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Introduction: Children with Apert syndrome have hypertelorism and midfacial hypoplasia, which can be treated with facial bipartition (FB), often aided by rigid external distraction. The technique involves a midline osteotomy that lateralizes the maxillary segments, resulting in posterior cross-bites and midline diastema. Varying degrees of spontaneous realignment of the dental arches occurs postoperatively. This study aims to quantify these movements and assess whether they occur as part of a wider skeletal relapse or as dental compensation., Methods: Patients who underwent FB and had high quality computed tomography scans at the preoperative stage, immediately postsurgery, and later postoperatively were reviewed. DICOM files were converted to three-dimensional bone meshes and anatomical point-to-point displacements were quantified using nonrigid iterative closest point registration. Displacements were visualized using arrow maps, thereby providing an overview of the movements of the facial skeleton and dentition., Results: Five patients with Apert syndrome were included. In all cases, the arrow maps demonstrated initial significant anterior movement of the frontofacial segment coupled with medial rotation of the orbits and transverse divergence of the maxillary arches. The bony position following initial surgery was shown to be largely stable, with primary dentoalveolar relapse correcting the dental alignment., Conclusions: This study showed that spontaneous dental compensation occurs following FB without compromising the surgical result. It may be appropriate to delay active orthodontic for 6-months postoperatively until completion of this early compensatory phase., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

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., (Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

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.

Objective: Critical cellular events at the palatal medial edge epithelium (MEE) occur in unperturbed mammalian palatogenesis, the molecular control of which involves a number of growth factors including transforming growth factor beta 3 (TGF beta 3). Apert syndrome is a monogenic human disorder in which cleft palate has been significantly correlated to the fibroblast growth factor receptor (FGFR) 2-Ser252Trp mutation. We report the relative expression of these genes in human palatogenesis., Methods: The expression of the IgIIIa/b and IgIIIa/c transcript isoforms of FGFR2 and the proteins FGFR1, FGFR2, and FGFR3 was studied in situ throughout the temporospatial sequence of human palatal shelf fusion and correlated with the expression of TGF beta 3. In addition, the immunolocalization of the ligand FGFs 2, 4, and 7 was undertaken together with the intracellular transcription factor STAT1, which is activated by FGFR signaling., Results: FGFRs are differentially expressed in the mesenchyme and epithelia of fusing palatal shelves, in domains overlapping those of their ligands FGF4 and FGF2 but not FGF7. Coexpression is seen with TGF beta 3, which is implicated in MEE dynamics and FGF and FGFR upregulation, and STAT1, an intracellular transcription factor that mediates apoptosis., Conclusions: The coregulation of molecules of the FGFR signaling pathway with TGF beta 3 throughout the stages of human palatal fusion suggests their controlling influence on apoptosis and epitheliomesenchymal transdifferentiation at the MEE. Experimental evidence links FGFR2-IgIIIa/b loss of function with palatal clefting, and these correlated data suggest a unique pathological mechanism for Apert cleft palate.

Object: Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome-affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of FGFR2. In contrast, a broad range of mutations throughout the extracellular domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses., Methods: In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b isoforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutation)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue and is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of FGFR2, which widely include preosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pfeiffer syndrome-affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas expression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome-affected cranial osteogenesis., Conclusions: Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in cases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.

Apert's syndrome (acrocephalosyndactyly type 1) is characterised by anomalies of the cranium, hands, and feet. The cranial and hand anomalies have been investigated, and the management of these is well established. In contrast, the anomalies affecting the feet and their management has previously received little attention. Forty-three children with Apert's syndrome underwent investigation of the anomalies affecting their feet. This consisted of history, clinical examination, and where possible, radiographic examination to establish the anomalies present, how these altered during development, and their clinical significance. The conclusion of the study is that there are widespread anomalies of the feet, with defects including both predictable dysmorphic changes and progressive fusions of the skeletal components during skeletal maturity. These fusions and their effect on growth combine to produce increasing deformity during childhood. The clinical significance of the anomalies is that walking is often delayed, and the increasing deformity results in difficulty obtaining footwear. This is the most common reason for surgery to the feet being undertaken during childhood to improve the shape of the feet to facilitate the provision of footwear. The unexpectedly high incidence of surgery in this study suggests that the management of foot deformities may require surgery more frequently than current literature would suggest.

Distraction osteogenesis is increasingly recognised as a potentially useful technique to achieve the co-ordinated augmentation of craniofacial skeletal and soft tissue. A case is presented where bilateral maxillary distraction was successfully used to advance the midface in the treatment of recurrent ocular dislocation, in a 10-month-old boy with Pfeiffer's syndrome.

Craniosynostosis may occur in conjunction with limb and visceral anomalies in more than 100 syndromes and may include anomalies of the elbow. Apert's, Pfeiffer's, Crouzon's, and Saethre-Chotzen syndrome have been linked with anomalies of the elbow, but the incidence and severity of such anomalies is unknown. A prospective radiographic study was undertaken to establish the types, incidence, and severity of elbow anomalies in patients with either Apert's, Pfeiffer's, Crouzon's, or Saethre-Chotzen syndrome attending the Craniofacial Centre at Great Ormond Street Hospital during a 12-month period. This study showed that elbow anomalies were very common in Apert's and Pfeiffer's syndrome, but less so in Crouzon's syndrome. The elbows in all patients with Saethre-Chotzen syndrome were normal. A range of anomalies was seen, with overlap between the syndromes. The severest anomaly seen in children with Crouzon's, Pfeiffer's, and Apert's syndrome was complete synostosis, which may require surgical intervention in due course. The results of this study suggest that the incidence of elbow anomalies in Apert's, Pfeiffer's, and Crouzon's syndrome is higher than the current literature suggests. Synostosis can be so severe that orthopedic review as part of the management of these children may be beneficial and may become increasingly important as more of these children survive into adulthood.

Broad toes are the classic clinical finding occurring in the feet in Pfeiffer's syndrome patients, but few cases undergo formal radiological assessment. However, the feet in other craniosynostosis syndromes resulting from mutations of the fibroblast growth factor receptor 2 gene have anomalies at many other sites within the feet, which raised the possibility that there may also be a wider range of anomalies other than broad big toes in the feet of those with Pfeiffer's syndrome. The object of this study was to assess prospectively the incidence and pattern of clinical and radiographic anomalies of the feet of patients with a confirmed diagnosis of Pfeiffer's syndrome. Twenty-two Pfeiffer's syndrome patients were examined both clinically and radiologically for anomalies of the feet. Clinical examination revealed broad big toes in 12 patients and syndactyly in 2. Radiographs of the feet were evaluated by a radiologist with an interest in skeletal dysplasia as well as by members of the Craniofacial team. A wider range of radiological than clinical anomalies involving the phalanges, metatarsals, and tarsals was seen. The severity of the anomalies observed ranged from normal to those resembling the feet of Apert's syndrome patients. Only 4 patients had radiologically normal feet. These radiographic findings suggest that there is a range of foot anomalies more extensive than the broad big toes, which are classically associated with Pfeiffer's syndrome.

The hand radiographs of fifteen patients with a diagnosis of Saethre-Chotzen syndrome were reviewed by a radiologist with an interest in skeletal dysplasia along with the craniofacial team. Eleven patients exhibited a range of bone abnormalities of the following sites: thumbs, fingers, metacarpals, and the radius. The epiphysis of the distal phalanx of the thumb was most commonly involved site with 7 of the 15 patients affected. In addition to the structural abnormalities all cases before puberty (14 out of 15 patients in this series) showed variable delay of the bone age.

Studies of cervical spine anomalies in patients with Crouzon's and Apert's syndromes have shown an increased incidence of fusions in comparison with that in the normal population. Currently, only small series of patients with Pfeiffer's syndrome who exhibit abnormalities have been published. The objective was to assess the incidence and pattern of radiological cervical spine abnormalities in patients with Pfeiffer's syndrome. All cervical spine radiographs of 22 patients with a confirmed diagnosis of Pfeiffer's syndrome treated at Great Ormond Street Hospital during the last 10 years were studied. All of the radiographs were reviewed by the craniofacial team along with a pediatric radiologist with experience in the assessment of skeletal dysplasias. Radiological abnormalities included hypoplasia of the neural arches, hemivertebrae, and a "butterfly" vertebra as well as vertebral fusion. Evidence of vertebral fusion was present in 16 (73%) of cases. Fusion of both the vertebral bodies and the posterior elements were noted. C2-C3 was the level most commonly involved, although fusion was noted at all levels within the cervical spine. Block fusions involving multiple vertebrae were noted. Analysis of sequential radiographs in 11 patients revealed evidence of progression in eight patients. These results reveal an incidence of anomalies that is higher than previously reported. The older age of the patients in our study demonstrates the progressive nature of the cervical fusions in Pfeiffer's syndrome.