Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS).

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

Relationship Between the Quantity of Nerve Exposure During Bilateral Sagittal Split Osteotomy Surgery and Sensitive Recovery.

AIM AND OBJECTIVES: The purpose of this study was to evaluate how different exposures of the V3 nerves during orthognathic surgery impact neurosensory disturbances. METHODS: The study included 127 patients who underwent either bilateral sagittal split osteotomy (BSSO) or BSSO with maxillary le Fort 1. They were divided into 6 groups, identified by the quantity of V3 nerve exposure. All patients were examined in a pre-op period and again after 1, 3, 6 months post-op. The standardized tests used were to clarify the objective and subjective neurosensory status of the exposed nerve. Neurosensory evaluation included; a pin prick test, the 2 points discriminator, light touch, warm and cold tests, and blunt discrimination. They were all done bilaterally on the lower lip area. RESULTS: In only 2 patients the nerve was damaged during surgery and thus they were not included in this study. In 10.2% of patients there was no nerve exposure, 25.2% had longitudinal vestibular segment nerve exposed, 22.8% had the longitudinal upper-vestibular segment exposed, 20.5% had the longitudinal lower-vestibular segment exposed, 14.2% had the longitudinal upper-lower-vestibular segment exposed, and in 7.1% of patients the nerve was totally exposed. Given the estimated time of 1 month there was 100% recovery in patients whose nerve was unexposed. Considering the other patients, the authors had a variable number of patients who did not recover completely. CONCLUSION: The authors estimate a correlation between the recovery time and the quantity of the exposed nerve. There is a high incidence of neurosensory disturbance in the lower lip and chin after BSSO and intraoperative quantity of nerve exposure.

A de novo proximal 3q29 chromosome microduplication in a patient with oculo auriculo vertebral spectrum.

Oculo auriculo vertebral spectrum (OAVS; OMIM 164210) is a clinically and genetically heterogeneous disorder originating from an abnormal development of the first and second branchial arches. Main clinical characteristics include defects of the aural, oral, mandibular, and vertebral development. Anomalies of the cardiac, pulmonary, renal, skeletal, and central nervous systems have also been described. We report on a 25-year-old male showing a spectrum of clinical manifestations fitting the OAVS diagnosis: hemifacial microsomia, asymmetric mandibular hypoplasia, preauricular pits and tags, unilateral absence of the auditory meatus, dysgenesis of the inner ear and unilateral microphthalmia. A SNP-array analysis identified a de novo previously unreported microduplication spanning 723 Kb on chromosome 3q29. This rearrangement was proximal to the 3q29 microdeletion/microduplication syndrome region, and encompassed nine genes including ATP13A3 and XXYLT1, which are involved in the organogenesis and regulation of the Notch pathway, respectively. The present observation further expands the spectrum of genomic rearrangements associated to OAVS, underlying the value of array-based studies in patients manifesting OAVS features.

Endoscopic endonasal versus transfacial approach for blowout fractures of the medial orbital wall.

In the last decades, the introduction of computed tomography has allowed an increase in the number of diagnosed fractures of the medial orbital wall. To repair medial wall fractures, many surgical techniques have been proposed (1), each one with its advantages and disadvantages. In this study, we compared endoscopic endonasal and transcutaneous reduction approaches in terms of surgery time and clinical outcome. Between 2001 and 2005, 81 patients with orbital wall fractures were treated at our department. Among these 81 patients, 24 (29.63%) were affected by a medial orbital fracture. Patients with fracture to both floor and medial walls underwent floor reduction by a transcutaneous subpalpebral approach (n = 9, 11.1%), whereas patients with isolated medial wall fracture underwent medial wall reduction by a transcutaneous subpalpebral approach using alloplastic implants (n = 8, 9.88%) or were treated by endoscopic approach (n = 5, 6.17%). After surgery, oculomotor function improved in all 22 patients. None of the patients had complications. Computed tomography revealed a well-consolidated site of fracture in both endoscopic endonasal and transcutaneous approaches. The average operating time for endoscopic endonasal and transfacial approach was 50 and 45 minutes, respectively. In this paper, the author proposed a results comparison between the endoscopic approach and the transcutaneous one.

Transoral endoscopic resection of low-grade, cricoid chondrosarcoma : endoscopic management of a series of seven patients with low-grade cricoid chondrosarcoma.

BACKGROUND: Low-grade chondrosarcomas account for 1 % of all laryngeal tumors and typically arise in the cricoid cartilage. They are usually indolent, slow-growing cancers that are locally invasive and rarely metastasize. Surgical excision is considered the treatment of choice. Radiotherapy and chemotherapy generally are ineffective. Surgical management must balance tumor clearance with preservation of laryngeal functions (swallowing, voice, and respiration). METHODS: Prospective outcome analysis of seven patients operated with endoscopic resection for low grade cricoid chondrosarcomas. RESULTS: Mean age at presentation was 61 years (range 49-75), male:female ratio was 4:3. All patients are currently alive and free of disease with an average follow-up of 80 months (range 63-138). Overall 5-year survival is 100 %, 5-year disease-free survival rate 85.7 %, and overall recurrence rates 14.3 %. One of the seven patients developed a limited recurrence at 21 months and underwent a second endoscopic resection. During initial management two patients needed temporary tracheotomy. Successful decannulation and normal breathing were obtained within 3 months with no long-term sequelae. The airway calibre of the remaining patients was minimally affected. All patients have normal postoperative swallowing function and adequate voice that is unassisted by amplification. CONCLUSIONS: These findings support the use of endoscopic resection for managing selected newly diagnosed cases of cricoid chondrosarcoma as well as the role of repeated endoscopic resection for managing cases of recurrent cricoid chondrosarcoma.

Mandibular subluxation as an adjunct in very distal carotid arterial reconstruction: incidence of peripheral and cerebral neurologic sequelae in a single-center experience.

BACKGROUND: The location of the carotid bifurcation and a very distal extension of internal carotid atherosclerotic disease may challenge vascular surgeons performing carotid endarterectomy (CEA) by increasing technical difficulty and possibly the incidence of cranial nerve damage or palsies. The objective of the present study is to report on the safety of CEA with mandibular subluxation (MS) and to compare results of CEA in 2 groups of patients treated by standard CEA or by MS-CEA according to rates of major neurologic complications, death, and the occurrence of postoperative peripheral nerve palsy. METHODS: Between July 2000 and June 2012, 1,357 CEAs were performed. MS was additionally used in 43 patients. Only patients with primary atherosclerotic internal carotid artery (ICA) lesions in the 2 groups (38 in the MS-CEA group and 1,289 in the standard CEA group) were considered for comparative analysis. RESULTS: MS-CEA patients were more frequently male (P = 0.03), presented more frequently with symptomatic lesions (P = 0.007), longer lesions (P = 0.01), and had common ICA bypass implantation (P = 0.02). Mean follow-up was 68.75 ± 37.87 months (range: 1-144 months). No perioperative neurologic mortality and no prolonged discomfort related to MS was recorded. The overall neurologic morbidity rate (major stroke/minor stroke/transient ischemic attach) was comparable in the 2 groups (P = 0.78). The overall immediate peripheral nerve injury rate was 7.89% in the MS-CEA group and 5.27% in the standard CEA group (P = 0.73). Three cases of permanent dysphonia in the standard CEA group (0.23%) and 1 case of dysphagia in the MS-CEA group (2.63%) were reported at follow-up (P = 0.24). CONCLUSIONS: MS-CEA can be a very useful technical adjunct for high-located carotid bifurcations or challenging carotid lesions, with an overall risk comparable to that of standard CEA.

Giant palatal schwannoma.

Schwannoma is a benign tumor that arises from nerves that contain Schwann cells. We report a case of giant schwannoma of the hard palate, which originated from the greater palatine nerve and is interesting for its large dimensions.

LEOPARD syndrome: maxillofacial care.

This article reports a case of a boy with LEOPARD syndrome with unusual mandibular osteolytic osteoclastic-like lesions and eruption disorder. The patient was referred to our department for bilateral facial swelling: systemic examinations, diagnosis, and dental and maxillofacial care are reported.

Management of a bulky capillary hemangioma in the parapharyngeal space with minimally invasive surgery.

In this article, the authors report their management with minimally invasive surgery of a bulky capillary hemangioma in the parapharyngeal space. Parapharyngeal space capillary hemangioma is a rare tumor in adults. Because of its rarity and difficulty to treat, we suggest a multidisciplinary approach in choosing the best treatment, with an accurate follow-up.

Temporomandibular synovial chondromatosis with numerous nodules.

Synovial chondromatosis of the temporomandibular joint is an uncommon disorder with an indolent clinical course and a slow progression. We report a rare case of unilateral early synovial chondromatosis of the temporomandibular joint with numerous nodules and discuss possible etiologies for the entity of loose bodies and the evolution of this disease.

Orthognathic surgery for correction of patients with mandibular excess: don't forget to assess the gonial angle.

PURPOSE: To evaluate the gonial angle (GA) and associated factors that can contribute to stability after bilateral sagittal split ramus osteotomy setback and Le Fort I advancement osteotomy for the treatment of patients with mandibular excess. MATERIALS AND METHODS: This retrospective study included 42 randomly selected, adult patients. Lateral cephalometric radiographs were obtained before and 1 week and 1 year after surgery. Patients in group 1 (n = 18) had a GA smaller than 125° and those in group 2 (n = 24) had a GA larger than 125°. Data were analyzed by analysis of variance and Pearson correlations. Multivariate linear regression analysis was used to identify factors that influenced postsurgical stability. RESULTS: Mean surgical changes were similar in the 2 groups. The mandible was set back an average of 5.4 mm in group 1 and 6.4 mm in group 2, whereas the maxilla was advanced 2.5 mm in group 1 and 1.7 mm in group 2. Statistically significant postoperative changes were noted for group 1 only. Relapse was found at the innermost point of the contour of the mandible between the incisor tooth and bony chin and the pogonion for the horizontal landmarks; the innermost point of the contour of the maxilla between the anterior nasal spine and incisor tooth and the menton for the vertical landmarks; and the GA, the angle between the sella-nasion line and the innermost point of the contour of the mandible between the incisor tooth and bony chin, and the esthetic plane to the upper lip for the dimensional landmarks. No statistically significant changes were noted for group 2 (GA >125°). CONCLUSION: Patients with a preoperative GA smaller than 125° have a greater risk of relapse after receiving bilateral sagittal split ramus osteotomy setback and Le Fort I advancement for the treatment of mandibular excess. Patients with a preoperative GA larger than 125° appear to have a more predictable procedure.

Mini-invasive lateral oropharyngectomy for T3-T4a oropharyngeal cancer.

Mandibular swing is the approach of choice for resection of advanced oropharyngeal carcinomas without bone involvement. This approach requires a mandibulotomy, which is associated with complications. A prospective outcome analysis was performed for 21 patients operated without mandibulotomy for T3-T4a oropharyngeal carcinoma. Tumour size was categorized as T3 in 14 patients (66.7 %) and as T4a (33.3 %) in 7 patients. Twelve patients were N0 (57.1 %), 2 (9.5 %) were N1, and 7 (33.3 %) were N2. Surgical margins were negative in 18 cases (85.7 %), positive in 1 (4.8 %), and close in 2 (9.5 %). Average hospital stay was 14.5 days (range 10-22). Adjuvant treatment (radiotherapy or concurrent chemoradiotherapy) was administered to all but three patients previously irradiated. In all cases radiotherapy started within 42 days of surgery. The 3-year overall survival was 85.7 %, and relapse-free survival was 71.4 %. Oropharyngectomy without mandibulotomy has the same indications as mandibular swing. It provides good access to achieve satisfactory clearance of tumours, sparing patients the morbidity associated with mandibulotomy.

Juvenile idiopathic/rheumatoid arthritis and orthognatic surgery without mandibular osteotomies in the remittent phase.

BACKGROUND: Orthognathic treatment of patients with juvenile idiopathic/rheumatoid arthritis is still controversial. Mandibular procedures may result in relapse and further condylar resorption and pain. Maxillary osteotomies and genioplasty may be effective for the correction of malocclusion and for aesthetics. PATIENTS AND METHODS: Five patients with juvenile idiopathic/rheumatoid arthritis with severe temporomandibular joint (TMJ) involvement underwent orthognathic surgery with a simultaneous Le Fort I osteotomy and advancement genioplasty. The age of the patients at the time of surgery ranged between 17 and 29 years (mean, 21.75 years). The patients were under follow-up for a minimum of 8 months after surgery, and measurements were performed using Dolphin 3D imaging. RESULTS: All 5 patients have an improved occlusion and improved facial aesthetics. The mean mandible rotation advancement was 5.6 mm (range, 4 to 7 mm). The mean posteroanterior face height ratio (S-Go/N-Me) after surgery was 63.9 (range, 62.9 to 65.8). No exacerbation of the juvenile rheumatoid arthritis was encountered as a result of the surgical procedure. CONCLUSIONS: Le Fort I osteotomy with impaction and advancement genioplasty are effective procedures for occlusal and aesthetic correction of juvenile idiopathic/rheumatoid patients. Mandibular procedures may evoke further condylar resorption with pain and functional impairment of the TMJ.

Surgical management of enophthalmos in Duane syndrome.

Duane syndrome is a congenital disorder of eye movement characterized by partial or absent development of the sixth cranial nerve nucleus and/or the sixth nerve itself. Patients often undergo procedures, both surgical and nonsurgical, to correct ocular misalignment and improve the resulting visual problems. We present a case report of a 49-year-old woman with left-sided Duane syndrome who underwent aesthetic surgical correction of enophthalmos.

Postsurgical predictive theoretical thickness (PTT) of frontal sinus anterior wall as key point in surgical management of frontal bossing: proposal of a new analytic method.

BACKGROUND: Frontal bossing is a malformation characterized by peculiar prominent forehead, and commonly it can be associated with cranial synostosis and endocrine disorder; however, nonsyndromic conditions are described as well.Literature controversies on proper frontal bossing surgical treatment showed evidence of 2 main surgical procedures: frontal bone reshaping and bone en bloc mobilization.A decision-making criterion between these 2 techniques has never been described in literature. METHODS: In this paper, the authors introduce their brand-new analytic method for decision-making between bur shaping and en bloc mobilization in frontal bossing treatment, and describe a successful case of a nonsyndromic frontal bossing patient, treated with their unconventional surgical technique. RESULTS: Our analytic method indicated that bur shaping was not indicated in this particular case: aggressive remodeling of excessive thin wall could lead to sinus perforation, which could turn into unsatisfied aesthetic and functional outcome.So we planned for a bilateral orbitofrontal en bloc reposition, followed by internal rigid fixation. No postoperative complications occurred. Postoperative CT scan revealed good bone repositioning and recovery. CONCLUSIONS: The authors explained their analytic method based on careful presurgical CT-scan measurements for decision-making between bur shaping and en bloc mobilization.

Complications of orbital floor repair with silastic sheet: the skin fistula.

Treatment of orbital floor fracture is a subject of great interest in maxillofacial surgery. Many materials have been described for its reconstruction.In this article, the authors report a case of a patient who, 7 years from a previous orbital floor fracture and treatment with silastic sheet, presented herself to their clinic for the failure of the material used for its reconstruction and a skin fistula.Orbital floor repair with silastic sheet is an old method that no one uses anymore, but we still observe cases of late complications with this material. So a fine knowledge of silastic sheet complications is needed for young surgeons.The authors report the case and perform a literature review about the use of more modern biomaterials for orbital floor reconstruction.

Compression and stretching in Graves orbitopathy: emergency orbital decompression techniques.

Visual loss from orbital compression and stretching of the optic nerve is an infrequent but well-recognized cause of dysthyroid optic neuropathy, occurring in less than 5% of thyroid eye disease cases. Another important but less recognized cause of vision loss due to thyroid-associated optic neuropathy is protracted stretching of the optic nerve. Of the reported cases of compression and stretch optic neuropathy, none have documented the rate of vision loss due to continuous stretching of the optic nerve.

Neuropeptide expression and T-lymphocyte recruitment in facial nucleus after facial nerve axotomy.

Axonal injury in the peripheral nervous system can have a strong impact on the neurons and the surrounding non-neuronals cells. The aim of this study was to evaluate the immunohistochemistry signals of the vasoactive intestinal peptide (VIP), substance P (SP), and CD3+ T cells and the messenger RNA levels of neuropeptides in the facial nucleus (FN) at 7, 14, and 21 days after peripheral facial nerve axotomy. Moreover, the authors assayed the peripheral blood levels of interleukin (IL-1ß), tumor necrosis factor-α, and IL-6 serum levels at 24 and 48 hours after the surgical procedures. Immunohistochemistry analysis revealed that VIP and SP expression is strongly induced in FN after peripheral facial nerve axotomy at 7 days, the CD3+ pan-T cells peak at 14 days. Polymerase chain reaction analysis for VIP and SP messenger RNA levels confirms the immunohistochemical data, but VIP level remains significantly high for 14 days. The serum level of IL-6 48 hours after axotomy was significantly higher than after 24 hours; there were no significant changes for IL-1ß and tumor necrosis factor-α serum levels between 24 and 48 hours. Our data reveal that FN neurons are under neuropeptidergic influence and show that modulation/modification of VIP and SP expression in FN injury models facilitates the crossing of the blood-brain barrier. On the contrary, our results emphasize the role of the T cells in preventing initial neurodegeneration or neuronal death. The high serum levels of IL-6 at 1 to 2 days suggest that this cytokine could play a central role in the initiation of immunosurveillance and provide advance information on the recruitment of CD3+ T lymphocytes in the FN.

Le Fort III external midface distraction: surgical outcomes and skeletal stability.

A retrospective study on the stability of Le Fort III midface advancement with distraction in craniofacial dysostosis. Twenty-six surgical procedures for midface advancement were performed between 2000 and 2009. Subjects were 14 consecutive patients who underwent Le Fort III osteotomy with midface advancement using a rigid external distraction device (Synthes) in the Dep of Maxillo-Facial Surgery of the University "Sapienza" of Rome. In this study, 8 patients (n = 3 females, n = 5 males) affected by craniofacial dysostosis (Crouzon, n = 5; Apert, n = 3; Pfeiffer syndrome, n = 1; and other, n = 1) were selected on the basis of age and radiologic documentation. The mean age at the time of the procedure was 8.6 years, and all the patients had at least 1 year of follow-up after distraction.The radiologic documentation of each case was composed of posteroanterior and lateral cephalograms preoperatively (T1), at the time of removal of the distractor device (T2), and at follow-up (T3).The average latency period before activation of the distractor was 5 days. The device was activated on an average of 15 mm (range, 7-22 mm) as recorded on the device at a rate of 1 mm/d. Activation period ranged from 7 to 15 days, and the consolidation period was 8 to 12 weeks.Seven anatomic landmarks and 5 cephalometric measurements were identified on the lateral cephalograms at each of the 3 time periods. The cephalograms underwent digital analysis via Dolphin imaging digitalization software by 2 operators independently. The displacement of each identified landmark was recorded and examined in relation to their position at each time point.Cephalometric analysis revealed stability of Le Fort III midface advancement during follow-up. However, bone growth after midface advancement is limited, and as reported in the literature, almost no spontaneous growth is present because of the intrinsic nature of malformations. Patients treated in the growing age benefit from midface advancement, with resolution of exophthalmos, ocular bulb exposure, airway impairment, and good aesthetic outcome.