De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis.

Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well described, but a genetic etiology remains elusive in a substantial fraction of probands. Analysis of exome sequence data from 526 proband-parent trios with syndromic CS identified a marked excess (observed 98, expected 33, p = 4.83 × 10-20) of damaging de novo variants (DNVs) in genes highly intolerant to loss-of-function variation (probability of LoF intolerance > 0.9). 30 probands harbored damaging DNVs in 21 genes that were not previously implicated in CS but are involved in chromatin modification and remodeling (4.7-fold enrichment, p = 1.1 × 10-11). 17 genes had multiple damaging DNVs, and 13 genes (CDK13, NFIX, ADNP, KMT5B, SON, ARID1B, CASK, CHD7, MED13L, PSMD12, POLR2A, CHD3, and SETBP1) surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNV in the retinoic acid receptor alpha (RARA; c.865G>A [p.Gly289Arg]) was identified in two probands with similar CS phenotypes. CS risk genes overlap with those identified for autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription, and osteoblast differentiation. Our results identify several CS loci and have major implications for genetic testing and counseling.

The effect of continuous positive airway pressure on obstructive sleep apnea in children with syndromic craniosynostosis.

BACKGROUND: Obstructive sleep apnea (OSA) is common in children with syndromic craniosynostosis (SC). However, objective data on the treatment of OSA in children with SC remain inadequate. This study aimed to explore the efficacy of continuous positive airway pressure (CPAP) in the management of OSA in children with SC. METHODS: A retrospective study was performed in children with SC and OSA diagnosed by polysomnography (PSG), which was defined as an apnea hypopnea index (AHI) ≥ 1. Patients were included if they were treated with CPAP and had baseline PSG and follow-up sleep studies. Clinical and demographic data were collected from all enrolled subjects. RESULTS: A total of 45 children with SC and OSA were identified, with an average age of 6.8 ± 4.7 years. Among them, 36 cases had moderate to severe OSA (22 with severe OSA) and received CPAP therapy followed by post-treatment sleep studies. Notably, there was a significant reduction in the AHI observed after CPAP treatment (3.0 [IQR: 1.7, 4.6] versus 38.6 [IQR: 18.2, 53.3] events/h; P < 0.001). CONCLUSIONS: CPAP is effective and acceptable in treating severe OSA in children with SC.

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.

Posterior cranial vault distraction in children with syndromic craniosynostosis: the era of biodegradable materials-a comprehensive review of the literature and proposed novel global application.

Distraction osteogenesis is utilized to increase intracranial volume in the treatment of restrictive pathologies, most commonly syndromic synostosis. Children too young for open calvarial vault expansion or other systemic or local contraindications to a direct reconstructive approach benefit greatly from distraction osteogenesis, typically addressing posterior vault expansion. Wound infection, cerebrospinal fluid (CSF) leak, device failure, need for a second surgery for removal, and cost, are issues that can limit the use of this approach. These challenges are more pronounced in low- and middle-income countries (LMICs) due to lack of access to the device, the financial burden of the need for a second surgery, and the severity of the implications of infection and CSF leak. Over the last five decades, there has been an increased acceptance of bioresorbable instrumentation in craniofacial surgery. Poly L-lactic acid, polyglycolic acid, and polydioxanone are the most commonly used polymers. New resorbable fixation tools such as ultrasound-activated pins and heat-activated pins are superior to conventional bioresorbable screws in allowing attachment to thinner bone plates. In this paper, we present a review of the literature on cranial vault distraction and the use of bioresorbable materials and propose a novel design of a fully absorbable cranial distractor system using external magnetic distraction control, eliminating the need for external activation ports and a second surgery to remove the hardware. The application of this technology in LMIC settings could advance access to care and treatment options for patients with syndromic synostosis.

The role of pathogenic TCF12 variants in children with coronal craniosynostosis-a systematic review with addition of two novel cases.

Craniosynostosis constitutes one of the most common congenital cranial malformations, affecting approximately 6/10,0000 live births. A genetic etiology has long been known for several forms of syndromic craniosynostosis, including pathogenic variants in TWIST1 and FGFR3 in children with Saethre-Chotzen and Muenke syndrome. Over the last decade, reports of genetic aberrations in TCF12 in children with craniosynostosis have emerged, in particular in cases with premature closure of the coronal suture(s). In this study, we, therefore, systematically reviewed the rapidly growing knowledge of TCF12-related coronal craniosynostosis, clearly illustrating its high degree of genotype and phenotype variability. With the two novel cases presented, at least 113 cases of TCF12-related coronal craniosynostosis have currently been reported. By pooling data from several prospectively collected undifferentiated craniosynostosis cohorts (ntotal = 770), we estimate a prevalence of pathogenic TCF12 variants of at least 2%. Overall, pathogenic germline variants in TCF12 are relatively frequent in children with coronal craniosynostosis, accounting for ∼10-20% of TWIST1- and FGFR1/2/3-negative cases, with even higher rates for bicoronal and syndromic cases. Genetic counseling is recommended for all children with craniosynostosis, and involvement of the coronal suture(s) should precipitate TCF12 testing.

A 3-Dimensional Morphometric Analysis of 4 Midsagittal Planes for CT Scan Reference Determination in Children with Syndromic Craniosynostosis.

OBJECTIVE: To identify the suitable and practical midsagittal plane (MSP) reference for computed tomography (CT) scan skull analysis in patients with syndromic craniosynostosis. DESIGN: Retrospective study. SETTING: Tertiary referral hospital. PATIENTS AND PARTICIPANTS: A total of 19 full skull CT scans of syndromic craniosynostosis patients. METHODS: Seven craniofacial landmarks located on the midline and 4 MSPs that was previously published and clinically recognized (Planes: SPBaS, SPNSANS, SPLOrPo and SPZFTP) were constructed from the CT images. The absolute distance of every plane from 7 landmarks were then calculated. These distances were subsequently subjected to statistical analysis. MAIN OUTCOME MEASURE(S): The absolute distance of different MSPs from 7 landmarks. RESULTS: The distances of landmarks measured to SPBaS were the highest, with the most prominent fluctuation. The fluctuation of the SPNSANS, SPLOrPo and SPZFTP had similar direction changes, with the latter being the closest. Pairwise comparisons demonstrated statistical differences (P < .008 using the Bonferroni correction) between the measured distances of A point (M = 0.25, SD = 0.16) and B point (M = 2.21, SD = 1.6) to SPNSANS. There were statistical significances between distances of B point (M = 1.68, SD = 1.07) and CG point (M = 0.55, SD = 0.37) to SPZFTP plane. There was no statistical significance on each landmark to SPLOrPo. CONCLUSIONS: The study demonstrates that SPBaS is not recommended for MSP reference. While SPNSANS should be carefully selected, the application of SPLOrPo and SPZFTP are interchangeable, with the SPZFTP plane slightly exaggerating the mandible deviation relative to the superior and posterior of the midface.

Health-Related Quality of Life in Mexican Children and Adolescents with Non-Syndromic Craniosynostosis.

OBJECTIVE: Assess the Health-Related Quality of Life in children and adolescents with non-syndromic craniosynostosis and compare it with participants without craniosynostosis. DESIGN: Non-experimental, cross-sectional design. SETTING: The assessment was done remotely and the instrument was sent via chat or email. PATIENTS/PARTICIPANTS: Participants (ages 8-17) with non-syndromic craniosynostosis (n = 27) and without craniosynostosis (n = 26). MAIN OUTCOME MEASURE(S): We used an adapted version for the Mexican population of the Health-Related Quality of Life Questionnaire for Children and Adolescents -KIDSCREEN-52. RESULTS: All scores were in the average clinical range and both groups scored similarly in all domains except those with craniosynostosis were significantly lower in the Social Support and Peers domain (rpb = 0.48). CONCLUSIONS: Children and adolescents with non-syndromic craniosynostosis reported similar Health-Related Quality of Life as the control group, except for the Social Support domain, which should be investigated in future studies.

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.

ERF-related craniosynostosis and surgical management in the paediatric cohort.

INTRODUCTION: ERF mutation is one of the most recently identified genetic aberrations associated with syndromic craniosynostosis. Data on the pattern of craniosynostosis, surgical management of ERF-related craniosynostosis and outcomes is limited. We report on our single-centre experience in paediatric cohort of patients with syndromic craniosynostosis secondary to ERF mutation. METHODS: A retrospective review of all paediatric craniofacial cases was performed over an 8-year period (2014-2022). All patients with genetically confirm ERF-related craniosynostosis were identified, and clinical parameters including, age, sex, pattern of craniosynostosis, associated tonsillar herniation and follow-up period were further analysed from electronic clinical and imaging systems. All patients were selected and discussed in multidisciplinary craniofacial meeting (composed of neurosurgical, maxillofacial, plastics and genetics teams) prior to any surgical intervention. RESULTS: Overall, 10 patients with ERF-related craniosynostosis were identified with a male-to-female ratio of 4:1 with mean age at the time of surgery of 21.6 months with a mean follow-up period of 5.2 years. ERF-confirmed cases led to variable craniosynostosis pattern with multi-sutural synostosis with concurrent sagittal and bilateral lambdoid involvement as the most common pattern (7/10). No patient pre-operatively had evidence of papilloedema on ophthalmological assessment. Eight out of 10 patients had associated low-lying tonsils/hind brain hernia pre-operatively. Eight out of 10 patients required surgery which included 2 fronto-orbital advancement, 3 calvarial remodelling, 2 posterior calvarial remodelling/release and 1 insertion of ventriculoperitoneal shunt. CONCLUSION: Involvement of sagittal and lambdoid sutures is the most common pattern of craniosynostosis. ERF-related craniosynostosis can have variable pattern of suture fusion, and management of each patient requires unique surgical planning and execution based on clinical needs for the optimal outcomes.

Facial skeleton dysmorphology in syndromic craniosynostosis: differences between FGFR2 and no-FGFR2-related syndromes and relationship with skull base and facial sutural patterns.

PURPOSE: To assess the role of FGFR2 mutations and sutural synostotic patterns on facial skeleton dysmorphology in children with syndromic craniosynostosis. METHODS: Preoperative high-resolution CT images in 39 infants with syndromic craniosynostosis were evaluated. Patients were divided into infants with and without FGFR2 mutations; each group was split according to synostotic involvement of minor sutures/synchondroses: isolated or combined involvement of middle (MCF) and posterior cranial fossae (PCF). Quantitative analysis of the midface and mandible measures was performed. Each subgroup was compared with a group of age-matched healthy subjects. RESULTS: Twenty-four patients with FGFR2 related syndromes were clustered in 3 subgroups: MCF + PCF (8 patients, 5.4 ± 1.75 months), MCF (8 patients, 3.62 ± 1.68 months), and PCF (8 patients, 2.75 ± 0.46 months). Fifteen no-FGFR2 patients were clustered in 2 subgroups: MCF + PCF (7 patients, 9.42 ± 0.78 months) and PCF (8 patients, 7.37 ± 2.92 months). Both FGFR2 and no-FGFR2 groups with involvement of minor sutures coursing in MCF showed more facial sutural synostoses. Children with minor suture/synchondrosis synostosis of MCF (MCF-PCF and MCF subgroups) showed altered position of glenoid fossa and mandibular inclination ([Formula: see text]), but children in the FGFR2 group had also reduced midfacial depth and maxillary length ([Formula: see text]). Children with minor suture/synchondrosis synostosis of PCF (PCF subgroups) had reduced posterior mandibular height, but those children in the FGFR2 group also showed reduced intergonion distance ([Formula: see text]). CONCLUSIONS: In children with syndromic craniosynostosis, both skull base and facial suture synostosis affect facial dysmorphology/hypoplasia. FGFR2 mutations may worsen facial hypoplasia both acting on bone development and causing an earlier premature closure of facial sutures.

Practical Algorithm for the Management of Multisutural Craniosynostosis with Associated Chiari Malformation and/or Hydrocephalus.

INTRODUCTION: The association between multisutural craniosynostosis with Chiari malformation (CM), venous hypertension, and hydrocephalus is widely described in the literature, especially in children with paediatric craniofacial syndromes. Some efforts have been done in the last years to understand the complex pathogenetic mechanisms underlying this association, and several theories have been proposed. In particular, it is now accepted that the hypothesis of the overcrowding of the posterior fossa due to precocious suture fusion is the cause of the cerebellar herniation in syndromic and non-syndromic patients, against the theory of intrinsic cerebellar anomalies, ventriculomegaly, and venous hypertension. However, whatever the pathophysiological mechanism, it is still unclear what the best management and treatment of CM and hydrocephalus are in multisutural craniosynostosis patients. The aim of this study was to report our 25 years' experience in treating paediatric patients affected by these rare pathologies in order to propose a simple and effective therapeutic flow chart for their management. MATERIALS AND METHODS: We retrospectively collected data of each patient who underwent a cranial vault remodelling (CVR) for complex multisutural craniosynostosis in our institution in the last 25 years, while monosutural craniosynostosis was excluded. We recorded data concerning type of craniosynostosis and craniofacial syndromes, presence of ventriculomegaly, and CM at presentation and clinical and radiological follow-up. Therefore, we evaluated the final outcomes (improved, stable, deteriorated) of these patients and created a practical flow chart that could help physicians choose the best surgical treatment when different pathological conditions, as Chiari malformation I (CMI) or hydrocephalus, affect complex craniosynostosis children. RESULTS: Thirty-nine patients (39 out of 55; 70.9%), with an isolated multisutural craniosynostosis at presentation, underwent a two-step CVR as first surgery; 36 patients (92.3%) had an improved outcome, 2 patients (5.1%) had a stable outcome, and 1 patient (2.56%) had a deteriorated outcome. Other eight children (8 out of 55; 14.5%) had a radiological evidence of asymptomatic CMI at presentation. In this group, we performed CVR as first surgery. As for the final outcome, 7 patients had an improved outcome (87.5%) with good aesthetic result and stability or resolution of CMI. Finally, 7 patients (7 out of 55; 12.7%) presented a various combination of CMI and ventriculomegaly or hydrocephalus at presentation. Among them, 3 patients had an improved outcome (42.8%), and 4 patients had a deteriorated outcome (57.1%). DISCUSSION: The prevalence of one pathological condition with associated symptoms over the others was the key factor leading our therapeutic strategy. When craniosynostosis is associated with a radiological CM, the assessment of clinical symptoms is of capital importance. When asymptomatic or pauci-symptomatic, we suggest a CVR as first step, for its efficacy in reducing tonsillar herniation and solving CM symptoms. When craniosynostosis is associated with ventricular enlargement, the presence of intracranial hypertension signs and symptoms forces physicians to first treat hydrocephalus with a ventriculo-peritoneal shunt or endoscopic third ventriculostomy. For patients with various degrees and severity of ventriculomegaly and associated CM, the outcomes were very heterogeneous, even when the same therapeutic strategy was applied to patients with similar starting conditions and symptoms. This is maybe the most unexpected and least clear part of our results. Despite the proposed algorithm comes from a clinical experience on 85% successfully treated patients with multiple craniosynostosis, more extensive and deep studies are needed to better understand CM and hydrocephalus development in such conditions.

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.

Primary Delayed Onset Craniosynostosis in a Child With ERF-Related Craniosynostosis Syndrome and Familial Cerebral Cavernous Malformation Syndrome.

Primary delayed onset craniosynostosis is defined as premature suture fusion that developed despite clear radiographic evidence of normal postnatal calvarial configuration and patent sutures earlier in life. It is rare in the literature and typically presents as secondary synostosis. In this brief clinical study, primary delayed onset craniosynostosis is described in its unique presentation at 4 years of age with a complex genetic history including ERF-related craniosynostosis syndrome and familial cerebral cavernous malformation syndrome. Although the delayed onset clinical course of ERF-related craniosynostosis syndrome has not been well described in the literature, our review suggests that it is distinctive to ERF-related craniosynostosis and should be considered when cases present without a history of trauma, when there is a positive family history, and particularly when cases present late onset; after 1 year of age.

Differential diagnosis of syndromic craniosynostosis: a case series.

PURPOSE: Syndromic craniosynostosis is a rare genetic disease caused by premature fusion of one or multiple cranial sutures combined with malformations of other organs. The aim of this publication is to investigate sonographic signs of different syndromic craniosynostoses and associated malformations to facilitate a precise and early diagnosis. METHODS: We identified in the period of 2000-2019 thirteen cases with a prenatal suspected diagnosis of syndromic craniosynostosis at our department. We analyzed the ultrasound findings, MRI scans, genetic results as well as the mode of delivery, and postnatal procedures. RESULTS: Eight children were diagnosed with Apert Syndrome, two with Saethre Chotzen syndrome, one with Crouzon syndrome, and one with Greig cephalopolysyndactyly syndrome. One child had a mutation p.(Pro253Leu) in the FGFR2 gene. We identified characteristic changes of the head shape as well as typical associated malformations. CONCLUSION: Second trimester diagnosis of syndromic craniosynostosis is feasible based on the identified sonographic signs. In case of a suspected diagnosis a genetic, neonatal as well as surgical counseling is recommended. We also recommend to offer a fetal MRI. The delivery should be planned in a perinatal center.

Craniofacial morphology and growth in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis.

OBJECTIVES: To determine whether the midface of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is hypoplastic compared to skeletal facial proportions of a Dutch control group. MATERIAL AND METHODS: We included seventy-four patients (43 patients with Muenke syndrome, 22 patients with Saethre-Chotzen syndrome, and 9 patients with TCF12-related craniosynostosis) who were referred between 1990 and 2020 (age range 4.84 to 16.83 years) and were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care and Orthodontics, Children's Hospital Erasmus University Medical Center, Sophia, Rotterdam, the Netherlands. The control group consisted of 208 healthy children. RESULTS: Cephalometric values comprising the midface were decreased in Muenke syndrome (ANB: ß = -1.87, p = 0.001; and PC1: p < 0,001), Saethre-Chotzen syndrome (ANB: ß = -1.76, p = 0.001; and PC1: p < 0.001), and TCF12-related craniosynostosis (ANB: ß = -1.70, p = 0.015; and PC1: p < 0.033). CONCLUSIONS: In this study, we showed that the midface is hypoplastic in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis compared to the Dutch control group. Furthermore, the rotation of the maxilla and the typical craniofacial buildup is significantly different in these three craniosynostosis syndromes compared to the controls. CLINICAL RELEVANCE: The maxillary growth in patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is impaired, leading to a deviant dental development. Therefore, timely orthodontic follow-up is recommended. In order to increase expertise and support treatment planning by medical and dental specialists for these patients, and also because of the specific differences between the syndromes, we recommend the management of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis in specialized multidisciplinary teams.

Posterior vault "free-floating" bone flap: indications, technique, advantages, and drawbacks.

BACKGROUND: The enlargement of the posterior cranial fossa volume is considered one of the main steps of the surgical management of children with multiple sutures craniosynostosis. Different management options have been proposed including fixed expansive craniotomy, free bone flap craniotomy, and distraction osteogenesis. OBJECTIVES: To review indications to "free bone flap" craniotomy for the posterior fossa expansion, detailing advantages, disadvantages, and complications related to the technique. RESULTS AND CONCLUSIONS: A review of the literature shows that "free bone flap" posterior expansion cranioplasty still has a role, particularly in infants with thin and "honeycomb" structure of the bone, allowing to gain adequate intracranial volume increases and to postpone to a more adequate time surgery aimed at anterior cranial fossa expansion.

Severe craniolacunae and upper and lower extremity anomalies resulting from Crouzon syndrome, FGFR2 mutation, and Ser347Cys variant.

Crouzon syndrome is a rare form of syndromic craniosynostosis (SC) characterized by premature fusion of the cranial and facial sutures, elevated intracranial pressure, varying degrees of ocular exposure due to exorbitism, and airway compromise caused by midface retrusion. Craniolacunae and upper and lower extremity anomalies are not frequently found in Crouzon syndrome. We present a girl with Crouzon syndrome caused by c.1040 C > G, p.Ser347Cys, a pathogenic mutation in the FGFR2 gene with atypical characteristics, including craniolacunae resembling severe Swiss cheese type of bone formation, and upper and lower extremity anomalies which are more commonly associated with Pfeiffer syndrome patients. Distinguishing between severe Crouzon syndrome patients and patients who have mild and/or moderate Pfeiffer syndrome can be challenging even for an experienced craniofacial surgeon. An accurate genotype diagnosis is essential to distinguishing between these syndromes, as it provides predictors for neurosurgical complications and facilitates appropriate family counseling related to long-term outcomes.

Venous anomalies in hypoplastic posterior fossa: unsolved questions.

INTRODUCTION: Anomalous intracranial venous anatomy is described in patients with syndromic craniosynostosis and is of significant importance when it comes to surgical morbidity. However, it is still controversial its origin, type of circulation in each syndrome, how it behaves over time, when it can be interrupted and wether it needs to be studied. The purpose of this paper is to discuss these issues by reviewing the literature. METHODS: A literature search was performed using the PubMed database with a focus on papers including detailed descriptions of the venous outflow in complex and syndromic craniosynostosis. Search details used were the following: ("veins"[MeSH Terms] OR "veins"[All Fields] OR "venous"[All Fields]) AND ("abnormalities"[Subheading] OR "abnormalities"[All Fields] OR "anomalies"[All Fields]) AND syndromic[All Fields] AND ("craniosynostoses" [MeSH Terms] OR "craniosynostoses"[All Fields] OR "craniosynostosis"[All Fields]). Studies that exposed details of venous anomalies found in syndromic or complex craniosynostosis were selected. RESULTS: Of a total of 211 articles found, 11 were selected for this review. Of these, 5 were case reports, 5 retrospective studies, and only 1 prospective study. From the 6 series of cases presented, 5 discussed the relationship between jugular foramen stenosis (JFS) and collateral venous drainage. The authors discuss data from the literature for each leading question presented: 1-collateral circulation: is it an intrinsic trouble, a consequence of stenosis of the cranial base foramina or related to raised intracranial pressure (ICP)?; 2-what venous anomalies should we search for, and what is the best exam to study them?; 3-collateral circulation changes with time?; 4-can neurosurgeons interrupt the collateral circulation?; 5-should we study all complex types of craniosynostosis? CONCLUSION: The importance of the study of the venous outflow in patients with complex craniosynostosis is evident in the literature. The real relationship between intracranial hypertension, hypoplastic skull base foramen, Chiari I malformation, hydrocephalus, and venous collateral circulation remains unknown. Prospective studies focusing on molecular biology analysis will possibly solve all of these leading questions.

Syndrome-related outcomes following posterior vault distraction osteogenesis.

PURPOSE: The most commonly occurring syndromic craniosynostoses are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, and Saethre-Chotzen syndrome. There is insufficient data regarding postoperative syndrome-related outcomes following the posterior vault distraction osteogenesis (PVDO) procedure, as well as data addressing whether or not additional procedures will be subsequently necessary to comprehensively treat children who undergo PVDO. Thus, the objective of this study is to describe and compare syndrome-related potential complications and outcomes associated with the PVDO procedure. METHODS: An observational retrospective study was performed on consecutive patients (n=24) with Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, or Saethre-Chotzen syndrome, respectively, who underwent PVDO between 2012 and 2019. Demographic data (patient gender and age when the PVDO procedure was performed), diagnosis, surgery-related data, and outcome data (perioperative and midterm complications and need for additional surgery) were verified. RESULTS: Total relative blood transfusion volumes per kilogram for the patients were as follows: 22.75 ± 9.30 ml for Apert syndrome, 10.73 ± 2.28 ml for Crouzon syndrome (Apert versus Crouzon, p<0.05), 18.53 ± 8.08 ml for Pfeiffer syndrome, and 19.74 ± 9.12 ml for Saethre-Chotzen syndrome. None of the patients required a secondary procedure to alleviate intracranial pressure except for a Saethre-Chotzen patient. CONCLUSION: PVDO is an effective technique to address elevated intracranial pressure in SC patients that alleviates the need for secondary procedures at midterm follow-up. Apert syndrome patients presented relatively higher total blood transfusion rates than Crouzon syndrome patients who were operated on at a later age and weighed more.

Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis: a single center experience.

INTRODUCTION: Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis (SC) requires understanding the underlying mechanisms that cause increased intracranial pressure (ICP) and the role of cerebrospinal fluid (CSF) in cranial vault expansion in order to select the best treatment option for each individual patient. METHODS: A total of 33 pediatric patients with SC requiring craniofacial surgery were retrospectively evaluated. Cases of nonsyndromic craniosynostosis and shunt-induced craniosynostosis were excluded. Six syndrome-based categories were distinguished: Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, cloverleaf skull syndrome, and others (Muenke syndrome, Sensenbrenner syndrome, unclassified). All of the patients were treated surgically for their cranial deformity between 2010 and 2016. The presence of ventriculomegaly and ventriculoperitoneal (VP) shunt requirement with its impact in cranial vault expansion were analyzed. Clinical and neuroimaging studies covering the time from presentation through the follow-up period were revised. The mean postoperative follow-up was 6 years and 3 months. A systematic review of the literature was conducted through a PubMed search. RESULTS: Of the total of 33 patients with SC, 18 (54.5%) developed ventriculomegaly and 13 (39.4%) required ventriculoperitoneal (VP) shunt placement. Six patients (18.2%) required shunt placement previous to craniofacial surgery. Seven patients (21.2%) required a shunt after craniofacial surgery. Seven fixed pressure ventriculoperitoneal shunts and six programmable valves were placed as first choice. All patients improved their clinical symptoms after shunt placement. Aesthetic results seemed to be better in patients with programmable shunts. CONCLUSIONS: Unless clear criteria for overt hydrocephalus are present, it is recommended to perform craniofacial surgery as a first step in the management of patients with SC in order to preserve the expansive effect of CSF for cranial vault expansion. In our experience, the use of externally programmable valves allows for the treatment of hydrocephalus while maintaining the expansive effect of CSF for the remodeling of the cranial vault. Prospective evaluations are needed to determine causality.