The 27 Facial Sutures: Timing and Clinical Consequences of Closure.

SUMMARY: Facial sutures contribute significantly to postnatal facial development, but their potential role in craniofacial disease is understudied. Since interest in their development and physiology peaked in the mid-twentieth century, facial sutures have not garnered nearly the same clinical research interest as calvarial sutures or cranial base endochondral articulations. In addition to reinforcing the complex structure of the facial skeleton, facial sutures absorb mechanical stress and generally remain patent into and beyond adolescence, as they mediate growth and refine the shape of facial bones. However, premature closure of these sites of postnatal osteogenesis leads to disrupted growth vectors and consequent dysmorphologies. Although abnormality in individual sutures results in isolated facial deformities, we posit that generalized abnormality across multiple sutures may be involved in complex craniofacial conditions such as syndromic craniosynostosis. In this work, the authors comprehensively review 27 key facial sutures, including physiologic maturation and closure, contributions to postnatal facial development, and clinical consequences of premature closure.

Facial Suture Pathology in Syndromic Craniosynostosis: Human and Animal Studies.

BACKGROUND: Facial deformities in syndromic craniosynostosis are not only functionally, psychosocially, and aesthetically impairing but also notoriously challenging to reconstruct. Whether facial suture synostosis plays a significant role in the pathogenesis of these deformities is inadequately studied in human patients. METHODS: The MEDLINE database was queried using a methodologically generated search term inventory. Article inclusion was adjudicated by 2 authors after independent review. Articles provided insight into facial suture involvement in either syndromic craniosynostosis patients or animal models of disease. RESULTS: Comprehensive review yielded 19 relevant articles meeting inclusion criteria. Mid-20th century craniofacial biologists characterized how patent facial sutures are essential for normal postnatal facial development. They also posited that premature ossification disrupts growth vectors, causing significant dysmorphologies. Recently, facial suture synostosis was found to cause midfacial deformities independent of cranial base pathology in mouse models of syndromic craniosynostosis. Few recent studies have begun exploring facial suture involvement in patients, and although they have paved the way for future research, they bear significant limitations. CONCLUSIONS: The hypothesis that facial suture synostosis acts in conjunction with cranial base pathology to produce the prominent, multifocal facial deformities in syndromic craniosynostosis may fundamentally alter surgical management and warrants further investigation. Methodically evaluating the literature, this review synthesizes all basic science and human clinical research thus far on the role of facial sutures in syndromic craniosynostosis and elucidates important topics for future research. We ultimately identify the need for rigorous imaging studies that longitudinally evaluate facial osteology across patients with various craniosynostosis syndromes.

Oral Flora and Perioperative Antimicrobial Interventions in Cleft Palate Surgery: A Review of the Literature.

BACKGROUND: The role of perioperative antibiotics in cleft palate remains a topic of debate. Advocates stress their importance in preventing local and systemic infections and decreasing the incidence of oronasal fistula formation. However, few studies to date have directly evaluated the role of antibiotics and other antimicrobial measures in cleft palate surgery. OBJECTIVE: The aim of this review is to evaluate the evidence surrounding the use of perioperative antibiotics and other antimicrobial interventions in cleft palate surgery. Additionally, we review the literature on the oral flora unique to the cleft palate patient population. METHODS: This was accomplished utilizing PubMed, Medline, and the Cochrane Library with MeSH and generic terms. Articles were selected based on predefined inclusion and exclusion criteria. RESULTS: This review highlights the lack of higher level evidence on perioperative antibiotic use and other antimicrobial interventions in cleft palatoplasty and calls for further research on the matter. CONCLUSIONS: The literature appears to support the use of preoperative antibiotics for cleft palatoplasty, but the benefits of prolonged postoperative antibiotic use remain questionable.

Effect of Cross-Sex Hormone Therapy on Venous Thromboembolism Risk in Male-to-Female Gender-Affirming Surgery.

Individuals with gender dysphoria often seek medical interventions, such as hormone treatment and surgery, to live as their identified gender. Cross-sex hormone therapy typically consists of various estrogen formulations which confer varying risks of venous thromboembolism (VTE). Currently, there is no standard practice by surgeons regarding the preoperative gender-affirming surgery (GAS) hormone regimen of male-to-female (MTF) patients to minimize thromboembolic postoperative complications. The aim of this review is to examine the current literature on VTE occurring in MTF transgender patients on cross-sex hormone therapy (CSHT) when undergoing various gender-affirming surgeries-facial feminization surgery (FFS), top surgery (TS), and bottom surgery (BS)-to understand how evidence-based recommendations regarding perioperative hormone regimens can be established to improve clinical outcomes. Within the past 25 years, 7 published studies have examined the incidence of VTE in MTF patients undergoing GAS procedures. Two of these articles examined MTF patients undergoing FFS, 1 article reported a patient who had undergone BS and FFS during the same hospitalization, and the remaining 4 articles investigated VTE risk in BS. Our review supports that plastic surgeons who perform GAS are divided on their preferred CSHT protocols, with some requiring patients to suspend their CSHT weeks before surgery and others allowing patients to continue CSHT through the day of surgery. Three of the 7 studies detailed a CSHT perioperative regimen which instructed patients to suspend CSHT sometime before surgery; 1 study tapered CSHT to lower levels before surgery; the remaining 3 studies did not specify a CSHT perioperative regimen. This review highlights the paucity of data failing to support that continuing CSHT through GAS elevates VTE risk. We conclude that in the absence of definitive VTE risk factors (e.g., smoking, clotting disorders, or malignancy), surgeons may engage MTF patients in joint decision-making process to determine the most optimal perioperative CSHT management plan on a case-by-case basis. Future studies are warranted to evaluate VTE risk based on patient age, type of surgery, operating time, prophylactic measures, follow-up time, and CSHT perioperative regimens.

Long-Term Orthognathic Considerations in the Pierre Robin Sequence Patient.

BACKGROUND: One of the arguments against early intervention for micrognathia in Pierre Robin sequence is the concept that the growth of the mandible will eventually "catch up." Long-term growth of the mandible and occlusal relationships of conservatively managed Pierre Robin sequence patients remain unknown. In this study, the authors evaluated the orthognathic surgery requirements for Pierre Robin sequence patients at skeletal maturity. METHODS: Orthognathic surgical requirements of conservatively managed Pierre Robin sequence and isolated cleft patients (aged ≥13 years) at two institutions were reviewed and analyzed using t test, chi-square test, and Fisher's exact test. Values of p < 0.05 were considered statistically significant. RESULTS: Of the Pierre Robin sequence patients (n = 64; mean age ± SD, 17.9 ± 2.9 years), 65.6 percent were syndromic (primarily Stickler and velocardiofacial syndrome), 96.9 percent had a cleft palate, and 39.1 percent required orthognathic surgery at skeletal maturity. Nonsyndromic and syndromic Pierre Robin sequence patients demonstrated no differences in occlusal relationships or mandibular surgery frequency. The majority of Pierre Robin sequence patients requiring mandibular advancement had a class II occlusion. Comparison of Pierre Robin sequence patients to isolated cleft palate patients (n = 17) revealed a comparable frequency of orthognathic surgery between the two; however, Pierre Robin sequence patients did require mandibular advancement surgery at a greater frequency than cleft palate patients (p = 0.006). CONCLUSIONS: The present study found that 39.1 percent of conservatively managed Pierre Robin sequence patients required orthognathic surgery at skeletal maturity, of which the vast majority required mandibular advancement for class II malocclusion. These data suggest that mandibular micrognathia in conservatively managed Pierre Robin sequence patients may not resolve over time and may require surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Virtual Surgical Planning for Mandibular Reconstruction With the Fibula Free Flap: A Systematic Review and Meta-analysis.

BACKGROUND: The fibula free flap (FFF) remains the criterion standard for complex mandibular reconstruction. Surgeons have incorporated virtual surgical planning (VSP) into the reconstructive algorithm with the assertion that VSP increases operative efficiency and may improve clinical outcomes. To date, no large-scale studies have analyzed these claims. This study examines the literature and tests the hypothesis that VSP improves operative efficiency, clinical outcomes, and accuracy when compared with traditional techniques. METHODS: A systematic review was performed to identify articles utilizing VSP and traditional techniques for FFF-based mandibular reconstruction. Two reviewers independently assessed all articles for methodological quality using a validated instrument (weighted Cohen κ for interrater reliability = 0.70). Outcomes included operative time, length of stay, complications, and accuracy. Meta-analytic comparisons were performed using data from comparative studies using a random-effects model and differences of means analysis for outcomes measured on identical scales. RESULTS: One hundred thirty-one articles were identified, and 25 met the inclusion criteria: 12 were VSP only, whereas 13 were comparative. There were 241 VSP patients and 214 traditional patients available for meta-analysis. Patients undergoing reconstruction with VSP had a significant reduction in operative time by 44.64 minutes (95% confidence interval [CI], -74.69 to -14.58 minutes; P < 0.01) and demonstrated a mean trend toward shorter hospital admission (mean difference, -1.24 days; 95% CI, -4.00 to 1.52 days; P = 0.38). There was no statistical difference between cohorts for major (odds ratio, 1.03; 95% CI, 0.46-2.31; P = 0.95) or minor complications (odds ratio, 0.97; 95% CI, 0.54-1.71; P = 0.90). Insufficient data were available for cost analysis and accuracy. CONCLUSIONS: Virtual surgical planning-guided mandibular reconstruction with FFF is associated with significantly decreased operative time and a mean trend toward shorter hospital admission. While multiple studies reported a high degree of accuracy, no standard measurement was available for meta-analysis.

Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells.

Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein.