Strategy for Bone Conservation in the Two-Stage Correction of Hypertelorism in Craniofrontonasal Dysplasia.

Pre-emptive planning to optimize safety and outcome is a defining principle of pediatric craniofacial surgery, in which "procedures that come before" should enhance and not compromise procedures that are planned to follow.A technical modification of fronto-orbital advancement/remodeling in 2-stage hypertelorism surgery for craniofrontonasal dysplasia is presented, where orbital hypertelorism is accompanied by coronal craniosynostosis. Fronto-orbital advancement/remodeling undertaken by this approach preserves bone in the supero-lateral bandeau and provides optimal quality bone stock for the subsequent orbital box shift osteotomy. In this way the second procedure is protected and enhanced by optimal planning of the primary procedure, with potential benefits to safety, quality, and outcome of the final result.

The Christmas tree foreheadplasty: a novel technique used in combination with a bandeau for fronto-orbital remodelling in craniosynostosis.

PURPOSE: Craniosynostosis of the coronal, metopic and frontosphenoidal sutures results in deformity of the forehead. This may cause both functional and psychological difficulties for patient and parent. We describe a novel surgical technique, the 'Christmas tree foreheadplasty', used in combination with a supraorbital bandeau to achieve fronto-orbital remodelling. METHODS: Between November 2008 and September 2011, 32 patients with craniosynostosis underwent fronto-orbital remodelling with a supraorbital bandeau in combination with Christmas tree foreheadplasty. Indications for surgery, age at surgery, blood transfusion requirements, length of hospital stay and perioperative complications were assessed. A 'blinded', independent reviewer, age-matched controlled, panel photograph study was also undertaken to review results of the surgery. A parental satisfaction survey by telephone questionnaire was undertaken. RESULTS: Mean age at surgery was 16 months. Average hospital stay was 3 days. Mean follow up time to this report was 19.5 months. Indications for the procedure included unicoronal, frontosphenoidal, metopic and bicoronal synostosis. Thirty of the 32 patients required a blood transfusion. One patient has required revision surgery following extrusion of prosthetic fixation plate. Surgical outcome measured by 'blinded' independent reviewers indicated that a significantly different preoperative score from normal was rendered to no significant difference from age-matched normal controls postoperatively. Parental satisfaction score of forehead appearance was significantly improved by the technique. CONCLUSION: The Christmas tree foreheadplasty is a commendable and reproducible technique for forehead remodelling in combination with supraorbital bandeau and is now used more widely for forehead reconstruction for congenital cases.

Design and manufacturing of a patient-specific nasal implant for congenital arhinia: Case report.

Arhinia (congenital absence of the nose) is a congenital rare disease, which has been reported in less than 60 cases in the literature. It consists of the absence of external nose, nasal cavities and olfactory apparatus and is generally associated with midline defects, microphthalmia, blepharophimosis and hypotelorism. Aesthetic problems as well as associated functional anomalies can potentially impact on the development and interpersonal relationships of the child at a later stage in life. Arhinia requires extensive management in early life in order to ensure airway patency and protection by means of tracheostomy, and to allow adequate pharyngeal and feeding function to the child. Aesthetic issues are managed with reconstructive surgery or an external prosthesis. There is no previous description in Literature of internal prosthetic devices used to sequentially shape soft tissues in complex reconstruction. We present an example of design and manufacturing of a bespoke nose implant produced by means of 3D printing and directly assessed on-table by means of 3D surface scanning.

Correcting Exorbitism by Monobloc Frontofacial Advancement in Crouzon-Pfeiffer Syndrome: An Age-Specific, Time-Related, Controlled Study.

BACKGROUND: In FGFR2 craniosynostosis, midfacial hypoplasia features oculo-orbital disproportion and symptomatic exorbitism. Clinical consequences may mandate surgery at a young age to prevent globe subluxation, corneal ulceration, and potential loss of vision. Monobloc osteotomy and distraction osteogenesis (monobloc distraction) seek to correct exorbitism. A report of the age-related impact of monobloc osteotomy and distraction osteogenesis on orbital volume, globe volume, and globe protrusion is presented. METHODS: Computed tomographic scan data from 28 Crouzon-Pfeiffer patients were assessed at preoperative, early postoperative, and 1-year follow-up time points. Orbital volumes, globe volumes, and globe protrusions were measured by manual and semiautomatic segmentation techniques, and these were compared to 40 age-matched controls. RESULTS: Crouzon-Pfeiffer syndrome orbital volumes are significantly small, and are significantly overexpanded by distraction to endpoints correcting symptomatic exorbitism. Globe volumes are significantly larger than controls under 5 years, do not independently correlate with globe protrusion, and are unaffected by surgery. Correlation between orbital volume expansion and reduction of globe protrusion is not significant. Age-related variations of postoperative growth potential occur to 1 year postoperatively. The Crouzon-Pfeiffer syndrome FGFR2 orbit exhibits early growth acceleration followed by premature growth arrest at 10 to 14 years. CONCLUSIONS: Orbital volume expansion by monobloc osteotomy and distraction osteogenesis is not the sole determinant of reduced globe protrusion. Mean volume relapse of the orbit at 1 year is insignificant across the series. Derived Crouzon-Pfeiffer growth curves suggest that "early functional monobloc" in infants occurs on a background of dynamic orbital growth, which remains programmed to a Crouzon-Pfeiffer FGFR2 phenotype and aligns with the incidence of delayed clinical regression and later secondary surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Orbital volume and shape in Treacher Collins syndrome.

Orbito-palpebral reconstruction is a challenge in Treacher Collins syndrome (TCS). This study investigates orbital phenotypes in TCS using cephalometry and orbital shape analysis. Eighteen TCS and 52 control patients were included in this study, using the Dr Warehouse database. Orbital cephalometry was based on 20 landmarks, 10 planes, 16 angles, and 22 distances. Orbits were segmented. Registration-based, age-specific mean models were generated using semi-automatic segmentation, and aligned and compared using color-coded distance maps - mean absolute distance (MAD), Hausdorff distance (HD), and Dice similarity coefficient (DSC). Symmetry was assessed by mirroring and DSC computing. Central orbital depth (COD) and medial orbital depth (MOD) allowed 100% of orbits to be classified. COD and lateral orbital depth (LOD) were different from the controls. Average MAD between TCS and controls was ≤1.5 mm, while for HD it was >1.5 mm, and for DSC <1. TCS orbits were more asymmetrical than controls, and orbital volumes were smaller when age was considered as a confounding factor, and had a trend for normalization with age. This report emphasizes the importance of combining different morphometric approaches in the phenotype characterization of non-trivial structures such as the orbit, and supports composite skeletal and soft-tissue strategies for the management of the peri-orbital region.

The Role of Bipartition Distraction in the Treatment of Apert Syndrome.

Apert syndrome is characterized by hypertelorism, a negative canthal axis, and central midfacial hypoplasia, resulting in a biconcave face. Bipartition distraction partially corrects these facial anomalies. This study investigates limitations of bipartition distraction using linear, angular, and geometric morphometric analysis. Preoperative and postoperative three-dimensional computed tomographic craniofacial constructs of 10 patients with Apert syndrome (aged 12 to 21 years) were annotated with 98 landmarks. Twelve age-, sex, and ethnicity-matched normal skulls provided control data. Principal component analysis was used to analyze shape characteristics within and between the groups and describe the changes occurring with surgery. Results were displayed graphically using difference color maps. Conventional point-based measurements documented midfacial width, height, and asymmetry. Apert three-dimensional constructs exhibited reduced upper midfacial height and greater extrinsic symmetric variation relative to controls. Facial bipartition partially corrected excessive midfacial width and interorbital distance but did not adequately correct deficient upper midfacial height. Excessive orbital diameter was unaltered by surgery. There was no demonstrable effect on intrinsic or extrinsic midfacial asymmetry. Principal component analysis demonstrated improved midfacial projection and correction of central biconcavity. Bipartition distraction corrects midfacial retrusion, exorbitism, and hypertelorism. It does not treat midfacial height disproportion or correct orbital shape. It leaves the face too wide at the zygomatic level and does not correct facial asymmetry. Although bipartition distraction is an improvement on the unmodified monobloc advancement, further refinements are needed to fully correct Apert dysmorphology.

Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme.

Syndromic craniosynostosis caused by mutations in FGFR2 is characterised by developmental pathology in both endochondral and membranous skeletogenesis. Detailed phenotypic characterisation of features in the membranous calvarium, the endochondral cranial base and other structures in the axial and appendicular skeleton has not been performed at embryonic stages. We investigated bone development in the Crouzon mouse model (Fgfr2C342Y) at pre- and post-ossification stages to improve understanding of the underlying pathogenesis. Phenotypic analysis was performed by whole-mount skeletal staining (Alcian Blue/Alizarin Red) and histological staining of sections of CD1 wild-type (WT), Fgfr2C342Y/+ heterozygous (HET) and Fgfr2C342Y/C342Y homozygous (HOM) mouse embryos from embryonic day (E)12.5-E17.5 stages. Gene expression (Sox9, Shh, Fgf10 and Runx2) was studied by in situ hybridisation and protein expression (COL2A1) by immunohistochemistry. Our analysis has identified severely decreased osteogenesis in parts of the craniofacial skeleton together with increased chondrogenesis in parts of the endochondral and cartilaginous skeleton in HOM embryos. The Sox9 expression domain in tracheal and basi-cranial chondrocytic precursors at E13.5 in HOM embryos is increased and expanded, correlating with the phenotypic observations which suggest FGFR2 signalling regulates Sox9 expression. Combined with abnormal staining of type II collagen in pre-chondrocytic mesenchyme, this is indicative of a mesenchymal condensation defect. An expanded spectrum of phenotypic features observed in the Fgfr2C342Y/C342Y mouse embryo paves the way towards better understanding the clinical attributes of human Crouzon-Pfeiffer syndrome. FGFR2 mutation results in impaired skeletogenesis; however, our findings suggest that many phenotypic aberrations stem from a primary failure of pre-chondrogenic/osteogenic mesenchymal condensation and link FGFR2 to SOX9, a principal regulator of skeletogenesis.

Evaluating the Efficacy of Monobloc Distraction in the Crouzon-Pfeiffer Craniofacial Deformity Using Geometric Morphometrics.

BACKGROUND: Crouzon-Pfeiffer syndrome is caused by mutations predominantly in the FGFR2 gene leading to syndromic craniosynostosis and midfacial hypoplasia. Monobloc distraction aims to correct both functional and aesthetic disharmony as a result of midfacial hypoplasia. This study evaluates the corrective effects and effectiveness of monobloc distraction in Crouzon-Pfeiffer patients. METHODS: Preoperative and postoperative scans were collected from 20 Crouzon and two Pfeiffer patients aged 7 to 20 years. Fifty-six normal skulls were used as a control group. Geometric morphometrics using 52 frontofacial landmarks were used to analyze the normal skull and preoperative and postoperative patient skulls. Color maps were created to visualize differences among the average normal, preoperative, and postoperative Crouzon-Pfeiffer patients. RESULTS: In the studied patient population, monobloc distraction with the use of an external distractor advanced the upper half of the midface more than the lower half of the midface. There was an anteroinferior rotation in the monobloc segment. The zygomatic arch length improved on average to 88 and 90 percent of normal (right and left, respectively), whereas globe protrusion was corrected from 134 percent to 84 percent and from 131 percent to 87 percent of normal (right and left, respectively) in the studied patient population. Compared with a normal skull, the maxillary region remained retruded. CONCLUSIONS: The advancement achieved by monobloc distraction is effective in the upper half of the midface; the lower half of the midface is advanced but remains retruded in comparison with the normal population. The midface is rotated anteroinferiorly. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Ocular Morbidity in the Correction of Orbital Hypertelorism and Dystopia: A 15-Year Experience.

BACKGROUND: Complex surgery for appearance change is controversial. Correction of orbital hypertelorism risks diplopia and loss of stereopsis for aesthetic gain. The risk-to-benefit ratio remains ill-defined. The aim of this study was to define specific ocular morbidity following orbital translocation. METHODS: The authors compared stable preoperative and postoperative orthoptic indices (i.e., angle of strabismus, ocular motility, and acuity) for 23 consecutive patients who underwent orbital translocation between 2000 and 2015 and noted the requirement for corrective surgery. RESULTS: Eighteen patients underwent 33 box osteotomies (15 bilateral and three unilateral). Five patients underwent facial bipartition. Diagnosis was craniofrontonasal dysplasia in 11, frontonasal dysplasia in six, facial cleft in four, and Saethre-Chotzen syndrome in two cases. Median grade of orbital hypertelorism was III. Median age at surgery was 13 years (range, 5 to 17 years). Nontransient change (favorable or unfavorable) in angle of strabismus was noted in 14 patients. Ocular motility was altered in 12. Six patients had stereopsis preoperatively that was disrupted in two cases because of changes in ocular alignment and/or motility. There was one perioperative ophthalmic emergency (superior orbital fissure syndrome) and three acute reexplorations for external ocular muscle entrapment. Corrective surgery for strabismus was performed for four patients. Three required secondary canthopexy and three required surgery for blepharoptosis. CONCLUSIONS: Orbital translocation is associated with ocular risks including changes to angle of strabismus, ocular motility, and (when present) loss of stereopsis. Secondary surgery to correct strabismus or eyelid malposition is common. Orbital translocation is an operative process, not a single procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Combined soft and skeletal tissue modelling of normal and dysmorphic midface postnatal development.

BACKGROUND: Midface hypoplasia as exemplified by Treacher Collins Syndrome (TCS) can impair appearance and function. Reconstruction involves multiple invasive surgeries with variable long-term outcomes. This study aims to describe normal and dysmorphic midface postnatal development through combined modelling of skeletal and soft tissues and to develop a surgical evaluation tool. MATERIALS AND METHODS: Midface skeletal and soft tissue surfaces were extracted from computed tomography scans of 52 control and 14 TCS children, then analysed using dense surface modelling. The model was used to describe midface growth, morphology, and asymmetry, then evaluate postoperative outcomes. RESULTS: Parameters responsible for the greatest variation in midface size and shape showed differences between TCS and controls with close alignment between skeletal and soft tissue models. TCS children exhibited midface dysmorphology and hypoplasia when compared with controls. Asymmetry was also significantly higher in TCS midfaces. Combined modelling was used to evaluate the impact of surgery in one TCS individual who showed normalisation immediately after surgery but reversion towards TCS dysmorphology after 1 year. CONCLUSION: This is the first quantitative analysis of postnatal midface development using combined modelling of skeletal and soft tissues. We also provide an approach for evaluation of surgical outcomes, laying the foundations for future development of a preoperative planning tool.

Fronto-facial advancement and bipartition in Crouzon-Pfeiffer and Apert syndromes: Impact of fronto-facial surgery upon orbital and airway parameters in FGFR2 syndromes.

A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon-Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon-Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes.

Small Molecule Inhibition of Transforming Growth Factor Beta Signaling Enables the Endogenous Regenerative Potential of the Mammalian Calvarium.

Current approaches for the treatment of skeletal defects are suboptimal, principally because the ability of bone to repair and regenerate is poor. Although the promise of effective cellular therapies for skeletal repair is encouraging, these approaches are limited by the risks of infection, cellular contamination, and tumorigenicity. Development of a pharmacological approach would therefore help avoid some of these potential risks. This study identifies transforming growth factor beta (TGFß) signaling as a potential pathway for pharmacological modulation in vivo. We demonstrate that inhibition of TGFß signaling by the small molecule SB431542 potentiates calvarial skeletal repair through activation of bone morphogenetic protein (BMP) signaling on osteoblasts and dura mater cells participating in healing of calvarial defects. Cells respond to inhibition of TGFß signaling by producing higher levels of BMP2 that upregulates inhibitory Smad6 expression, thus providing a negative feedback loop to contain excessive BMP signaling. Importantly, study on human osteoblasts indicates that molecular mechanism(s) triggered by SB431542 are conserved. Collectively, these data provide insights into the use of small molecules to modulate key signaling pathways for repairing skeletal defects.

Surgical care burden in orbito-temporal neurofibromatosis: Multiple procedures and surgical care duration analysis in 47 consecutive adult patients.

Patients with orbito-temporal neurofibromatosis (OTNF) bear a heavy burden of surgical care. We studied 47 consecutive patients with OTNF from the French Neurofibromatosis 1 Referral Center cohort (n > 900), over a 15-year period to determine the clinical features most likely to predict repeat surgery and longer duration of surgical care. Forty-seven patients (5.2% of the NF1 patients' cohort) underwent 79 procedures with a 4.8 years average follow-up. Soft-tissue surgery had a high revision rate (19/45 patients), skeletal surgery did not (2/13 patients). Transosseous wire canthopexy and facial aesthetic unit remodeling were associated with stable outcome. Ptosis repair carried an unfavorable outcome, particularly in the presence of sphenoid dysplasia. Stable skeletal remodeling was achieved with polyethylene implants and/or cementoplasty. Multiple procedures were undertaken in 70% of patients and were predicted by the NF volume, canthopexy, skeletal dysplasia, or a Jackson's classification 2 and/or 3; but not by declining visual acuity. A classification based upon predictive risk of repeated procedures is proposed: Group 1: Isolated soft tissue infiltration not requiring levator palpebrae or canthal surgery; Group 2: Soft tissue involvement requiring ptosis repair or canthopexy, or NF great axis over 4.5 cm; Group 3: Presence of sphenoid dysplasia with pulsatile proptosis, regardless of visual acuity.

The management of midline frontonasal dermoids: a review of 55 cases at a tertiary referral center and a protocol for treatment.

BACKGROUND: The incidence of midline frontonasal dermoid cysts is one in 20,000 to one in 40,000. These lesions may have intracranial extension. This is explained by the anatomy and embryology of nasofrontal development. Skin involvement may also be extensive. Incomplete excision frequently leads to recurrence. The authors report their experience and pathway for management of midline dermoids. METHODS: Databases were searched to identify patients who had undergone surgery for removal of a dermoid cyst. Preoperative imaging and indications for surgery were reviewed. Cases were grouped according to surgical approach, and outcomes and complications were identified. RESULTS: Fifty-five patients were treated. Magnetic resonance imaging or computed tomography was used to delineate the anatomy, and surgical excision was expedited if there was a history of infection, especially if imaging suggested intracranial extension. Twelve patients were treated endoscopically (one was converted to open). Eleven required transcranial approaches for intracranial extension (20 percent). Of these, one lesion breached the dura. The remaining 32 patients had dermoids excised with an open approach (direct, bicoronal, or rhinoplasty). There were no recurrences in the open group and there was one recurrence in the transcranial group. This was treated by reexcision. CONCLUSION: Midline dermoid cysts are relatively uncommon. However, knowledge of the pathogenesis of these lesions together with the authors' experience over 15 years has allowed them to develop a protocol-driven approach, with a low incidence of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Advances in the molecular pathogenesis of craniofacial conditions.

The impact that the understanding of fibroblast growth factor receptor (FGFR) biology and its relevance to the pathogenesis of the craniosynostoses has made cannot be underestimated. As the genetic and molecular pathology of other conditions become increasingly understood, there is much hope that robust and relevant animal models of these conditions may be generated. From these models-and in conjunction with laboratory studies in vitro-comes a real hope of improved therapeutic strategies. The future lies in increased cooperation between clinicians working in high-volume centers and basic scientists. This article decribes the results of a decade of research in which the molecular pathology of the craniosynostoses was unravelled. The understanding of the importance of FGFR mutations to the genetic etiology of craniosynostosis opened up novel studies in developmental biology in various tissues. Such studies describe the functional effects of FGFR mutations. Investigations of FGFR expression in human craniofacial development have related functional molecular studies to human craniosynostosis syndromes, which provides a link between the gene mutation and the affected child.

Correcting the typical Apert face: combining bipartition with monobloc distraction.

BACKGROUND: Bipartition distraction is a novel procedure combining frontofacial bipartition and monobloc distraction. Apert syndrome and other syndromic craniofacial dysostoses are often characterized by hypertelorism, with a negative canthal axis and counterrotated orbits. Central midface hypoplasia can result in a biconcave face in both midsagittal and axial planes. Bipartition distraction can correct these facial abnormalities. METHODS: Twenty patients (19 Apert syndrome patients and one Pfeiffer syndrome patient, aged 1.6 to 21 years) underwent bipartition distraction. Severity of appearance was graded preoperatively and postoperatively as mild, moderate, or severe. Functional problems were documented by a multidisciplinary team. Central and lateral midface skeletal advancement were measured. Follow-up ranged from 15 months to 7 years. RESULTS: Bipartition distraction consistently produced more central than lateral facial advancement. Mean central advancement was 13.2 ± 5.9 mm at sella-nasion and 11.7 ± 5.4 mm at sella-A point. Lateral advancement was 4.7 ± 2.8 mm. Unbending the face improved aesthetic appearance. Airway function, eye exposure, and elevated intracranial pressure were improved. Complications included six temporary cerebrospinal fluid leaks (four needing a lumbar drain), five patients with postoperative seizures, five patients requiring Rigid External Distraction frame repositioning, one palatal fistula, one velopharyngeal incompetence, five pin-site infections, one abscess under frontal bone, three cases of sepsis, nine patients with worsened strabismus, two patients with enophthalmos, one patient with partial visual field loss, and three patients who required reintubation because of aspiration. CONCLUSIONS: : Bipartition distraction is an effective procedure with which to differentially advance the central face in Apert syndrome. It improves both function and aesthetics. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, IV.