The role of genetics on behavioral outcomes in nonsyndromic sagittal synostosis.

OBJECTIVE: Previous work identified an association between genetics and neurodevelopmental delays in patients with nonsyndromic craniosynostosis. The authors investigated the role of genetic mutations on behavioral outcomes of patients with treated sagittal synostosis. METHODS: Parents of children aged 6-18 years with surgically corrected sagittal synostosis were recruited to complete the Child Behavioral Checklist (overall behavioral problems), Conners 3rd Edition-Parent (attention-deficit/hyperactivity disorder), Social Responsiveness Scale 2nd Edition (autism spectrum disorder [ASD]), and Behavior Rating Inventory of Executive Function 2nd Edition (executive function). Genomic analysis was completed, and patients were identified if they had mutations in high probability of loss of function intolerant (pLI) genes (high pLI vs nonhigh pLI). Genetic burden was assessed relative to controls. Multivariate linear regression determined the association of mutations in high pLI genes with behavioral scores, while controlling for sociodemographic factors, age at surgery, surgery type, and IQ. RESULTS: Sixteen of 45 patients were in the high pLI group. There were no differences between the groups in terms of sociodemographic factors. A greater proportion of children in the high pLI group scored at or above borderline clinical levels for aggression (18.8% vs 0.0%, p = 0.05) and externalizing problems (31.3% vs 3.7%, p = 0.02). Among children in the nonhigh pLI group, older age at surgery was associated with worse scores on the rule-breaking, aggression, and externalizing problems domains and four out of five ASD domains. CONCLUSIONS: Children with treated nonsyndromic sagittal synostosis and mutations in high pLI genes had worse behavioral problems in externalizing behaviors and aggression, whereas older age at surgery was a significant predictor of worse behavioral outcomes in patients without mutations in high pLI genes.

Does Initial Cleft Lip Width Predict Final Aesthetic Outcome?

A natural aesthetic appearance of the lip and a favorable scar are essential goals of cleft lip repair. Wider clefts intuitively pose a greater technical challenge; however, the relationship between initial width and aesthetic outcome remains controversial. The current study aimed to determine whether lip adhesion can help wider clefts achieve safe, consistent aesthetic outcomes. METHODS: A retrospective cohort study was conducted on unilateral cleft lip patients who underwent lip repair within a 2-year period by the senior author. Subjects were divided into three groups based on cleft severity: (1) wide complete clefts that required lip adhesion before definitive repair, (2) narrower complete clefts that did not require lip adhesion, and (3) incomplete clefts. Aesthetic outcomes related to the vermillion and upper lip scar were rated by 48 blinded observers. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney tests. Nasal outcomes were not assessed. RESULTS: Seventeen patients were included in the study: five in group 1, six in group 2, and six in group 3. Patients with the widest clefts did not have inferior results compared with the other groups. In fact, they had statistically significantly higher aesthetic scores in all scar-related outcomes compared with those in groups 2 and 3 (P < 0.0001). CONCLUSIONS: This study suggests that a wide cleft does not necessarily foreshadow a poor surgical outcome. In fact, wide clefts may have pleasing results, and the use of a staged lip adhesion approach can be useful for achieving the desired outcome in wider clefts.

Long-term Follow-up of Preoperative Infant Event-related Potentials in School-age Children with Craniosynostosis.

BACKGROUND: Previous studies demonstrated impaired auditory processing in children with sagittal and metopic craniosynostosis before surgical correction. This study investigated whether worse presurgical neural response as assessed by event-related potentials (ERP) was predictive of poorer school-age neurocognition. METHODS: Preoperative infant ERP was recorded in 15 sagittal and 18 metopic patients. Mismatch negativity and P150 paradigms were derived from ERP recordings, as previously published. Of those, 13 sagittal and 13 metopic patients returned for neurocognitive evaluation 6 or more years later. ERP was correlated to neurocognitive outcomes using Spearman's correlations controlling for age. Two-tailed t-tests were used to evaluate the influence of age at the time of surgery (6 months) and morphologic severity on neurocognitive outcomes. RESULTS: In the sagittal group, no significant correlations were found between preoperative mismatch negativity or P150 amplitudes and neurocognitive outcomes. Although no correlation was found between mismatch negativity and neurocognitive outcome in the metopic group, those with lower P150 amplitudes had higher scores in performance IQ (r = -0.877, P < 0.001) and full-scale IQ (r = -0.893, P < 0.001). Morphologic severity and neurocognitive outcomes showed no relationship in the sagittal or metopic groups. Patients who received surgery at less than 6 months had higher full-scale IQ (109.69 versus 95.92, P = 0.025), visuomotor integration (103.15 versus 90.46, P = 0.041), and visual perception scores (105.69 versus 96.08, P = 0.033). CONCLUSIONS: Preoperative infant ERP does not correlate with school-age neurocognitive outcomes. Earlier age at the time of surgery was associated with improved neurocognitive outcomes.

Special Considerations in Chinese Face-Lift Procedure: Insights From a 15-Year Experience of 1026 Cases.

BACKGROUND: There is extensive literature on different face-lift techniques; however, few articles published in the English language address the particularities of the face-lift for Chinese patients. Because of differences in facial anatomy, facial aging, and patient expectations, facial rejuvenation procedures for Chinese patients can be quite different from those of White patients. METHODS: The study includes 1026 consecutive primary face-lift cases performed by the senior author (D.Y.) from 2006 to 2019. Of these, 1010 patients were female and 16 were male. The average age of the patient at the time of primary face-lift was 40.5 years. The face-lift procedures included midface lift in 108 cases, midface and lower-face lift in 882 cases, and midface and lower-face lift with brow lift in 36 cases. All patients received superficial musculoaponeurotic system (SMAS) treatment, in the form of lateral SMASectomy in 607 cases, high-SMAS technique in 84 cases, modified high-SMAS short-scar technique in 108 cases, minimal access cranial suspension technique in 38 cases, and modified minimal access cranial suspension technique in 189 cases. Photographs of patients were analyzed to assess persistent features of facial aging. Complications such as hematoma, skin slough, infection, and nerve injury were also reviewed. RESULTS: Most patients obtained consistently good results with minimal risk and complications. All surgical techniques discussed were safe and reproducible, providing various options for surgeons. CONCLUSIONS: Special attention should be taken when planning a facial rejuvenation procedure for Chinese patients. Anatomic variations dictate a greater emphasis on the management of tissue ptosis, particularly regarding lateral brow descent and malar fat pad descent. In our practice, various face-lift techniques can produce excellent results. Surgeons must adopt a technique that serves patients well and is, ideally, safe, consistent, easily reproducible, and applicable to various anatomic problems. In addition, every surgery is customized to the patient's anatomy and concerns. Therefore, the surgeon must adopt individualized technique according to the needs and desires of each patient.

Long-Term Neurocognitive Outcomes in Sagittal Synostosis: The Impact of Reoperation.

INTRODUCTION: Optimal age at surgery in nonsyndromic sagittal craniosynostosis continues to be debated. Previous reports suggest that earlier age at whole vault cranioplasty more frequently requires reoperation. It is unknown, however, whether reoperation affects neurocognitive outcome. This study examined the impact of reoperation on neurocognitive outcome in children with nonsyndromic sagittal craniosynostosis using comprehensive neurocognitive testing. METHODS: Forty-seven school-age children (age 5-16 years) with nonsyndromic sagittal craniosynostosis who underwent whole-vault cranioplasty were included in this analysis. Participants were administered a battery of standardized neuropsychological testing to measure neurocognitive outcomes. RESULTS: Thirteen of the 47 participants underwent reoperation (27.7%); 11 out of the 13 reoperations were minor revisions while 2 reoperations were cranioplasties. Reoperation rate was not statistically different between patients who had earlier surgery (at age ≤6 months) versus later surgery (at age >6 months) (P > 0.05). Nonreoperated patients who had only one later-in-life surgery did not perform statistically better than reoperated patients on any outcome measure of neurocognitive function, including IQ, academic achievement, visuomotor integration, executive function, and behavior. Comparing reoperated earlier surgery patients with nonreoperated later surgery patients, reoperated earlier surgery patients had higher full-scale and verbal IQ (P < 0.05), scored higher on word reading, reading comprehension, spelling, numerical operations, and visuomotor integration (P < 0.05), and had fewer indicators of suspected learning disabilities (P < 0.01) compared to nonreoperated later surgery patients. CONCLUSION: Reoperation rate after whole vault cranioplasty was 27.7%, with few cases of repeat cranioplasty (4.2% of all patients). Reoperation was not associated with worse neurocognitive outcome. Reoperated earlier surgery patients in fact performed better in IQ, academic achievement and visuomotor integration when compared to nonreoperated later surgery patients.

Frustration and Emotional Regulation in Nonsyndromic Craniosynostosis: A Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nonsyndromic craniosynostosis may manifest with complex behavioral, attentional, and emotional sequelae. The authors characterized higher level brain connectivity in adolescent nonsyndromic craniosynostosis patients in response to emotional frustration. METHODS: Surgically corrected patients older than 9 years with nonsyndromic craniosynostosis were age/sex/handedness matched to controls. Patients participated in a "go/no-go" task, structured as win/lose/recovery paradigms. BioImage Suite was used to analyze whole-brain intrinsic connectivity between tasks with cluster-corrected group-level t maps. A value of p < 0.05 was significant. RESULTS: Seven unilateral coronal (average age, 12.2 years), six metopic (average age, 11.5 years), and controls were included. Unilateral coronal had worse emotional regulation scores on the Behavior Rating Inventory of Executive Function survey (p = 0.065) and performed poorly on the go/no-go task (p < 0.001). Metopic had four regions of interest, with the majority having decreased activity compared with controls, and few differences between tasks. Unilateral coronal patients had 11 regions of interest; the majority decreased during the win and lose conditions, but all increased during the recovery condition. Metopic patients had decreased blood oxygenation level- dependent signal in the posterior cingulate (p = 0.017) and middle temporal gyrus (p = 0.042). Unilateral coronal had decreased signal in the posterior cingulate (p = 0.023), middle temporal gyrus (p = 0.027), and thalamus (p = 0.033), but increased signal in the cuneus (p = 0.009) and cerebellum (p = 0.009). Right unilateral coronal, but not metopic/controls, had increased right brain activity in the caudate (p = 0.030), thalamus (p = 0.011), temporal lobe (p = 0.012), and cerebellum (p = 0.029). CONCLUSIONS: Unilateral coronal patients may have emotional dysregulation in response to frustration, whereas metopic patients may have attenuated emotional reactions. Evidence of right unilateral coronal brain laterality suggests that the area of suture fusion may contribute to the mechanism of dysfunction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

An Investigation of Brain Functional Connectivity by Form of Craniosynostosis.

PURPOSE: Long-term neurocognitive sequelae of nonsyndromic craniosynostosis (NSC) patients are just beginning to be clarified. This study uses functional MRI (fMRI) to determine if there is evidence of altered brain functional connectivity in NSC, and whether these aberrations vary by form of synostosis. METHODS: Twenty adolescent participants with surgically treated NSC (10 sagittal synostosis, 5 right unilateral coronal synostosis [UCS], 5 metopic synostosis [MSO]) were individually matched to controls by age, gender, and handedness. A subgroup of MSO was classified as severe metopic synostosis (SMS) based on the endocranial bifrontal angle. Resting state fMRI was acquired in a 3T Siemens TIM Trio scanner (Erlangen, Germany), and data were motion corrected and then analyzed with BioImage Suite (Yale School of Medicine). Resulting group-level t-maps were cluster corrected with nonparametric permutation tests. A region of interest analysis was performed based on the left Brodmann's Areas 7, 39, and 40. RESULTS: Sagittal synostosis had decreased whole-brain intrinsic connectivity compared to controls in the superior parietal lobules and the angular gyrus (P = 0.071). Unilateral coronal synostosis had decreased intrinsic connectivity throughout the prefrontal cortex (P = 0.031). The MSO cohort did not have significant findings on intrinsic connectivity, but the SMS subgroup had significantly decreased connectivity among multiple subcortical structures. CONCLUSION: Sagittal synostosis had decreased connectivity in regions associated with visuomotor integration and attention, while UCS had decreased connectivity in circuits crucial in executive function and cognition. Finally, severity of metopic synostosis may influence the degree of neurocognitive aberration. This study provides data suggestive of long-term sequelae of NSC that varies by suture type, which may underlie different phenotypes of neurocognitive impairment.

Normalization of Speech Processing After Whole-Vault Cranioplasty in Sagittal Synostosis.

BACKGROUND: Neurocognitive studies have found impairments in language-related abilities in nonsyndromic craniosynostosis, highlighting clinical importance of early language processing. In this study, neural response to speech sounds in infants with nonsyndromic sagittal craniosynostosis (NSC) is compared, preoperatively and postoperatively, using event-related potentials (ERPs) to objectively characterize development in language processing. METHODS: Electroencephalogram was recorded while 39 infants (12 NSC and 27 controls; ages 73-283 days) listened to the Hindi dental /(Equation is included in full-text article.)a/ and retroflex /da/ phonemes (non-native phonemic discrimination task). The mismatch negativity (MMN) ERP was extracted as the peak amplitude of the largest negative deflection in the difference wave over 80 to 300 milliseconds poststimulus. Differences in MMN were analyzed using repeated measures analysis of variance. RESULTS: The MMN amplitude was attenuated in the infants with NSC preoperatively compared with controls (P = 0.047). A significant region by group interaction (P = 0.045) was observed, and infants with NSC displayed attenuated MMN in the frontal electrodes compared with controls (P = 0.010). Comparing the preoperative and postoperative MMN, a time by group interaction trend (P = 0.070) was observed. Pair-wise comparisons showed a trend for increase in MMN amplitude from preoperatively to postoperatively in the infants with NSC (P = 0.059). At the postoperative time point, infants with NSC showed no significant difference in MMN from controls (P = 0.344). CONCLUSION: Infants with NSC demonstrated atypical neural response to language preoperatively. After undergoing surgery, infants with NSC showed increased MMN amplitude which was not significantly different from controls. These findings support the idea that whole vault cranioplasty may improve neurocognitive outcomes in sagittal craniosynostosis.

The Severity of Deformity in Metopic Craniosynostosis Is Correlated with the Degree of Neurologic Dysfunction.

BACKGROUND: In recent years, metopic synostosis has represented up to 25 percent of all nonsyndromic craniosynostosis cases, manifesting with varying degrees of trigonocephaly. It is unknown whether the degree of severity of anterior dysmorphology is proportionate to neurologic dysfunction. This knowledge is essential to guide future surgical treatment recommendations. Given the reported correlation of abnormal auditory processing with future language dysfunction and poorer academic performance in craniosynostosis patients, the present study aims to evaluate auditory processing in preoperative patients with moderate and severe metopic synostosis, and in control infants, to discern the neurologic risk carried by different severities of trigonocephaly. METHODS: Thirty-eight infants underwent evaluation of auditory processing: nine patients with severe metopic synostosis, seven with moderate metopic synostosis, and 22 controls. Brain activity was recorded by electroencephalography while the participants listened to language-based stimuli. Electroencephalographic data were analyzed to extract event-related potentials evoked by the speech sounds. RESULTS: Severe metopic synostosis patients demonstrated significantly attenuated event-related potential responses in the left frontal scalp region overlying the left frontal lobe compared with controls (p < 0.05). The moderate metopic synostosis patients did not show significantly different language processing compared to the control infants or the severe metopic synostosis patients in the frontal scalp region. CONCLUSIONS: The results of this study suggest that untreated severe metopic synostosis is associated with reduced language response in the frontal cortex. Less severe (moderate) forms are indeterminate, and mild forms do not show calculable irregularity by the event-related potential method of analysis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP - induced osteoblast differentiation (p<10-20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

The impact of age at surgery on long-term neuropsychological outcomes in sagittal craniosynostosis.

BACKGROUND: The relationship between surgical age and long-term neuropsychological outcomes in sagittal-suture craniosynostosis remains equivocal. Whole-vault cranioplasty and strip craniectomy are performed at various times in individuals with sagittal-suture craniosynostosis. This study used comprehensive neurological testing to examine the relationship between age at time of surgery and long-term neuropsychological function. METHODS: Seventy sagittal-suture craniosynostosis patients who had previously undergone either whole-vault cranioplasty or strip craniectomy were examined divided into three groups: treatment before 6 months (n = 41), between 6 and 12 months (n = 21), and after 12 months (n = 8). To examine long-term cognitive functioning, participants between the ages of 5 and 25 years underwent neurodevelopmental tests to evaluate intelligence, achievement, and learning disabilities. RESULTS: Compared with those treated between 6 and 12 months and after 12 months, patients who underwent surgery before 6 months demonstrated higher full-scale IQ (p < 0.01) and verbal IQ (p < 0.01). Patients who received surgery before 6 months also demonstrated superior abilities in word reading (p < 0.01), reading comprehension (p < 0.01), spelling (p < 0.01), and numerical operations (p < 0.05) relative to those who had surgery between 6 and 12 months old. A statistically significant higher percentage of patients treated after 6 months had one or more reading-related learning disabilities as compared with those undergoing earlier surgery. CONCLUSIONS: This study suggests that surgery before 6 months old results in improved long-term neurological outcomes. Future studies should examine how the technique of surgery impacts these neuropsychological measures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The effects of whole-vault cranioplasty versus strip craniectomy on long-term neuropsychological outcomes in sagittal craniosynostosis.

BACKGROUND: The optimal type of surgical management for isolated sagittal synostosis remains a source of significant debate. There is a paucity of data regarding possible differences in long-term neuropsychological outcomes following treatment with whole-vault cranioplasty or endoscopic strip craniectomy. This study provides the first comparative analysis examining the effects of the two techniques related to long-term intellectual functioning. METHODS: A total of 70 patients were enrolled in this multicenter study, 29 of whom had previously undergone endoscopic strip craniectomy and 41 of whom had previously undergone whole-vault cranioplasty. All patients completed a battery of neurodevelopmental tests (Beery-Buktenica Developmental Test of Visual-Motor Integration, Wechsler Abbreviated Scale of Intelligence, and Wechsler Fundamentals) to evaluate various domains of neuropsychological function. RESULTS: In a group comparison of those treated before 6 months of age, whole-vault patients obtained higher scores relative to endoscopic strip craniectomy patients on visuomotor integration, full-scale intelligence quotient, verbal intelligence quotient, word reading, and reading comprehension (p < 0.05 for all). When compared against strip craniectomy performed before 3 months of age, the whole-vault group still showed significantly higher scores in verbal intelligence quotient, reading comprehension, and word reading (p < 0.05 for all). CONCLUSIONS: The type of surgical intervention for isolated sagittal synostosis impacts long-term neuropsychological outcomes. Patients undergoing early whole-vault cranioplasty attained higher intelligence quotient and achievement scores relative to those undergoing strip craniectomy. Surgical management with whole-vault cranioplasty performed before 6 months of age provides the most favorable long-term intellectual outcomes in patients with isolated sagittal synostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Hypoxia preconditioning enhances the viability of ADSCs to increase the survival rate of ischemic skin flaps in rats.

UNLABELLED: Use of a skin flap has been a common technique in reconstructive surgery for more than five decades. However, partial necrosis of its distal end is still a serious postoperative complication. Many theories about this problem have been proposed, including deficient blood supply, which is the most accepted theory. In this study we demonstrated that hypoxic preconditioning enhanced the viability of adipose-derived stem cells (ADSCs) in vivo and improved their ability to increase the survival rate of ischemic skin flaps in rats. Seven days after flap elevation, the flap survival rate in the hypoxic preconditioned ADSC group was higher than that in the control group. Moreover, histological examination showed that more ADSCs survived in flaps treated by hypoxic preconditioning. Vascular density in the hypoxic preconditioned ADSC group was 30-90 % greater than that in the control group. In addition, the expressions of vascular endothelial growth factor and hypoxia inducible factor-1α (HIF-1α) were higher in the hypoxic preconditioned ADSC group than in the control group (p < 0.05). This enhancive phenomenon reached its highest level at the precondition times of 3 and 7 days in the hypoxic preconditioned ADSC group. We conclude that hypoxia preconditioning effectively enhances the viability of ADSCs to increase the survival rate of ischemic skin flaps. Furthermore, 3 days is the optimal preconditioning time point. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Utilizing muscle-derived stem cells to enhance long-term retention and aesthetic outcome of autologous fat grafting: pilot study in mice.

Autologous fat grafting has been regarded as the ideal soft tissue filler for more than a century. Low long-term retention rate and unpredictability limit it from widespread clinical practice. Many theories for this have been proposed: lack of sufficient blood supply and subsequent necrosis is the most accepted. In this pilot study, we showed both macroscopically and microscopically the viability of muscle-derived stem cells (MDSCs) cotransplanted with fat placed intramuscularly for 3 months. MRI scanning showed a stronger fat signal in the MDSC-treated group than that of the control group. Moreover, histological evaluation exhibited well-preserved and intact fat cells in the MDSC-treated group. In contrast, the control group showed extensive fibrosis and fat graft loss. Furthermore, the MDSC-treated group possessed almost threefold greater capillary density than the control group. We conclude that cotransplantation of muscle-derived stem cells and autologous fat tissue improves the long-term survival of intramuscular fat transplants by promoting neovascularization.

Muscle derived stem cell contains the potential to enhance long term retention as well as an aesthetic outcome of autologous fat grafting.

Autologous fat graft has been mentioned as a prospective source of soft-tissue filler for decades. It gives a natural consistency, is easy and safe to harvest, exhibits no hypersensitivity or foreign body reactions, and is readily available. However, the traditional fat grafting has its limitations in long term process, such as partial necrosis, loss of volume, and internal calcification. They all compromise the functional and aesthetic outcome of this procedure. In recent studies, the best results were obtained by transplanting fat tissue inside muscle, thus benefiting from its better blood supply. Muscle-derived stem cells have recently emerged as a promising source of multipotent cells which give rise to muscle fibers within muscular environment. Previous studies have also proved that muscle-derived stem cells are capable of releasing various kinds of angiogenesis agents, such as VEGF, HGF, and FGF. These cytokines are known to promote revascularization. Based on the foregoing facts, we postulate that co-transplant of autologous fat and muscle derived stem cells may enhance the long term retention and aesthetic outcome of fat grafting.

Medial plantar artery perforator flap for soft-tissue reconstruction of the heel.

Soft-tissue wounds of the foot and especially the heel are challenging problems for reconstructive surgeons. An important principle that guides heel reconstruction is to provide sensate skin with a similar thickness to resurface the weight-bearing heel and avoid late flap ulceration. Among various techniques to achieve this result, the sensate medial plantar perforator flap is an excellent option, which provides durability to friction, a cushioning effect, and sensation. An anatomic study was performed to clarify the anatomy of the cutaneous perforators of the medial plantar artery and to determine the optimal method of medial plantar artery perforator flap harvest. Fifteen cases of heel reconstruction with the sensate medial plantar perforator flap are presented. The outcome of surgery at a mean follow-up of 12 months is reported. The indications for surgery, operative procedures, advantages and disadvantages, and results are presented. Satisfactory results were obtained with a good color and texture match for heel repair and a good sensory recovery. No functional deficit was found at the donor site.