Comparison of post-surgical soft tissue changes between bilateral cleft patients treated with and without a modified nasoalveolar molding appliance: A cohort study.

INTRODUCTION: The advantages of nasoalveolar molding (NAM) treatment for cleft lip and palate (CLP) patients have been well documented. A modified design for bilateral CLP was introduced. AIMS: This paper aimed to: 1- quantify the soft tissue changes after applying modified NAM treatment to these patients; and 2-compare post-surgical changes to a control group where no NAM was used. MATERIAL AND METHODS: At a tertiary care paediatric hospital, a historical cohort group of complete BCLP patients (n=15) was compared to a prospectively collected group of complete BCLP patients who underwent NAM therapy (n=15). In the NAM group (mean age: 1.1mos±0.2), a new modification of the NAM appliance was implemented. In the control group (mean age: 5mos±0.2), no NAM treatment was adopted prior to lip closure surgery. Soft tissue nasolabial segments were measured on initial (T1), post-NAM (T2) and 3 months post-surgery (T3) photographs; measurements were analysed statistically. RESULTS: In the NAM group, cleft size was reduced by 68 to 70% in 4-5months and all measurements improved between T1 and T2. Columellar crest inclination decreased by 74%, columellar length increased by 184%, nostril and bialar widths decreased by 36% and 16%, respectively. The lip philtrum was elongated by 49.5%. At T3, all soft tissue variables statistically improved better in NAM versus non-NAM groups. CONCLUSION: The modified NAM appliance provided improved results of lip approximation and nasal measurements compared to non-NAM treatment.

Three-dimensional surgical management of a patient with Pruzansky I hemifacial microsomia and severe facial asymmetry: A 4-year follow-up.

Treatment of hemifacial microsomia is challenging and often requires multiple interventions to restore function and facial esthetics. In this article, the combined orthodontic-surgical treatment of a young patient exhibiting Pruzansky I hemifacial microsomia is reported. The patient was aged 15 years, but his bone age was determined to be 18 years. His facial asymmetry was severe, with the nose and a retrusive chin deviated to the left side and a canted smile. The presurgical phase was aimed at centering the mandibular midline to the center of the chin through the distal movement of the mandibular left buccal dentition. The surgery was planned with 3-dimensional computer-aided surgical simulation and included a LeFort I and unilateral sagittal split osteotomies combined with a genioplasty. This report illustrates the therapeutic stages and a 4-year follow-up of a unique and complex orthognathic surgical approach, chosen among other alternatives and leading to improved function and appearance and stable results.

Dysregulation of Rho GTPases in orofacial cleft patients-derived primary cells leads to impaired cell migration, a potential cause of cleft/lip palate development.

Cleft lip and/or palate are a split in the lip, the palate or both. This results from the inability of lip buds and palatal shelves to properly migrate and assemble during embryogenesis. By extracting primary cells from a cleft patient, we aimed at offering a better understanding of the signaling mechanisms and interacting molecules involved in the lip and palate formation and fusion. With Rho GTPases being indirectly associated with cleft occurrence, we investigated the role of the latter in both. First, whole exome sequencing was conducted in a patient with cleft lip and palate. Primary fibroblastic cells originating from the upper right gingiva region were extracted and distinct cellular populations from two individuals were obtained: a control with no cleft phenotype and a patient with a cleft lip and palate. The genetic data showed three candidate variables in ARHGEF18, EPDR1, and CUL7. Next, the molecular data showed no significant change in proliferation rates between healthy patient cells and CL/P patient cells. However, CL/P patient cells showed decreased migration, increased adhesion and presented with a more elongated phenotype. Additionally, RhoA activity was upregulated in these cells, whereas Cdc42 activity was downregulated, resulting in loss of polarity. Our results are suggestive of a possible correlation between a dysregulation of Rho GTPases and the observed phenotype of cleft lip and palate patient cells. This insight into the intramolecular aspect of this disorder helps link the genetic defect with the observed phenotype and offers a possible mechanism by which CL/P occurs.

Altered regulation of cell migration in IRF6-mutated orofacial cleft patients-derived primary cells reveals a novel role of Rho GTPases in cleft/lip palate development.

Orofacial clefts are the most common congenital craniofacial birth defects. They occur from a failure in cell proliferation and fusion of neural crest cells of the lip buds and/or palatal shelves. In this study, we investigate the genetic basis and molecular mechanisms in primary cells derived from a cleft and lip palate patient presenting van der Woude syndrome (VWS). Since mutations in the integrin genes are widely correlated with VWS, Interferon Regulatory Factor 6 (IRF6) screening was conducted in a cohort of 200 participants presenting with orofacial anomalies. Primary fibroblastic cells derived from the upper right gingiva and palatal regions were isolated and two cellular populations from two participants were obtained: a control with no cleft phenotype and a patient with a cleft phenotype typical of van der Woude syndrome (VWS). IRF6 targeted sequencing revealed mutations in two distinct families. Our results showed no alteration in the viability of the CLP/VWS patient cells, suggesting the phenotype associate with the disease is not secondary to a defect in cell proliferation. We did however detect a significant decrease in the migratory ability of the CLP with Van der Woude syndrome (CLP/VWS) patient cells, which could account for the phenotype. When compared to normal cells, patient cells showed a lack of polarization, which would account for their lack of mobility. Patient cells showed protrusions all around the cells and a lack of defined leading edge. This was reflected with actin staining, WAVE2 and Arp2 around the cell, and correlated with an increase in Rac1 activation. Consistently with the increase in Rac1 activation, patient cells showed a loss in the maturation of focal adhesions needed for contractility, which also accounts for the lack in cell migration. Our findings give increased understanding of the molecular mechanisms of VWS and expands the knowledge of van der Woude syndrome (VWS) occurrence by providing a strong molecular evidence that CLP with Van der Woude syndrome (CLP/VWS) phenotype is caused by a defect in normal physiological processes of cells.

Unilateral sagittal split osteotomy: effect on mandibular symmetry in the treatment of class III with laterognathia.

The bilateral sagittal split osteotomy is considered the standard surgery to correct facial asymmetries. More recently, unilateral sagittal split osteotomy (USSO) was used to treat such malocclusions. AIM: To assess facial symmetry following USSO in the treatment of class III laterognathia. METHODS: Frontal facial photographs of four groups of patients were assessed: (1) pre-surgical group (n = 30) with skeletal asymmetry, (2) postsurgical group assessing patients of the first group 2 years after USSO, (3) control group (n = 30) of patients judged to have harmonious facial norms, and (4) mirrored group (n = 30) in which the control photographs were altered by duplicating the right half side of the face to replace the left half, thus creating perfectly symmetrical faces. All 120 photographs were distributed to 40 expert orthodontists to evaluate and score facial symmetry using the visual analog scale. Skin sensitivity and temporomandibular joint (TMJ) disorders were also assessed clinically pre and postsurgically. RESULTS: Statistically significant differences were observed between the pre-surgical group and each of the postsurgical and control groups (p < 0.001). The control and postsurgical groups received similar scores of symmetry (p = 0.774). The mirrored group received statistically significantly higher symmetry scores than either of the control or the postsurgical groups (p < 0.001). A reduction in TMJ disorders was noted after USSO and all patients reported normal skin sensation 2 years post-surgery. CONCLUSION: When indicated, USSO is a dependable and practical surgical approach to correct facial asymmetries associated with class III malocclusion.

Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review.

BACKGROUND: Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. CASE PRESENTATION: Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. CONCLUSION: Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.