Apert syndrome: neurosurgical outcomes and complications following posterior vault distraction osteogenesis.

PURPOSE: Posterior vault distraction osteogenesis (PVDO) has been utilized during the past 15 years to treat a variety of clinical features commonly presented by patients with Apert syndrome. The objective of this study is to determine the efficacy of PVDO in addressing both elevated intracranial pressure (ICP) and ectopia of the cerebellar tonsils (ECT) in young Apert patients. In addition, we aimed to determine the prevalence of hydrocephalus in Apert syndrome patients who underwent PVDO. METHODS: A retrospective study was made with a cohort of 40 consecutive patients with syndromic craniosynostosis (SC), previously diagnosed with Apert syndrome, who underwent PVDO between 2012 and 2022, and thereafter received at least 1 year of follow-up care. Demographic data and diagnosis, along with surgical and outcome data, were verified using medical records, clinical photographs, radiologic examination, and interviews with the parents of all cohort patients. RESULTS: The average patient age when PVDO was performed was 12.91 ± 10 months. The average posterior advancement distance achieved per patient was 22.68 ± 5.26 mm. The average hospital stay per patient was 3.56 ± 2.44 days. The average absolute and relative blood transfusion volumes were 98.47 ml and 17.63 ml/kg, respectively. Although five patients (14%) presented ECT preoperatively, this condition was completely resolved by PVDO in three of these five patients. One of the three patients whose ECT had completely resolved presented syringomyelia postoperatively, requiring subsequent extra dural foramen magnum decompression. All of the remaining four patients were asymptomatic for ECT for at least 1 year of follow-up, and none of these four patients required any additional treatments to address ECT. Two patients presented hydrocephalus requiring ventriculoperitoneal shunt placement. CONCLUSIONS: This study demonstrates that PVDO both reduces diagnosed elevated ICP symptoms and is partially effective in treating ECT in Apert syndrome patients. Hydrocephalus in Apert syndrome is an uncommon feature. The effectiveness of PVDO in addressing hydrocephalus is uncertain.

Webplasty using an external fixator for complex syndactyly caused by Apert syndrome.

BACKGROUND: Webplasty can be conducted for complex syndactyly caused by Apert syndrome (also referred to as Apert hand) by extending the soft tissue in the lateral direction using an external fixator. This study aimed to verify the usefulness of webplasty without skin grafting. METHODS: Webplasty with lateral extension was conducted at a single institution from 2015 to 2023. The patients were four children with Apert hand aged 1-3 years. A custom-made small external fixator was used for all of the soft tissue extension. RESULTS: Webplasty without skin grafting was completed by the time all five patients were 5-6 years of age. CONCLUSION: Webplasty without skin grafting was possible with lateral extension of the soft tissue using a simple external fixator.

Three-dimensional quantification of soft tissue changes and its relationship to skeletal changes after Le Fort III, monobloc, and facial bipartition in syndromic craniosynostosis.

To determine the effect of midface surgery on soft tissue changes and their relationship to hard tissue changes in patients with syndromic craniosynostosis. A retrospective analysis of patients who had undergone Le Fort III (LFIII), monobloc (MB), or facial bipartition (FB) was conducted. A 3D soft tissue mesh was generated from the preoperative scan and registered to the postoperative scan, after which the advancement was visualised. A total of 68 patients were included: 28 had undergone LFIII, 27 MB, and 13 FB. The included diagnoses were Apert (n = 23), Crouzon (n = 34), and craniofrontonasal syndrome (n = 11). After LFIII, most soft tissue advancement was seen around subnasale and pronasale (mean 15.1 ± 5.9 mm and 14.7 ± 5.7 mm, at age 7-12 years). After MB, a greater hard tissue than soft tissue advancement was seen for most landmarks, showing a high positive correlation. In patients undergoing FB without distraction (n = 10), mean preoperative inter-canthal distance was 48.9 mm, this reduced by 6.9 mm postoperatively. This study provides a comprehensive overview of the outcomes after midface surgery using 3D quantification for a better understanding of the soft tissue changes and their relationship to hard tissue changes.

Skeletal changes after midface surgery in patients with craniofacial deformities: a three-dimensional quantification method.

To determine the skeletal changes after midface surgery in patients with syndromic craniosynostosis who underwent Le Fort III (LFIII), monobloc (MB), or facial bipartition (FB). This was a retrospective study including 75 patients: 33 treated by LFIII, 29 by MB, and 13 by FB. Twenty-five had a diagnosis of Apert, 39 Crouzon, and 11 craniofrontonasal syndrome. A three-dimensional mesh was created from the preoperative scan and registered to the postoperative scan to visualise the advancement. LFIII at age 7-12 years effectuated a higher mean advancement in the maxillary (15.5 mm) and zygomatic (7.6 mm) regions when compared to ≥13 years (10.2 mm and 5.5 mm). After MB, mean advancement of the fronto-orbital region was higher at <7 years (16.4 mm), and similarly lower at ages 7-12 (13.8 mm) and ≥13 (12.5 mm). The mean preoperative inter-dacryon distance (34.4 ± 4.4 mm) was reduced by 8.7 ± 4.2 mm after FB without distraction (n = 10). More advancement was seen when midface surgery was performed at a younger age, due to more severe cases and a desire for overcorrection. The highest mean advancement was observed in the fronto-orbital region. Antero-inferior rotational movement was seen after all three techniques.

Successful reverse total shoulder replacement in a patient with Apert syndrome.

Apert syndrome, first described in the literature by a French pediatrician Eugene Apert, is a rare congenital form of acrocephalodactyly with autosomal dominant inheritance. Classically, this syndrome is characterized by craniosynostosis, midface hypoplasia, and symmetrical syndactyly of hands and feet resulting from embryonic anomalies during the third week of gestation. It is also associated with a variety of abnormalities of the viscera, involving the neurological, genitourinary, and cardiorespiratory systems. Glenohumeral manifestations of Apert syndrome include glenoid dysplasia, an oblong humeral head with a prominence of the greater tuberosity, acromial prominence, and inferior subluxation of the glenohumeral joint. This pathological anatomy results in progressive degenerative changes, synchondrosis, and restriction in shoulder joint mobility, particularly in flexion and abduction. While surgical options for the accompanying deformities of the feet and spine are described, interventions for shoulder pathology are not well-defined. Joint replacement surgery could offer such patients pain relief and improved function. Reverse total shoulder arthroplasty is yet to be described in Apert syndrome and this case report presents the outcome in a 48-year-old male. Level of evidence: IV case report.

Coexistence of Two Rare Conditions Complicating the Other's Management: Propionic Acidemia and Apert Syndrome.

Introduction: Propionic acidemia (PA) is an inborn error of organic acid metabolism inherited in an autosomal recessive manner. The neonatal-onset disease may present with feeding difficulties and vomiting; seizures, coma, and death may occur if untreated. In addition, catabolic processes such as infections and surgical procedures could cause metabolic decompensation, so patients with organic acidemia should be followed closely. Case Presentation: Here, a patient diagnosed with PA and Apert syndrome in the neonatal period and the complications caused by the coexistence of the two entities are mentioned. The difficulties precipitated by the coexistence of Apert syndrome and PA make this case unique. She has had prolonged hospitalizations due to metabolic decompensations after cranioplasty and inguinal hernia repair, both triggered by nosocomial respiratory infections, complicating both the surgical treatment of Apert syndrome and the management of PA. Conclusion: Coexistence of these two serious disorders mandates a more prudent clinical management as Apert syndrome patients undergo several surgical procedures, rendering them susceptible to catabolic decompensations.

Ser252Trp mutation in fibroblast growth factor receptor 2 promotes branching morphogenesis in mouse salivary glands.

OBJECTIVES: The purpose of this study was to perform morphological and immunohistochemical (IHC) analysis of the submandibular glands (SMGs) in early development in Apert syndrome model mice (Ap mice). METHODS: ACTB-Cre homozygous mice were mated with fibroblast growth factor receptor 2 (Fgfr2+/Neo-S252W) mice; ACTB-Cre heterozygous mice (ACTB-Cre mice) at embryonic day (E) 13.5 served as the control group, and Fgfr2+/S252W mice (Ap mice) served as the experimental group. Hematoxylin and eosin (H&E) staining was performed on SMGs; Total SMG area and epithelial area were determined, and the epithelial occupancy ratio was calculated. Immunostaining was performed to assess the localization of FGF signaling-related proteins. Next, bromodeoxyuridine (BrdU)-positive cells were evaluated to assess cell proliferation. Finally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to assess apoptosis in SMGs. RESULTS: The epithelial occupancy ratio was significantly higher in SMGs of Ap mice compared with that in SMGs of controls. FGF7 and bone morphogenetic protein 4 (BMP4) exhibited different localizations in SMGs of Ap mice compared with SMGs of controls. Cell proliferation was higher in SMGs of Ap mice compared with that of controls; however, apoptosis did not different significantly between the two groups. CONCLUSION: Our results suggest that enhanced FGF signaling conferred by missense mutations in FGFR2 promotes branching morphogenesis in SMGs of Ap mice.

Unraveling the Complexity of Apert Syndrome: Genetics, Clinical Insights, and Future Frontiers.

Apert syndrome (AS), also known as type I acrocephalosyndactyly, is a rare congenital condition characterized by craniosynostosis resulting from missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. This comprehensive review delves into AS, covering its clinical manifestations, genetics, diagnosis, medical management, psychosocial considerations, and future research directions. AS presents with distinct features, including a brachycephalic skull, midface hypoplasia, and limb anomalies such as syndactyly. It follows an autosomal dominant inheritance pattern with mutations in the FGFR2 gene. Prenatal diagnosis is possible through advanced imaging techniques and molecular testing. The multidisciplinary approach to AS management involves surgical interventions, orthodontics, and psychological support. Although no curative treatment exists, early interventions can significantly improve function and aesthetics. The quality of life for AS patients is influenced by psychosocial factors, necessitating comprehensive support for both patients and their families. Future research directions include gene therapy, understanding cellular responses to FGFR2 mutations, and addressing genetic heterogeneity. Collaborative efforts are vital to advancing knowledge about AS and its genetic underpinnings. Overall, this review serves as a valuable resource for healthcare professionals, educators, and researchers, contributing to a deeper understanding of AS and facilitating advancements in diagnosis and treatment.

Clinical and operative risk factors for complications after Apert hand syndactyly reconstruction.

This study evaluated how Apert hand syndactyly presentations and reconstructive techniques influence reconstruction outcomes. All cases at a major paediatric hospital between 2007 and 2022 were analysed, including 98 web space reconstructions in 17 patients. Overall, 62% of hands developed complications and 15% required revision surgery. Upton hand type was significantly associated with postoperative complication incidence, specifically including range-of-motion deficits, flexion contracture, web creep and revision surgery. More severe syndactylies may benefit from additional measures to reduce complications. Rectangular commissural flaps showed 1.9 times greater complication risk than interdigitating triangular flaps, including 11.2 times greater risk of web creep. Zigzag volar finger flaps showed 1.8 times greater complication risk than straight-line incisions, including 3.8 times greater risk of web creep. Our study showed that interdigitating triangular commissural flaps and straight-line volar finger incisions are preferable to rectangular commissural and zigzag finger flaps in most cases of Apert hand syndactyly to minimize complications. LEVEL OF EVIDENCE: III.

Outcome of Bilateral Hand Reconstruction in a Child Presenting Late With Apert Syndrome: A Case Report and Literature Review.

Apert syndrome is a rare inherited syndrome characterised by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet. Syndactyly of the hands is categorised into three types with varying severity, requiring a diverse range of surgical techniques to produce good functional and aesthetic outcomes. The best age to initiate hand reconstruction is between three and 12 months. We present a case of a three-year-old boy with type III syndactyly who first presented at a volunteer outreach surgical campus in Pemba, Zanzibar. A three-stage bilateral hand reconstruction was initiated to sequentially create the first, fourth, and second web spaces. Postoperative healing was uneventful. He underwent a hand rehabilitation program and demonstrated good functional outcomes, being able to attend school, hold a pen, and write by seven years old. A literature review revealed that the best age to initiate hand reconstruction or the best surgical technique to use has yet to be agreed upon. It is agreed that the diverse symptoms of Apert syndrome make it difficult to manage, requiring multidisciplinary collaboration to provide physical and emotional benefits to patients and families.

Cleft Palate in Apert Syndrome: A Descriptive Study of Incidence and Surgical Outcome.

OBJECTIVE: Apert syndrome (AS) is a rare congenital craniofacial disorder that requires a multidisciplinary approach to treatment and multiple surgeries. Given that cleft palate (CP) is presented in some of these cases, this poses an additional risk of aggravating obstructed airways after closure. The timing and outcome of CP repair in these patients remains disputed and requires additional attention. DESIGN: This retrospective analysis included patients diagnosed with CP and AS, born between 1950 and 2020, and treated at our institution. Data were collected from medical records and evaluated using descriptive statistics. SETTING: Data analyses were conducted at Sahlgrenska University Hospital in Gothenburg, Sweden. PATIENTS/PARTICIPANTS: A registry of 83 patients with AS resulted in a cohort of 26 patients also presenting with CP. MAIN OUTCOME MEASURES: Postoperative complications, requirement for intensive care, and reoperations following CP repair. RESULTS: CP incidence among all registered patients was 31%. Patients undergoing CP repair at low age (mean: 22.5 months) tended to experience more frequent postoperative complications and requirements for intensive care. Among the evaluated cohort with medical records describing CP repair (n = 14), 29% experienced postoperative complications, all of which involved aggravation of obstructed airways. CONCLUSIONS: This study highlights the importance of airway assessment before and after CP repair in AS. The findings suggest that surgical outcomes might benefit from postponing CP repair, avoiding combined surgeries, and operating in two stages when indicated. However, additional and larger studies are required.

Apert Syndrome - caveats of squint management.

Apert Syndrome (AS) is a rare form of acrocephalosyndactyly. The aim of the manuscript was to underline the challenging squint management in a case of Apert Syndrome. A 1.5-year-old male with craniosynostosis, diagnosed at birth, with history of incomplete closure of eyes, more so in the right eye, and squinting of left eye since birth, was brought to eye OPD by the mother. Presence of acrocephaly, prominent forehead with bony irregularity, chin down with left head tilt, fused cervical vertebrae, marked proptosis, cleft palate, dental anomaly and syndactyly confirmed the diagnosis of AS. Old serial photographs of the child were examined to look for progression of squint and proptosis. Squint evaluation revealed 70-75 PD exotropia with 10PD right hypertropia in primary gaze. The right hypertropia increased further in the left gaze, whereas a left hypertropia was noted in the right gaze. The patient underwent bilateral LR recession of 9 mm with full muscle width transposition (upshift) with Inferior Oblique recession of 4:1 mm in the right eye and 3:2 mm in the left eye. Post-operative follow-up after 2 months showed that V pattern collapsed with residual exotropia of 20 PD. Post-operative follow-up after 1 year showed improvement in head posture with pattern collapsed. However, recurrent exotropia was noted on evaluation, for which bilateral medial recti resection was done later. The management of squint in AS and other craniosynostosis poses a multitude of challenges for the ophthalmologists. Frequent follow-ups are needed in patients with AS for the timely management of its ocular manifestations and better visual rehabilitation.

Apert Syndrome: Selection Rationale for Midface Advancement Technique.

Apert syndrome is characterized by a wide spectrum of craniofacial clinical features that have been successfully addressed via a variety of midface advancement techniques. Although surgeons have individual preferences as to which specific procedures should be performed to best treat Apert patients, craniofacial plastic surgeons, working in tandem with pediatric neurosurgeons, can identify and evaluate functional limitations and facial morphologic disproportions, and establish appropriate criteria for effective midface advancement technique indication and selection. The purpose of this review article is to present and discuss our rationale for midface advancement technique selection based upon the most common craniofacial characteristics presented by Apert syndrome patients. The present article also provides a grading system that stratifies as major, moderate, and mild, the effect of each midface advancement technique on the different types of Apert syndrome facial features. Surgeons should take into consideration the maximum effect and benefit of each craniofacial osteotomy and how these procedures will alter the craniofacial skeleton. By understanding the long-term effect of each osteotomy on the most common craniofacial characteristics of Apert syndrome patients, craniofacial plastic surgeons and neurosurgeons will be able to customize the surgical procedures they perform in order to achieve the best possible outcomes.

Exosome-mediated small interfering RNA delivery inhibits aberrant osteoblast differentiation in Apert syndrome model mice.

OBJECTIVE: Apert syndrome, an autosomal dominant congenital disorder characterized by craniosynostosis, is caused by a missense mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Exosomes are naturally occurring carriers that deliver nucleic acids, including small interfering RNA (siRNA), to induce gene silencing. This study aimed to develop siRNA-loaded exosomes (Ex-siRNAFgfr2S252W) to silence the Fgfr2S252W gain-of-function mutation, thereby inhibiting the increased osteoblastic differentiation caused by the constitutive activation of FGFR2 signaling in calvarial osteoblastic cells isolated from Apert syndrome model mice. DESIGN: Primary calvarial osteoblast-like cells were isolated from the embryonic calvarial sutures of the Apert syndrome model (Fgfr2S252W/+) and littermate wild-type mice (Ap-Ob and Wt-Ob, respectively). Exosomes were extracted from the serum of wild-type mice, validated using biomarkers, and used to encapsulate siRNAs. After exosome-mediated siRNA transfection, cells were analyzed under a fluorescence microscope to validate the delivery of Ex-siRNAFgfr2S252W, followed by western blot and real-time reverse transcription polymerase chain reaction analyses. RESULTS: After 24 h of Ex-siRNAFgfr2S252W delivery in both Ap-Ob and Wt-Ob, siRNA-loaded exosome delivery was validated. Moreover, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, runt-related transcription factor 2 (Runx2), and collagen type 1 alpha 1 (Col1a1) mRNA expression, and alkaline phosphatase (ALP) activity were significantly increased in Ap-Ob. The levels of phospho-p44/42 protein, Runx2, Col1a1, and ALP were significantly decreased after Ex-siRNAFgfr2S252W transfection but did not affect Wt-Ob. CONCLUSIONS: These results indicate that exosome-mediated delivery of siRNA targeting Fgfr2S252W is a potential non-invasive treatment for aberrant FGF/FGFR signaling.

Posterior Cranial Distraction in Craniosynostosis: A Systematic Review of the Literature.

OBJECTIVE: Posterior cranial distraction (PCD) is a surgical technique to address craniosynostosis, especially in syndromic patients. The technique has the ability to significantly expand the cranium, while requiring minimal dural dissection, compared to cranial remodeling. Our goals were to determine the patient characteristics and surgical outcomes of PCD. The two questions that we sought to answer were: 1) What is the average published complication rate and the most common complications of PCD? and 2) How much intracranial volume expansion can one expect with PCD? DESIGN: A PubMed database search of articles on PCD was performed. Case reports and articles with overlapping patients were excluded. A systematic review was performed using the remaining articles. MAIN OUTCOME MEASURES: Patient data were extracted in order to determine the total number of patients, patients with a syndrome, types of syndromes, mean age at surgery, mean distraction distance, mean increase in intracranial volume, and complications. RESULTS: 18 articles representing 325 patients were analyzed. A syndrome was present in 68.6% of patients. The mean age at time of surgery was 22.1 months. Mean distraction amount was 24.7 mm. Mean increase in intracranial volume was 253.2 cm3. The overall complication rate was 32.2%, with the most common complications being surgical-site infection, hardware-related complications and delayed wound healing. CONCLUSIONS: PCD is a powerful technique in the management of syndromic craniosynostosis, although complication rates are significantly higher than traditional remodeling techniques. Future studies should compare the effects of supratorcular and infratorcular osteotomies on intracranial volume, cosmesis and complications.

Clinical manifestations of Apert syndrome.

Apert syndrome presents similarly to the one we presented in this image, and a genetic study is used for confirmation. This image shows the typical findings of physical examination, so that if this appears in the outpatient department, the diagnosis of Apert syndrome should be assumed.

Psychological Adjustment in Apert Syndrome: Parent and Young Person Perspectives.

To date, limited research has been carried out into the psychological impact of having a diagnosis of Apert syndrome (AS) and the life experiences of families living with this condition. The aim of the current study was to explore psychological adjustment to AS from the perspectives of young people, and their parents, with the broader goal of informing care, and support for this population.Four young people (2 male) aged 11 to 15 years and their mothers were interviewed in their homes using a semistructured interview guide and photo-elicitation methods. Transcripts were analyzed using Interpretive Phenomenological Analysis.Three superordinate themes were identified from the data: (1) Acceptance and Adjustment: A Cyclical Journey; (2) A Barrier to Adjustment: Navigating Treatment; and (3) Facilitating Adjustment: Social Support. Families described adjustment as a cyclical process, which was sensitive to change, particularly in the context of ongoing medical treatment. Families also utilized many resources, particularly in the form of social support, to adjust to the challenges of AS and build resilience.The findings of this study have important implications for the implementation of patient-centered care within designated craniofacial treatment centers, which should at a minimum include the provision of reliable information throughout the treatment pathway, additional support from health professionals at key times of transition, and the coordination of support across medical teams, and other key organizations in the child's life.

Cranial Morphology Associated With Syndromic Craniosynostosis: A Potential Detection of Abnormality in Patient's Cranial Growth Using Angular Statistics.

INTRODUCTION: Apert, Crouzon, and Pfeiffer syndromes are common genetic syndromes related to syndromic craniosynostosis (SC), whereby it is a congenital defect that occurs when the cranial growth is distorted. Identifying cranial angles associated with these 3 syndromes may assist the surgical team to focus on a specific cranial part during the intervention planning, thus optimizing surgical outcomes and reducing potential morbidity. OBJECTIVE: The aim of this study is to identify the cranial angles, which are associated with Apert, Crouzon, and Pfeiffer syndromes. METHODS: The cranial computed tomography scan images of 17 patients with SC and 22 control groups aged 0 to 12 years who were treated in the University Malaya Medical Centre were obtained, while 12 angular measurements were attained using the Mimics software. The angular data were then divided into 2 groups (patients aged 0 to 24 months and >24 months). This work proposes a 95% confidence interval (CI) for angular mean to detect the abnormality in patient's cranial growth for the SC syndromes. RESULTS: The 95% CI of angular mean for the control group was calculated and used as an indicator to confirm the abnormality in patient's cranial growth that is associated with the 3 syndromes. The results showed that there are different cranial angles associated with these 3 syndromes. CONCLUSIONS: All cranial angles of the patients with these syndromes lie outside the 95% CI of angular mean of control group, indicating the reliability of the proposed CI in the identification of abnormality in the patient's cranial growth.

Synchondrosis fusion contributes to the progression of postnatal craniofacial dysmorphology in syndromic craniosynostosis.

Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this study, we chronologically evaluated skull morphology change after abnormal fusion of the sutures and synchondroses in mouse models of syndromic CS for further understanding of the disease. We found fusion of the inter-sphenoid synchondrosis (ISS) in Apert syndrome model mice (Fgfr2S252W/+ ) around 3 weeks old as seen in Crouzon syndrome model mice (Fgfr2cC342Y/+ ). We then examined ontogenic trajectories of CS mouse models after 3 weeks of age using geometric morphometrics analyses. Antero-ventral growth of the face was affected in Fgfr2S252W/+ and Fgfr2cC342Y/+ mice, while Saethre-Chotzen syndrome model mice (Twist1+/- ) did not show the ISS fusion and exhibited a similar growth pattern to that of control littermates. Further analysis revealed that the coronal suture synostosis in the CS mouse models induces only the brachycephalic phenotype as a shared morphological feature. Although previous studies suggest that the fusion of the facial sutures during neonatal period is associated with midface hypoplasia, the present study suggests that the progressive postnatal fusion of the cranial synchondrosis also contributes to craniofacial dysmorphology in mouse models of syndromic CS. These morphological trajectories increase our understanding of the progression of syndromic CS skull growth.