A European multicenter outcome study on the different perioperative airway management policies following midface surgery in syndromic craniosynostosis: a proposal for a Standard Operating Procedure.

BACKGROUND: Perioperative airway management following midface advancements in children with Apert and Crouzon/Pfeiffer syndrome can be challenging, and protocols often differ. This study examined airway management following midface advancements and postoperative respiratory complications. METHODS: A multicenter, retrospective cohort study was performed to obtain information about the timing of extubation, perioperative airway management, and respiratory complications after monobloc / le Fort III procedures. RESULTS: Ultimately, 275 patients (129 monobloc and 146 Le Fort III) were included; 62 received immediate extubation and 162 delayed extubation; 42 had long-term tracheostomies and nine perioperative short-term tracheostomies. Short-term tracheostomies were in most centers reserved for selected cases. Patients with delayed extubation remained intubated for three days (IQR 2 - 5). The rate of no or only oxygen support after extubation was comparable between patients with immediate and delayed extubation, 58/62 (94%) and 137/162 (85%) patients, respectively. However, patients with immediate extubation developed less postoperative pneumonia than those with delayed, 0/62 (0%) versus 24/161 (15%) (P = 0.001), respectively. Immediate extubation also appeared safe in moderate/severe OSA since 19/20 (95%) required either no or only oxygen support after extubation. The odds of developing intubation-related complications increased by 21% with every extra day of intubation. CONCLUSIONS: Immediate extubation following midface advancements was found to be a safe option, as it was not associated with respiratory insufficiency but did lead to fewer complications. Immediate extubation should be considered routine management in patients with no/mild OSA and should be the aim in moderate/severe OSA after careful assessment.

Neoforehead Remodelling Techniques for Fronto-Orbital Advancement and Remodelling in the Oxford Craniofacial Unit: Lateral Remodelling and a Novel Central Self-Stabilizing S-Osteotomy Technique.

Fronto-orbital advancement and remodelling (FOAR) has undergone many modifications over the years, aimed at improving outcomes and reducing risks for patients. This work describes 2 techniques for remodelling the neoforehead used by the Oxford Craniofacial Unit since 1995: lateral remodelling and a central S-Osteotomy. Both methods adopt bone from the vertex as a neoforehead, but they differ in their techniques to adapt its shape to that of the newly remodelled orbital bandeau. The novel S-Osteotomy technique can be successfully applied to all FOAR procedures, irrespective of underlying synostosis and calvarial symmetry. It was originally developed for when 2 separate bony panels were required to create a neoforehead in asymmetrical cases, but was adopted for single panel neoforehead designs in metopic synostosis with the idea it may reduce temporal hollowing. An investigation of temporal hollowing in these patients who underwent either of the described methods was undertaken to assess this hypothesis with no statistically significant difference seen ( P =0.1111). Both techniques on average resulted in minimal hollowing that was not felt to require any revision, supporting the belief that temporal hollowing is a multifactorial issue. This work describes 2 successful methods of neoforehead remodelling and introduces the S-Osteotomy technique that can be applied in all FOAR procedures.

Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene.

ABSTRACT: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF- related craniosynostosis, together with three of their carrier parents.There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity.It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties.The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF -related mutation.

Implications for the Multi-Disciplinary Management of Children With Craniofrontonasal Syndrome.

The purpose of this retrospective study was to assess the genetic and phenotypic features of patients with craniofrontonasal syndrome (CFNS), and the implications of the condition for multidisciplinary management.The subjects were 25 female patients with a mutation of EFNB1, who presented to the Oxford Craniofacial Unit during a 38-year period. Medical records were reviewed for genetic and phenotypic information. Mean duration of follow-up was 12.6 years (range 0-30.7 years).This study examines neurodevelopment in constituent parts, with specific reference to speech, language, and cognition in relation to genotype. Three children had deletions extending beyond the EFNB1 gene; the 2 with available data presented with speech, language, or cognitive delay. The remaining 25 patients had intragenic mutations of EFNB1. Of these 25, those assessed in detail showed variable difficulties with speech and language development; 57% had receptive language difficulties (n = 4/7) and 88% had expressive language difficulties (n = 8/9). 55% presented with speech difficulties (n = 6/11). 2/3 patients with abnormal hearing had speech difficulties; 4/5 with normal hearing had normal speech development. Cognitive assessments indicated that IQ is variable; with full scale IQ ranging from 69 to 100.The complex, multifactorial presentation of patients with CFNS contributed to 41% (n = 7/17) of patients requiring additional educational support.Our results demonstrated significant multidisciplinary input is required, including Speech and Language Therapy, Plastic and Reconstructive Surgery, Genetics, Ear, Nose and Throat, Maxillofacial, Orthodontic, Orthopaedic, Clinical Psychology and Orthoptic teams. The results of this study reinforce the importance of multi-disciplinary long-term follow-up of children with CFNS.

ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome.

Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari-1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF-related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan-) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari-1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow-up.

Disruption of TWIST1 translation by 5' UTR variants in Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5' UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may represent an under-ascertained cause of monogenic disease.

A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.

The Management of Trigonoscaphocephaly as a Result of Combined Metopic and Sagittal Synostosis.

BACKGROUND: The combination of sagittal and metopic synostosis is rare, resulting in a scaphocephalic shape, but with an absence of frontal bossing and therefore varying degrees of trigonocephaly and occipital prominence. Treatment is primarily surgical, with a combination of procedures to address both the scaphocephaly and trigonocephaly required involving multiple operations. The authors discuss their experience of treating combined trigonoscaphocephaly in a single-stage procedure and propose a management strategy based on the severity of the presenting deformity. METHODS: The Oxford Craniofacial Unit database was searched from inception in October of 2004 to August of 2013 to identify all patients with combined sagittal and metopic synostosis. Case notes were then manually searched to identify those patients who had true trigonoscaphocephaly. RESULTS: Of 2856 patients in the authors' database, a total of nine were identified as having had true trigonoscaphocephaly. Seven of these patients underwent a combined single-stage procedure with an average cephalic index of 68.7 percent preoperatively and 80.3 percent postoperatively. CONCLUSIONS: Management of trigonoscaphocephaly has been traditionally performed by multiple, staged surgical procedures. The authors propose that it can instead be managed in a single surgical procedure, with the choice of procedure determined by the severity of the deformity. If the deformity is mild to moderate with no occipital bullet, a combined fronto-orbital advancement remodeling and subtotal calvarial remodeling can be performed; however, if there is an occipital bullet, the authors propose the combination of fronto-orbital advancement remodeling and total calvarial remodeling performed in one operation with the patient turned from prone to supine intraoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Diagnostic value of exome and whole genome sequencing in craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. METHODS: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. RESULTS: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). CONCLUSIONS: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

Association of mutations in FLNA with craniosynostosis.

Mutations of FLNA, an X-linked gene that encodes the cytoskeletal protein filamin A, cause diverse and distinct phenotypes including periventricular nodular heterotopia and otopalatodigital spectrum disorders (OPDS). Craniofacial abnormalities associated with OPDS include supraorbital hyperostosis, down-slanting palpebral fissures and micrognathia; craniosynostosis was previously described in association with FLNA mutations in two individual case reports. Here we present four further OPDS subjects who have pathological FLNA variants and craniosynostosis, supporting a causal link. Together with the previously reported patients, frontometaphyseal dysplasia was the most common clinical diagnosis (four of six cases overall); five patients had multiple suture synostosis with the sagittal suture being the most frequently involved (also five patients). No genotype-phenotype correlation was evident in the distribution of FLNA mutations. This report highlights the need to consider a filaminopathy in the differential diagnosis of craniosynostosis, especially in the presence of atypical cranial or skeletal features.

The incidence of raised intracranial pressure in nonsyndromic sagittal craniosynostosis following primary surgery.

OBJECT Raised intracranial pressure (ICP) is recognized to occur in patients with nonsyndromic isolated sagittal craniosynostosis (SC) prior to surgery. However, the incidence of raised ICP following primary surgery is rarely reported and there appears to be a widely held assumption that corrective surgery for SC prevents the later development of intracranial hypertension. This study reports the incidence of postoperative raised ICP in a large cohort of patients with SC treated by 1 of 2 surgical procedures in a single craniofacial unit. METHODS A retrospective review was performed of all patients with SC who underwent either a modified strip craniectomy (MSC) or calvarial remodeling (CR) procedure under the care of the Oxford Craniofacial Unit between 1995 and 2010 and who were followed up for more than 2 years. The influence of patient age at surgery, year of surgery, sex, procedure type, and the presence of raised ICP preoperatively were analyzed. RESULTS Two hundred seventeen children had primary surgery for SC and were followed up for a mean of 86 months. The overall rate of raised ICP following surgery was 6.9%, occurring at a mean of 51 months after the primary surgical procedure. Raised ICP was significantly more common in those patients treated by MSC (13 of 89 patients, 14.6%) than CR (2 of 128 patients, 1.6%). Also, raised ICP was more common in patients under 1 year of age, the majority of whom were treated by MCS. No other factor was found to have a significant effect. CONCLUSIONS Postoperative raised ICP was found in more than 1 in 20 children treated for nonsyndromic SC in this series. It was significantly influenced by the primary surgical procedure and age at primary surgery. Careful long-term follow-up is essential if children who develop raised ICP following surgery are not to be overlooked.

Long-term morphological outcomes in nonsyndromic sagittal craniosynostosis: a comparison of 2 techniques.

Correction of scaphocephaly is one of the principle goals of surgery in sagittal craniosynostosis. Reported relapse in head shape after surgery and continued head growth into late adolescence underscores the need for long-term outcomes to be considered when comparing between different surgical approaches in this condition; yet there are relatively few reports of results to 5 years and beyond in the literature. Therefore, a retrospective review was performed of the anthropometric data of 224 patients with sagittal craniosynostosis who underwent primary surgery between 1994 and 2012. During this period, patients underwent either a modified strip craniectomy (MSC) or calvarial remodeling (CR) procedure. Sixty-two patients were treated by MSC and followed up for a mean of 44 months. One hundred sixty-two patients had CR, with follow-up for a mean of 45 months. Overall, 90 patients were seen up to 5 years, and 47 patients to 9 years or more after surgery. The cephalic index (CI) of MSC-treated patients improved from a mean of 67.0 to 72.7, with 31% achieving a CI greater than 75 at one year. Calvarial remodeling was significantly more effective at correcting the scaphocephalic deformity. Patients treated with CR improved from a mean CI of 66.7 to 76.1. Sixty-two percent of the patients achieved a CI greater than 75. In both groups, outcomes were stable throughout follow-up with no significant relapse up to 14 years after surgery.

The aesthetic outcome of surgical correction for sagittal synostosis can be reliably scored by a novel method of preoperative and postoperative visual assessment.

BACKGROUND: Aims of surgical correction for isolated sagittal synostosis are functional and aesthetic. Multiple surgical techniques exist; however, reliable assessment of aesthetic outcome is poorly documented, limiting direct comparisons. The pinched appearance of the temporal regions is particularly challenging to correct. A visual analogue scale was designed to grade skull shape in patients who had total or subtotal calvarial remodeling for isolated sagittal synostosis. METHODS: Twenty-two assessors graded preoperative and postoperative photographs from 42 consecutive cases of sagittal synostosis under a single surgeon. Five aspects were graded (i.e., narrow elongated skull, frontal bossing, temporal pinching, occipital bullet, and overall shape) from 0 (normal) to 100 (severe). Interobserver and intraobserver agreement were analyzed by calculating within-subject standard deviation, coefficient of variation, and intraclass correlation coefficient. Linear regression analysis determined predictors of outcome. RESULTS: Surgery improved outcome dramatically across all five aspects of skull shape, with a 72.6 to 76.4 percent decrease in severity score. Improvements in severity score were greater after total calvarial remodeling, and type of calvarial remodeling (total versus subtotal) was an independent predictor of outcome in all aspects of skull shape (p≤0.001). Temporal pinching was improved in a subset of patients who also had onlay bone grafts in this region. CONCLUSIONS: Calvarial remodeling is a powerful technique for improving skull shape. A panel can detect gross and subtle aesthetic changes after surgical correction of sagittal synostosis using a visual analogue scale, with moderate interobserver and intraobserver agreement. This provides a tool for future outcome assessment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The preoperative incidence of raised intracranial pressure in nonsyndromic sagittal craniosynostosis is underestimated in the literature.

OBJECT: The presence of raised intracranial pressure (ICP) in untreated nonsyndromic, isolated sagittal craniosynostosis (SC) is an important functional indication for surgery. METHODS: A retrospective review was performed of all 284 patients presenting with SC to the Oxford Craniofacial Unit between 1995 and 2010. RESULTS: Intraparenchymal ICP monitoring was performed in 39 children following a standard unit protocol. Monitoring of ICP was offered for all patients in whom nonoperative management was considered on the basis of minimal deformity or in cases in which parents were reluctant to agree to corrective surgery. These patients presented at an older age than the rest of the cohort (mean age 56 months), with marked scaphocephaly (16/39, 41%), mild scaphocephaly (11, 28%), or no scaphocephalic deformity (12, 31%). Raised ICP was found in 17 (44%) patients, with no significant difference in its incidence among the 3 different deformity types. Raised ICP was not predicted by the presence of symptoms of ICP or developmental delay or by ophthalmological or radiological findings. CONCLUSIONS: The incidence of raised ICP in SC reported here is greater than that previously published in the literature. The lack of a reliable noninvasive method to identify individuals with elevated ICP in SC mandates consideration of intraparenchymal ICP monitoring in all patients for whom nonoperative management is contemplated.

A novel use of the rigid external distraction frame: acute on-table distraction with autologous bone grafting.

Distraction osteogenesis with an external distraction device such as the rigid external distraction (RED) frame has become an established method for treating midface hypoplasia. It allows for greater advancement of the midface than achievable with traditional Le Fort III osteotomies; however, there are a number of problems associated with frame application such as pin site migration and need for frame removal. We present 2 cases of the novel use of the RED frame, in both a pediatric patient and an adult patient. The RED frame was used to achieve table soft tissue distraction, greater than previously achievable with traditional Le Fort III osteotomy. This was then combined with acute bone grafting, allowing the RED frame to be removed intraoperatively and thereby removing the complications associated with long-term frame application. We believe this to be the first reported use of the RED frame for acute on-table distraction of the midface. This has allowed far greater advancement of the midface than would be achievable with traditional Le Fort III advancement but, when combined with autologous bone grafting, has allowed intraoperative removal of the frame, thus negating some of the complications of long-term distraction osteogenesis using the RED frame.

Lessons learned in posterior cranial vault distraction.

INTRODUCTION: Posterior distraction (PD) is rapidly emerging as an important technique to increase the intracranial volume and correct calvarial morphology in patients with severe brachycephaly or turribrachycephaly. METHODS: A retrospective review was performed of all 31 patients who underwent PD at the Oxford Craniofacial Unit between 2007 and 2012. RESULTS: Twenty-three patients (74.2%) underwent PD as a primary procedure at a median age of 8 months. Eight patients (25.8%) had PD as a secondary transcranial procedure at a median age of 48 months. Full distraction to 20 mm was achieved in 28 patients (90.3%). Of these, all but 1 demonstrated a significant improvement in morphology, with a resolution of the symptoms and signs of raised intracranial pressure in all proven to have it preoperatively. Unanticipated events occurred in 61.3% of patients, with 19.4% undergoing one or more unplanned procedures. Wound infection (29.0%) and tissue necrosis (22.6%) were the commonest. Cerebrospinal fluid leaks were rarer (6.5%) but prevented full distraction. Nine patients (29.0%) had a consolidation period of less than 30 days without experiencing relapse. In 11 patients who had a later fronto-orbital advancement and remodeling, wound closure was tight, resulting in dehiscence in 3 cases (27.3%). CONCLUSIONS: Posterior distraction is an effective procedure in the management of severe brachycephaly or turribrachycephaly but has associated risks. Our protocol has evolved with experience to favor a reduced latency period and consolidation phase and the use of 2 distractor devices.

A novel technique to secure the Rigid External Distraction (RED) frame in a thin skull allowing sutural mid-face distraction.

Distraction osteogenesis (DO) has revolutionised the treatment of mid-face hypoplasia in children, allowing advancement of the mid-face in excess of that achievable by traditional Le Fort III osteotomy. One method of performing DO is to use an externally applied frame, such as the Rigid External Distraction (RED) frame. However, at young ages the cranial bone is often too weak to support the frame, preventing its safe use. We present the case of a patient with Crouzon syndrome who required mid-face distraction at 4-months of age due to severe exorbitism, raised intracranial pressure and airway compromise. In order to allow safe application of an external distraction frame laminated bone grafts were secured to the cranium at the areas of frame pin insertion. We believe this to be the first reported case of the use of the patients own cranial bone to create laminated bone grafts and thicken the site of pin insertion. The method described adds to the armamentarium of the surgeon treating these patients who require placement of an external distraction frame for DO at a young age where the thickness of the cranial bone may otherwise prevent safe application.

The relationship between scaphocephaly at the skull vault and skull base in sagittal synostosis.

HYPOTHESIS: The skull vault is scaphocephalic in sagittal synostosis but little is known about the deformity at the skull base. If differential progressive deformity occurs between the vault and base, this might affect decision making regarding the timing of surgical intervention. We used 3-dimensional CT (3DCT) scans to compare deformity at the vault, base and posterior fossa in sagittal synostosis. Cephalic index (CI) was measured in 34 consecutive cases of isolated sagittal synostosis and 16 controls using predefined landmarks on the 3DCT volume data set. Planes were generated by a Vitrea™ workstation. Data were analysed by Student's t-test and Pearson coefficient. RESULTS: Ratios of CI between the vault and base, and the vault and posterior fossa were significantly reduced in sagittal synostosis (p < 0.0001 and p = 0.0031) demonstrating a milder deformity at the base and posterior fossa. However there was strong positive correlation between CI at the vault and base (r = 0.77, p < 0.0001). We have therefore shown for the first time that the deformity at the base is less severe, but is still closely correlated with the vault in unoperated sagittal synostosis. This study provides a basis for future work analysing the progression of these deformities before and after surgery.