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.

A Procedure for Designing Custom-Made Implants for Forehead Augmentation in People Suffering from Apert Syndrome.

This paper presents a methodological procedure, based on the anatomical reconstruction and constrained deformation, to design custom-made implants for forehead augmentation in people affected by Apert syndrome, experiencing a frontal bone deficiency. According to the anthropometric theory, a cranial landmarks identification procedure was applied to retrieve, from a repository, a healthy skull, used as reference geometry for implant modelling. Then, using constrained deformation and free-form modelling techniques, it was possible to design a patient-specific implant. At last, the implant was realised using a custom mould, specially designed according to the patient's needs to provide an accurate fit of the defect site. The design procedure was tested on a patient suffering from Apert syndrome. Three implants were virtually modelled and 3D-printed for pre-surgical evaluation. Their shapes were 3D compared with a reference one (handcrafted by a surgeon) to test the accuracy. Deviations are negligible, and the customised implant fulfilled the surgeon's requirements.

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.

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.

Treatment strategies and long-term outcomes in patients with congenital microphthalmia-anophthalmia with cyst.

BACKGROUND/AIMS: Microphthalmia and anophthalmia are rare conditions, which represent ocular maldevelopment; both may be associated with orbital cysts. Current literature recommends retention to stimulate orbital growth during socket rehabilitation but does not illustrate their potential to deform the periocular tissues. This study aims to illustrate the long-term outcomes when other elements, such as forniceal and lid development, are also considered when formulating bespoke treatment plans for patients. METHODS: Retrospective case series of 78 patients attending a single prosthetics clinic between 1988 and 2020. Clinical and surgical notes, radiological imaging, clinical photographs and patient/doctor satisfaction questionnaires were used to report patient outcomes and natural history data. RESULTS: 89 sockets of 78 patients (11 bilateral) were included; average age of presentation being 2.8 years (9 days to 29.5 years). Cysts were clinically detected (48%) or were incidental findings (52%). The mean follow-up time was 7.2 years (6 months to 28 years). Cysts in 46% of sockets underwent surgical excision while the remainder were retained. Satisfaction surveys were obtained for 75 patients, with cosmetic outcomes rated as 'excellent' or 'good' in 90% of cases by physicians and 97% of cases by patients or guardians. CONCLUSION: The favourable long-term outcomes in this study have resulted from bespoke plans which considered periocular tissue development, regional orbital growth and orbital volume replacement. The authors contemplate cyst excision if the prosthetic fitting or retention is impeded by the cyst as this often heralds the increased risk of long-term periocular distortion.

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.

Lipostructure in Parry-Romberg disease.

Parry-Romberg syndrome is a disease characterized by progressive hemifacial atrophy. Multiple surgical procedures have been used to improve the facial volume and contours of patients with this disease, including alloplastic, silicone, or collagen implants; lipofilling; and pedicled or free-flap transplants. The present case describes the successful application of lipostructure to treat a woman with Parry-Romberg syndrome affecting the left side of her face.

Orbital volume and surface after Le Fort III advancement in syndromic craniosynostosis.

There are no quantitative standards for the volumetric measurements of the orbital cavity after Le Fort III advancement. Computed tomography (CT) scan images have given the opportunity to compare with accuracy the real anatomic changes and potentially the functional improvements that resulted after a surgical treatment.Three-dimensional CT scan images processed by DICOM files in Dolphin 3D Software were used to assess orbital volume and surface in 12 subjects affected by craniofacial syndromic malformations treated with Le Fort III advancement. The preoperative (T0) and postoperative (T1: 6 months after surgery) three-dimensional craniofacial CT scans of the subjects were collected and retrospectively analyzed. Image segmentation of the anatomic orbital cavity and the three-dimensional graphic rendering were done by using the Dolphin Imaging Plus 11.0 software.The orbital volume was increased after surgery, with statistical significance, from 22,267 to 22,706.3 mm(3) in the right eye and from 26,511 mm(3) to 26,256.4 mm(3) in the left eye. The surface of both bony orbits had an expansion, which is statistically significant. In conclusion, this study showed that the orbital advancement in white subjects after Le Fort III advancement was significant and produced a significant augmentation of the orbital volume and surface area with correction of the ocular bulb proptosis.

Condylar volume and surface in Caucasian young adult subjects.

BACKGROUND: There have been no quantitative standards for volumetric and surface measurements of the mandibular condyle in Caucasian population. However, the recently developed cone-beam computed tomography (CBCT) system allows measurement of these parameters with high accuracy. METHODS: CBCT was used to measure the condylar volume, surface and the volume to surface ratio, called the Morphometric Index (MI), of 300 temporo-mandibular joints (TMJ) in 150 Caucasian young adult subjects, with varied malocclusions, without pain or dysfunction of TMJs. RESULTS: The condylar volume was 691.26 ± 54.52 mm3 in males and 669.65 ± 58.80 mm3 in, and was significantly higher (p< 0.001) in the males. The same was observed for the condylar surface, although without statistical significance (406.02 ± 55.22 mm2 in males and 394.77 ± 60.73 mm2 in females).Furthermore, the condylar volume (693.61 ± 62.82 mm3 ) in the right TMJ was significantly higher than in the left (666.99 ± 48.67 mm3, p < 0.001) as was the condylar surface (411.24 ± 57.99 mm2 in the right TMJ and 389.41 ± 56.63 mm2 in the left TMJ; t = 3.29; p < 0.01). The MI is 1.72 ± 0.17 for the whole sample, with no significant difference between males and females or the right and left sides. CONCLUSION: These data from temporomandibular joints of patients without pain or clinical dysfunction might serve as examples of normal TMJ's in the general population not seeking orthodontic care.

Bilateral orbital roof fracture.

Bilateral orbital roof fractures are rare events usually associated with high-energy impact trauma. The clinical picture is often multiple because of involvement of cranial, cerebral, and facial injuries. The primary diagnostic and therapeutic approaches aim to safeguard the cerebral state and to intercept the consequences of severe orbital trauma. The latter may present dramatic events and determine permanent ocular bulb or optic nerve damage, even vision impairment and blindness. Immediate intraorbital decompression decreases the pressure exerting directly or indirectly on the optic nerve. Surgical decompression of the orbit was performed in a young man showing almost complete blindness after bilateral orbital roof fracture. The final result showed good recovery of vision and functional motility of the bulbs.

Three-dimensional temporomandibular joint modeling and animation.

The three-dimensional (3D) temporomandibular joint (TMJ) model derives from a study of the cranium by 3D virtual reality and mandibular function animation. The starting point of the project is high-fidelity digital acquisition of a human dry skull. The cooperation between the maxillofacial surgeon and the cartoonist enables the reconstruction of the fibroconnective components of the TMJ that are the keystone for comprehension of the anatomic and functional features of the mandible. The skeletal model is customized with the apposition of the temporomandibular ligament, the articular disk, the retrodiskal tissue, and the medial and the lateral ligament of the disk. The simulation of TMJ movement is the result of the integration of up-to-date data on the biomechanical restrictions. The 3D TMJ model is an easy-to-use application that may be run on a personal computer for the study of the TMJ and its biomechanics.

Retrospective analysis of 301 patients with orbital floor fracture.

The purpose of this study was to retrospectively analyse patients with orbital floor fracture who were treated at the Department of Odontostomatology and Maxillofacial Surgery, Policlinico Umberto I, Sapienza University of Rome, Italy, between 2008 and 2013. Patients were evaluated by age, sex, aetiology, clinical findings, fracture pattern, ocular injury, treatment, complications, and sequelae. We evaluated surgical outcomes and complications with the use of different surgical approaches and various materials used to reconstruct the orbital floor. In total, there were 301 orbital fractures. Two hundred and seventeen patients were men (72.1%) and 84 were women (27.9%). The average age of the patients was 37.2 years (range, 9-90 years). The leading cause of these fractures was violent assault (27.3%). Pure blow-out fractures (50.2%) were the most represented pattern, followed by zygomatic complex (46.5%). The most common symptom was hypoesthesia extending through the territory of the second trigeminal branch (TBH; 32.9%). Diplopia was present in 20.2% of patients followed by enophthalmos (2.3%) and extraocular movement limitation (1.7%). Ocular symptoms significantly improved following surgical repair. The most common postoperative complications included TBH in 34.2%, scarring 26%, and diplopia in 16.4% of the patients.

Contralateral botulinum injections in patients with residual facial asymmetry and contralateral hyperkinesis after primary facial palsy surgery.

AIM: In patient with facial paralysis, facial appearance and muscular ability are impaired, and the psychological integrity is affected. Botulinum toxin A may be used to improve facial symmetry in patients suffering with facial palsy reducing the progressive contralateral hyperkinesis and facial asymmetry after primary surgery for facial paralysis. MATERIAL OF STUDY: Six patients, whom have been suffering unilateral facial palsy with an House-Brackmann score grade from III to VI, were included in this study for a residual facial asymmetry and contralateral hyperkinesis after previous facial reanimation. They were treated with 50 units of botulinum toxin type A injected in muscles of the unaffected side of face to improve muscular ability and facial symmetry. RESULTS: This study demonstrated reduction in contralateral hyperkinesis and facial asymmetry that lasted approximately 120 days. All patients reported satisfactory results with the treatment. COMMENTS: Botulinum toxin type A injections improved facial asymmetry and muscular function in all patients. DISCUSSION AND COMMENTS: Botulinum toxin type A injections may be an indispensable technique as a nonsurgical treatment or as a complementary measure in postsurgical treatments and should be certainly considered for temporary or permanent asymmetries in patients who suffer from facial palsy. CONCLUSIONS: Contralateral botulinum toxin type A injection was useful in reducing muscular hyperkinesis in patients with residual facial asymmetry after primary surgery for facial palsy, improving aesthetic and functional facial recovery with not widely common adverse events.

A novel osteogenic distraction device for the transversal correction of temporozygomatic hypoplasia.

BACKGROUND: Hemifacial microsomia (HFM) is a congenital disorder characterized by craniofacial malformation of one or both sides of the lower face. Since these anomalies are associated with soft-tissue deficiencies, corrective surgery is often difficult. Bone grafts have typically been used for augmentation, but distraction osteogenesis now offers an alternative for many craniofacial deficiencies, but there are few if any appropriate distraction devices and surgical procedures for the augmentation of craniofacial transversal dimensions. METHODS: The aim of this study was to evaluate a technique for guided augmentation of craniofacial transversal dimensions through distraction osteogenesis. We tested the efficacy of a prototype distractor, developed in collaboration with Medartis, using cadavers and demonstrated its application for the correction of the transverse dimension of the temporozygomatic region in a patient with Goldenhar syndrome. RESULTS: CT scans showed a 4-mm transverse augmentation of the bony surface after 9 days and a 10-mm increase after 30 days. Upon removal of the distractor (60 days after the first surgery) CT indicated good bony fusion and a stable result in the transverse plane. Six months after removal of the distractor, 3D computed tomography confirmed the success of the transverse augmentation, as it appeared to be stable and reliable. CONCLUSIONS: Distraction osteogenesis, using our device, can be used to correct the transverse dimension of the temporozygomatic region in HFM patients. It should also be considered for the correction of residual postsurgical skeletal deficiency due to surgical relapse or deficient growth, and unsatisfactory skeletal contour.

Surgical timing of craniosynostosis: what to do and when.

Craniosynostosis, both isolated and syndromic, are challenging malformations for the craniofacial team. They present the team with an articulated cascade of choices, which need to be addressed early in life and in the growing age to intercept, remove, or correct the direct and indirect consequences of the malformation. Timing of treatment is thus critical and it stands on the experience of a multi-specialty trained craniofacial team. In this paper the authors discuss the timing of treatment of the major craniosynostosis, isolated and syndromic, reviewing the options for treatment and their experience in this complex field.

Metastatic uterine leiomyosarcoma in the upper buccal gingiva misdiagnosed as an epulis.

Uterine leiomyosarcoma (LMS) is a rare tumor constituting 1% of all uterine malignancies. This sarcoma demonstrates an aggressive growth pattern with an high rate of recurrence with hematologic dissemination; the most common sites are lung, liver, and peritoneal cavity, head and neck district being rarely interested. Only other four cases of metastasis in the oral cavity have been previously described. The treatment of choice is surgery and the use of adjuvant chemotherapy and radiation has limited impact on clinical outcome. In case of metastases, surgical excision can be performed considering extent of disease, number and type of distant lesions, disease free interval from the initial diagnosis to the time of metastases, and expected life span. We illustrate a case of uterine LMS metastasis in the upper buccal gingiva that occurred during chemotherapy in a 63-year-old woman that underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy for a diagnosis of LMS staged as pT2bN0 and that developed lung metastases eight months after primary treatment. Surgical excision of the oral mass (previously misdiagnosed as epulis at a dental center) and contemporary reconstruction with pedicled temporalis muscle flap was performed in order to improve quality of life. Even if resection was achieved in free margins, "local" relapse was observed 5 months after surgery.

Long-term follow-up of syndromic craniosynostosis after Le Fort III halo distraction: a cephalometric and CT evaluation.

BACKGROUND: Midface distraction osteogenesis (DO) in craniofacial synostosis (CFS) patients has been described by several authors. However, very few cephalometric and computed tomography (CT) long-term follow-up studies are available. METHOD: A total of 40 consecutive patients affected by CFS subjected to Le Fort III and rigid external distraction (RED) were examined. All patients had pre-DO cephalometric records, immediately post-DO and 6-12 months post-DO. Twenty-seven patients had mid-term records (3 years post-DO) and 20 patients had long-term records (5-10 years post-DO). Fourteen patients had CT data within 1-year of DO, while 10 patients had long-term CT data (range 5-9 years). RESULTS: Excellent post-surgical stability was recorded. Short- and long-term CT data demonstrated excellent ossification at the osteotomy sites post-DO. In the growing patients, surface resorption in the zygomatic-temporal and in the subspinal area (p < 0.05) was observed in the long-term follow-up, as well as a mild increment of the corrected exorbitism (p < 0.05), as only appositional and no sutural growth occurs post Le Fort III, whereby orbital volume does not increase after surgery. CONCLUSION: Significant advancement of the midface can be achieved and maintained through Le Fort III and RED. In the long term, in growing patients, in general a class III malocclusion does not re-occur, but physiological remodelling processes at the maxillary-zygomatic level, not coupled with sutural growth, tend to mildly re-express the original midfacial phenotype and the exorbitism.