancement was first described in 1950 and has since become a key technique in the armamentarium of craniofacial surgeons. The application of distraction osteogenesis to the craniofacial skeleton has allowed for large movements to be performed safely in young patients. This technique is valuable for correcting exorbitism, airway obstruction owing to midface retrusion, and class III malocclusion. It can be performed with either an external distractor or internal distractors. Although serious complications have been reported, these occur rarely when performed by experienced providers.

OBJECTIVE/UNASSIGNED:Utilize 3-dimensional (3D) photography to evaluate the nasolabial changes in infants with bilateral cleft lip and palate (BCLP) who underwent nasoalveolar molding (NAM) and primary reconstructive surgery. DESIGN/UNASSIGNED:coordinates to obtain the linear and angular measurements. Nasal form changes were measured and analyzed between T1 (0.5 months old), T2 (5 months old), and T3 (6 months old). Intraclass correlation coefficient was performed for intrarater reliability. Averaged data from the 3D images was statistically analyzed from T1 to T2 and T2 to T3 with Wilcoxon tests. Unaffected infant norms from the Farkas publication were used as a control sample. RESULTS/UNASSIGNED:After NAM therapy, statistically significant changes in the position of subnasale and labius superius improved nasolabial symmetry. Both retruded after NAM were displaced downward after NAM and surgical correction with respect to soft tissue nasion. The nasal tip's projection was maintained with NAM and surgical correction. The columella lengthened from 1.4 to 4.71 mm following NAM. CONCLUSIONS/UNASSIGNED:There was a significant improvement in the nasolabial anatomy after NAM, and this was further enhanced after primary reconstructive surgery.