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Background and Purpose: Craniosynostoses are rare congenital craniofacial malformations, variably affected by hearing loss, often requiring repeated CT examinations to assess skull or temporal bone (TB) abnormalities. In order to avoid radiation exposure in these young patients, efforts are made to assess the skull abnormalities on MR bone imaging sequences, such as Black Bone (BB). Our aim is to compare BB, a radiation-free imaging technique, with CT for the assessment of the TB., Materials and Methods: 48 patients who underwent both BB and CT (2016-2021) in Sophia Children's Hospital, Erasmus MC, Rotterdam, were retrospectively investigated. BB and CT (the diagnostic gold standard for imaging the temporal bone) were evaluated blindly and independently by 3 observers; visibility and abnormalities of TB structures and cranial nerves were scored; abnormal findings were confirmed by a senior pediatric neuroradiologist. The statistical analysis was performed using Gwet's AC1 agreement and modified versions of the Wilcoxon signed-rank test and sign test with a Bonferroni-Holm correction (p < 0.05)., Results: CT was rated higher than BB in structure visibility (global p = 0.0002), but was rated similar to BB when assessing TB anatomy and pathology (global p = 0.58). The visibility ratings showed better interobserver agreement values on CT than BB. In the normal/abnormal ratings, both BB (0.75-1) and CT (0.88-1) showed high interobserver agreement values., Conclusion: Our preliminary results suggest that BB is a promising tool for screening TB pathology in patients with craniosynostosis who require MR imaging., Competing Interests: Declarations. Ethical approval: The study was approved by the local Ethics Committee. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Informed consent: Informed consent was obtained from legal guardians. Conflict of interest: The authors declare no conflicts of interest related to the content of this article., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is considerable variability in the management of common orofacial clefts across Europe, reflecting differing opinions on optimal treatments. An updated overview of treatment protocols for orofacial clefts across 26 expert centres in the European Reference Network CRANIO is presented here. A structured questionnaire was distributed to map the surgical protocol and additional standard procedures for cleft palate (CP), unilateral cleft lip and palate (UCLP), and bilateral cleft lip and palate (BCLP). A surgical protocol was defined as the unique combination of a sequence of standard surgeries, their timing, and the surgical techniques employed. Overall, 33 unique surgical protocols for CP, 54 for UCLP, and 51 for BCLP were identified. Notable findings included the trend towards early hard palate closure, uniform timing of lip closure, and the popularity of primary cleft rhinoplasty. Nevertheless, practice variations were most pronounced in the timing of alveolar closure, the number of standard surgeries, and the application of additional standard procedures. This study highlights the diversity of treatment protocols across Europe, despite considerable convergence of treatment practices over time. To allow for further convergence, establishing objective criteria for protocol selection, adequate documentation of customizations, and consensus on the terminology of surgical techniques, are necessary., Competing Interests: Conflict of Interest This research is generated within the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose and throat (ENT) disorders (ERN CRANIO). ERN CRANIO is funded by the European Union. The content of this paper represents the views of the authors only and it is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the European Health and Digital Executive Agency (HaDEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains. Thus, the authors of current study had no competing interest caused by the (partial) funding of this research. The authors that contributed to current study also have no other competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Metopic synostosis patients are at risk for neurodevelopmental disorders despite a negligible risk of intracranial hypertension. To gain insight into the underlying pathophysiology of metopic synostosis and associated neurodevelopmental disorders, we aimed to investigate brain volumes of non-syndromic metopic synostosis patients using preoperative MRI brain scans. MRI brain scans were processed with HyperDenseNet to calculate total intracranial volume (TIV), total brain volume (TBV), total grey matter volume (TGMV), total white matter volume (TWMV) and total cerebrospinal fluid volume (TCBFV). We compared global brain volumes of patients with controls corrected for age and sex using linear regression. Lobe-specific grey matter volumes were assessed in secondary analyses. We included 45 metopic synostosis patients and 14 controls (median age at MRI 0.56 years [IQR 0.36] and 1.1 years [IQR 0.47], respectively). We found no significant differences in TIV, TBV, TGMV or TCBFV in patients compared to controls. TWMV was significantly smaller in patients (-62,233 mm 3 [95% CI = -96,968; -27,498], Holm-corrected p = 0.004), and raw data show an accelerated growth pattern of white matter in metopic synostosis patients. Grey matter volume analyses per lobe indicated increased cingulate (1378 mm 3 [95% CI = 402; 2355]) and temporal grey matter (4747 [95% CI = 178; 9317]) volumes in patients compared to controls. To conclude, we found smaller TWMV with an accelerated white matter growth pattern in metopic synostosis patients, similar to white matter growth patterns seen in autism. TIV, TBV, TGMV and TCBFV were comparable in patients and controls. Secondary analyses suggest larger cingulate and temporal lobe volumes. These findings suggest a generalized intrinsic brain anomaly in the pathophysiology of neurodevelopmental disorders associated with metopic synostosis., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Background: Perioperative airway management following midface advancements in children with Apert and Crouzon-Pfeiffer syndromes 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 or Le Fort III procedures., Results: A total of 275 patients (monobloc surgery, n = 129; Le Fort III surgery, n = 146) were included. Sixty-two patients received immediate extubation and 162 received delayed extubation; 42 had long-term tracheostomies, and 9 had perioperative short-term tracheostomies. In most centers, short-term tracheostomies were reserved for selected cases. Patients with delayed extubation remained intubated for 3 days (interquartile range, 2 to 5 days). The rate of no or only oxygen support after extubation was comparable between immediate and delayed extubation groups (58 of 62 patients [94%] and 137 of 162 patients [85%], respectively). However, the immediate extubation group developed fewer cases of postoperative pneumonia than did the delayed group (0 of 62 [0%] versus 24 of 161 [15%]; P = 0.001). Immediate extubation also appeared safe in moderate to severe obstructive sleep apnea, as 19 of 20 patients (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 or mild obstructive sleep apnea, and should be the aim in moderate to severe obstructive sleep apnea cases after careful assessment., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons.)

Background: Craniosynostosis, a congenital condition characterized by the premature fusion of cranial sutures, necessitates objective methods for evaluating cranial morphology to enhance patient treatment. Current subjective assessments often lead to inconsistent outcomes. This study introduces a novel, quantitative approach to classify craniosynostosis and measure its severity., Methods: An artificial neural network was trained to classify normocephalic, trigonocephalic, and scaphocephalic head shapes based on a publicly available dataset of synthetic 3D head models. Each 3D model was converted into a low-dimensional shape representation based on the distribution of normal vectors, which served as the input for the neural network, ensuring complete patient anonymity and invariance to geometric size and orientation. Explainable AI methods were utilized to highlight significant features when making predictions. Additionally, the Feature Prominence (FP) score was introduced, a novel metric that captures the prominence of distinct shape characteristics associated with a given class. Its relationship with clinical severity scores was examined using the Spearman Rank Correlation Coefficient., Results: The final model achieved excellent test accuracy in classifying the different cranial shapes from their low-dimensional representation. Attention maps indicated that the network's attention was predominantly directed toward the parietal and temporal regions, as well as toward the region signifying vertex depression in scaphocephaly. In trigonocephaly, features around the temples were most pronounced. The FP score showed a strong positive monotonic relationship with clinical severity scores in both scaphocephalic (ρ = 0.83, p < 0.001) and trigonocephalic (ρ = 0.64, p < 0.001) models. Visual assessments further confirmed that as FP values rose, phenotypic severity became increasingly evident., Conclusion: This study presents an innovative and accessible AI-based method for quantifying cranial shape that mitigates the need for adjustments due to age-specific size variations or differences in the spatial orientation of the 3D images, while ensuring complete patient privacy. The proposed FP score strongly correlates with clinical severity scores and has the potential to aid in clinical decision-making and facilitate multi-center collaborations. Future work will focus on validating the model with larger patient datasets and exploring the potential of the FP score for broader applications. The publicly available source code facilitates easy implementation, aiming to advance craniofacial care and research., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Purpose: Trigonocephaly is associated with suboptimal visual outcomes in young children. However, the presence of orthoptic abnormalities after completed visual development remains unknown. The purpose of this study is to assess the prevalence of orthoptic abnormalities in trigonocephaly patients, after completed visual development., Methods: A retrospective study among non-syndromic trigonocephaly patients aged 8 years and older was conducted at the Dutch Craniofacial center. Ophthalmologic records were reviewed for refractive errors and a history of strabismus and amblyopia. Refractive errors were classified as follows: myopia: spherical equivalent (SE) ≤ -0.50 diopters (D), emmetropia: SE -0.50 D to + 0.50 D, hyperopia: ≥ + 0.50 D, astigmatism: cylinder error ≥ 1.00 D. The history of strabismus and amblyopia was assessed retrospectively. Prevalence and cumulative incidence of these abnormalities in healthy age-matched populations were retrieved from literature., Results: We included 78 trigonocephaly patients with a median (interquartile range) age of 10.0 (9.0-12.0) years. Thirty-four (43.6%) of these patients presented with a refractive error after the age of 8 years. Specific findings in these 78 patients versus controls were hyperopia in 35.9% vs 8.4%; myopia in 6.4% vs 11.4%; astigmatism in 20.5% vs 11.9%; strabismus in 14.1% vs 2.65%; amblyopia in 6.4% vs 3.4%., Conclusions: Trigonocephaly patients have a two-to-threefold higher risk of hyperopia, astigmatism, amblyopia, and strabismus, as compared to healthy populations. We recommend screening and, in case of abnormalities, regular follow-up before completed visual development. In addition, we recommend long-term surveillance of visual functioning by a pediatric ophthalmologist and/or orthoptist., Competing Interests: Declarations. Ethical approval: This study was exempted from review by the relevant institutional review boards (MEC-2016–312) in view of the retrospective nature of the study and the procedures being performed were part of the routine care. Conflict of interest: There are no conflicts of interest in relation to the materials or subject matter dealt with in this article., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patient-Reported Outcome Measures (PROMs), such as the CLEFT-Q, have become essential for outcomes in patients with CL/P. Normative values of the CLEFT-Q for non-CL/P peers have not yet been established. This study aims to establish normative values for the CLEFT-Q in the general Dutch population. Dutch nationals aged 16-24 years without CL/P were recruited through an online survey. Participants completed the CLEFT-Q, excluding the lip scar and eating and drinking scales. Data were weighted based on the Dutch Central Bureau of Statistics. Normative values were calculated as means and standard deviations, stratified by sex and education category. Tobit regression models were used to analyze associations between CLEFT-Q scores and demographic variables. In total, 870 participants responded, of which 160 were excluded due to potential craniofacial anomalies. Significant variations in CLEFT-Q scores based on sex were found, with females scoring lower than males. Level of education had a modest impact on CLEFT-Q scores, with lower education having lower scores on certain scales. Age marginally influenced CLEFT-Q scores, with younger participants scoring lower than older participants. Positive correlations were found between all CLEFT-Q scales. The strongest correlation was observed between the social and school functioning scales. This study provides the first set of normative values for the CLEFT-Q in the Dutch general population. Significant differences in CLEFT-Q scores based on sex, level of education and age were found. These normative values are useful for clinicians interpreting CLEFT-Q scores and help make informed decisions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

Objective: The exact association between the frequently present anomalous intracranial venous vasculature, emissary collaterals, ventriculomegaly, and increased intracranial pressure (ICP) in children with Apert and Crouzon syndromes remains an enigma. This study aimed to evaluate the association between the aberrant venous system and ventricle size and increased ICP, and to assess the development of the venous structures over time., Methods: This retrospective cohort study included all patients with Apert or Crouzon syndrome with available CT venography (CTV) scans of the brain. Anomalous venous vasculature was assessed by the total collateral score (TCS), which scored 9 intra- and extracranial venous structures (TCS range 0-16). Ventricle size (fronto-occipital horn ratio [FOHR]) was measured on the same scan. The presence of increased ICP, a shunt, tonsillar herniation, and head circumference were extracted from electronic patient records and were used as secondary covariates. Subsequent CTV scans were scored when available., Results: Ninety patients were included in this study. The mean TCS was 7.5 ± 2.5, and was comparable for patients with Apert and Crouzon syndromes (mean 8.0 and 7.3, respectively). The presence of an extra abnormal venous structure was associated with an increase of the FOHR of 3.2% (p < 0.01). After dividing the venous structures into intra- and extracranial, a similar association between both and the FOHR was found (4.1% and 2.3%, respectively; p < 0.01). The TCS was similar for patients with normal and increased ICP at the time of the scan. Sixteen patients had dual CTV scans. The median time between both scans was 3.2 years. The presence of collaterals remained stable over time (median ΔTCS = 0.3). Seven patients with functioning shunts also maintained high TCSs (median TCS = 9)., Conclusions: In patients with Apert and Crouzon syndromes, a close relationship between venous collaterals and ventricle size was observed, in which a more extensive aberrant venous drainage pattern, both intra- and extracranial, was associated with larger ventricles. Preliminary longitudinal data suggested that the presence of venous collaterals remained constant over time despite effective treatment of increased ICP, indicating reliance on these collaterals even in cases of normal ICP. The authors hypothesize that this dependence on collateral drainage is the result of their aberrant internal venous anatomy and predisposes individuals to increased ICP.

Background: In patients with craniosynostosis, the authors evaluated the diagnostic accuracy of fundoscopy and optical coherence tomography (OCT) to detect intracranial hypertension (ICH), the time course of retinal thickness after treatment of ICH, and the relationship between high hyperopia (HH) and fundoscopy/OCT scan findings., Methods: Patients with syndromic, multisuture, unicoronal, unilambdoid, or sagittal synostosis visiting the authors' national center were included in this longitudinal cohort study and formed a consecutive series. Retinal layers on OCT, OCT fundus images, and fundoscopy results were evaluated. ICH was scored according to presence of abnormal intracranial pressures, hydrocephalus, progressive cerebellar tonsillar herniation or fingerprinting, and growth arrest. Diagnostic accuracy of OCT, fundoscopy, and fundus image; the time course of retinal thickness after ICH; and interference of HH were analyzed using linear mixed models., Results: A total of 577 OCT scans in 307 patients were included. ICH was found in 7.2%. Combining total retinal thickness (TRT), OCT fundus imaging and fundoscopy resulted in a sensitivity of 76% and 81% specificity to detect signs of ICH. TRT was increased in patients who had had signs of ICH versus patients who had never had signs of ICH (β +44.9 µm in patients who had had ICH [95% CI, 9.0 to 80.8]; P = 0.01). TRT decreased to normal in the years after surgery (β -3.6 µm/yr [95% CI, -7.2 to -0.05]; P = 0.047). There were greater odds of having increased TRT in patients with HH (OR, 2.9 [95% CI, 1.1 to 7.6]; P = 0.03)., Conclusions: The correlation among TRT, OCT fundus image, fundoscopy, and particularly the combination of these measures with intracranial pressure surrogate markers is fair. Increased TRT in the presence of a clinical suspicion of ICH warrants further screening., Clinical Question/level of Evidence: Diagnostic, III., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons.)

There is still no unanimous agreement on the optimal surgical protocol(s) for the treatment of unilateral cleft lip and palate (UCLP), and a huge variety of protocols are employed by cleft centres across the world. The aim of this systematic review and meta-analysis was to compare reported patient outcomes of the Oslo protocol (and modifications) (OP) and delayed hard palate closure protocols (DHPCP) from a multidisciplinary perspective. A systematic search of multiple databases was conducted until September 2023. Studies reporting any patient outcomes of these protocols were included. Random-effects meta-analyses were performed for evidence synthesis, including comparisons of results between the types of protocol. The quality of evidence was evaluated using the ROBINS-I tool. In total, 62 articles (42 studies) reporting patients with UCLP were reviewed, involving 1281 patients following the OP and 655 following DHPCP. Equally poor long-term sagittal maxillofacial growth was found, and similar results for velopharyngeal insufficiency and nasolabial appearance. In contrast, OP was associated with a lower rate of oronasal fistulas. Disregarding the scarcity of comparable evidence for some domains, the results of this review, overall, favour OP over DHPCP. However, caution should be taken when interpreting the results on velopharyngeal insufficiency and oronasal fistulas, since the possibility of confounding and other biases remains., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study is to describe and compare head shape in surgically and conservatively treated patients using 3D photogrammetry., Methods: A retrospective review (2017-2020) of consecutive patients with isolated metopic synostosis based on 3D photogrammetry was conducted at the age of 4 years old. Images were aligned using a healthy age-matched template, and mean head shapes were reconstructed to evaluate shape development. A comparative sub-analysis based on phenotype was performed between patients that have been treated surgically and conservatively., Results: 44 patients with isolated metopic synostosis were included: 22 received conservative treatment and 22 underwent fronto-orbital advancement. At 4 years of age the surgical group showed retrusion of the complete frontal area, while the conservative group showed a slight frontal prominence. Both groups showed temporal depression with respect to the control. In the sub-analysis, a similar degree of temporal depression was observed between surgical and conservative treatment. Head shape patterns showed considerable similarity across all severity phenotypes., Conclusion: This study shows a deviation in forehead shape from normal controls in patients with metopic synostosis following both surgical and conservative treatment by the age of 4 years. Comparison between surgical and conservative treatment shows a similar degree of temporal depression, a slight prominence in the center of the forehead in the conservative group, and retrusion of the entire frontal area in the surgical group. This observed difference is of considerable similarity across all severity types., Level of Evidence Therapeutic: III., Competing Interests: Conflicts of interest: No conflicts of interest, (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.)

Study Objectives: We examined the association between pulse transit time (PTT) and obstructive sleep apnea (OSA) in children with syndromic craniosynostosis (SCS), where OSA is a common problem and may cause cardiorespiratory disturbance., Methods: A retrospective study of children (age < 18 years) with SCS and moderate-to-severe OSA (ie, obstructive apnea-hypopnea index ≥ 5) or no OSA (obstructive apnea-hypopnea index < 1) who underwent overnight polysomnography. Children without SCS and normal polysomnography were included as controls. Reference intervals for PTT were computed by nonparametric bootstrap analysis. Based on reference intervals of controls, the sensitivity and specificity of PTT to detect OSA were determined. In a linear mixed model, the explanatory variables assessed were sex, age, sleep stage, and time after obstructive events., Results: In all 68 included children (19 with SCS with OSA, 30 with SCS without OSA, 19 controls), obstructive events occurred throughout all sleep stages, most prominently during rapid eye movement (REM) sleep and non-REM sleep stages N1 and N2, with evident PTT changes. The greatest reductions were observed 4-8 seconds after an event ( P < .05). In SCS with OSA, PTT reference intervals were lower during all sleep stages compared with SCS without OSA. The highest sensitivity was observed during N1 (55.5%), and the highest specificity during REM sleep (76.5%). The lowest PTT values were identified during N1., Conclusions: Obstructive events occur throughout all sleep stages with transient reductions in PTT. However, PTT as a variable for OSA detection is limited by its sensitivity and specificity., Citation: Yang S, van Twist E, van Heesch GGM, et al. Severe obstructive sleep apnea in children with syndromic craniosynostosis: analysis of pulse transit time. J Clin Sleep Med . 2024;20(8):1233-1240., (© 2024 American Academy of Sleep Medicine.)

Objective: This study assesses the level of child-patient satisfaction with the surgical result after scaphocephaly correction and the difference between child-patient and parents' perspectives., Methods: A questionnaire was sent out to children between 6 and 18 years old with isolated sagittal synostosis, who had undergone either a frontobiparietal remodeling or extended strip craniotomy, and separately to their parents., Results: The questionnaire was completed by 96 patients, 81.2% of the patients considered their head to be similar or slightly different from others. Despite the majority being satisfied with the outcome, 33% would change the shape of their head if they could. Patients who underwent extended strip craniotomy wanted to change the back of their head more often ( P = 0.002), whereas patients who underwent frontobiparietal remodeling wanted to change their forehead ( P = 0.005). The patients' own perspective on head shape was independent of the cephalic index (CI). However, patients with a relatively narrow CI received more remarks from others about their heads ( P = 0.038). Parent and child agreement was 49.7% on average. Differences between child-patients and parents were found in reporting adaptive behavior., Conclusion: The majority of patients were satisfied with the outcome of their intervention. The child's perspective seems to be a valuable addition to evaluate sagittal synostosis surgery as it is independent of the CI and differentiates between different surgical techniques. In addition, the patient's perspective is comparable to the parent's perspective, but gives more details on adaptive behavior., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

The European Reference Network for Rare Craniofacial Aanomalies and Ear-Nose-Throat disorders aims to improve care for patients with such afflictions, including cleft lip and palate (CL/P) across Europe. Cleft treatment remains varied throughout European centers, inhibiting meaningful comparison of treatment outcomes. To overcome these issues, a European-wide common CL/P dataset and registry was developed, facilitating standardized treatment endpoints and outcome measures for international comparison and benchmarking of CL/P centers. Questionnaires and semi-structured interviews were used to determine the set-up of the registry. Previous CL/P initiatives were analyzed to create an initial dataset, refined through consensus meetings. In total, 87 cleft specialists working in specialized CL/P centers from 16 European nations participated. Consensus on a common dataset was reached. A "Level 1" dataset, with mandatory clinical and patient-reported outcome measures, and "Level 2" dataset with additional outcome measures. Finally, 2 dashboards were developed for data dissemination. The development of the European CL/P common dataset and registry tackled challenges with resource disparities, variations in specialists within CL/P teams, regulatory differences in patient data usage, patient-reported outcome measures availability in European languages, and use of assessment tools. This study described the successful development of the European Reference Network for Rare Craniofacial Aanomalies and Ear-Nose-Throat disorders CL/P common dataset and registry. This achievement will help improve patient care and outcomes for patients with CL/P in Europe. Furthermore, this study provides useful information for initiatives with similar aims., Competing Interests: The authors report on conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

With increasing interest in 3D photogrammetry, diverse methods have been developed for craniofacial shape analysis in craniosynostosis patients. This review provides an overview of these methods and offers recommendations for future studies. A systematic literature search was used to identify publications on 3D photogrammetry analyses in craniosynostosis patients until August 2023. Inclusion criteria were original research reporting on 3D photogrammetry analyses in patients with craniosynostosis and written in English. Sixty-three publications that had reproducible methods for measuring cranial, forehead, or facial shape were included in the systematic review. Cranial shape changes were commonly assessed using heat maps and curvature analyses. Publications assessing the forehead utilized volumetric measurements, angles, ratios, and mirroring techniques. Mirroring techniques were frequently used to determine facial asymmetry. Although 3D photogrammetry shows promise, methods vary widely between standardized and less conventional measurements. A standardized protocol for the selection and documentation of landmarks, planes, and measurements across the cranium, forehead, and face is essential for consistent clinical and research applications., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

Background: The CLEFT-Q, a questionnaire developed and validated specifically for cleft patients, contains seven appearance scales. The International Consortium of Health Outcomes Measurement (ICHOM) has incorporated only some CLEFT-Q appearance scales in the Standard Set to minimize burden. This study evaluates which appearance scales provide the most meaningful information in the different cleft types at specific ages, for the most efficient cleft appearance outcome assessment., Methods: Within this international multicenter study, outcomes of the seven appearance scales were collected, either as part of the ICHOM Standard Set, or as part of the field test study performed to validate the CLEFT-Q. Analyses were performed in separate age groups and cleft types, and involved univariate regression analyses, trend analyses, t tests, correlations, and floor and ceiling effects., Results: A total of 3116 patients were included. Scores for most appearance scales showed a downward trend by age group, with the exception of the Teeth and Jaw scales. In all cleft types, several scales correlated strongly with each other. No floor effects were observed, but ceiling effects were found in several scales in different age groups, most often in the CLEFT-Q Jaw scale., Conclusions: A proposition for the most meaningful and efficient appearance outcome assessment in cleft patients is made. It was composed so that recommendations are of value for different cleft protocols and initiatives. Suggestions for the use of scales in the ICHOM Standard Set at different ages are given, and also from a clinical perspective. Use of the CLEFT-Q Scar, Lips, and Nose scales will provide additional relevant information., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Craniosynostosis, characterized by premature fusion of one or more cranial sutures, results in a distorted skull shape. Only three studies have assessed facial asymmetry manually in unicoronal synostosis patients. It is therefore important to understand how uni- and bicoronal synostosis affect facial asymmetry with a minimum risk of human bias. An automated algorithm was developed to quantify facial asymmetry from three-dimensional images, generating a mean facial asymmetry (MFA) value in millimeters to reflect the degree of asymmetry. The framework was applied to analyze postoperative 3D images of syndromic patients (N = 35) diagnosed with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis with respect to MFA values from a healthy control group (N = 89). Patients demonstrated substantially higher MFA values than controls: Muenke syndrome (unicoronal 1.74 ± 0.40 mm, bicoronal 0.77 ± 0.21 mm), Saethre-Chotzen syndrome (unicoronal 1.15 ± 0.20 mm, bicoronal 0.69 ± 0.16 mm), and TCF12-related craniosynostosis (unicoronal 1.40 ± 0.51 mm, bicoronal 0.66 ± 0.05 mm), compared with controls (0.49 ± 0.12 mm). Longitudinal analysis identified an increasing MFA trend in unicoronal synostosis patients. Our study revealed higher MFA in syndromic patients with uni- and bicoronal synostosis compared with controls, with the most pronounced MFA in Muenke syndrome patients with unilateral synostosis. Bicoronal synostosis patients demonstrated higher facial asymmetry than expected given the condition's symmetrical presentation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study evaluated the health-related quality of life (HR-QoL) in patients with sagittal synostosis (SS), and the influence of frequent headaches and surgical techniques on the HR-QoL., Method: Patients with SS aged 8 to 18 years were invited to participate between June 2016 and February 2017. The Child Health Questionnaire was used to assess the HR-QoL. A detailed questionnaire was used to assess the severity of headache symptoms. The control group consisted of 353 school children aged 5 to 14 years., Results: In all, 95 parents of patients with SS were invited to participate, of whom 68 (71.6%) parents completed the CHQ-PF50. The mean age of the participating patients was 12.4 years (10.8 to 14.2). The Psychosocial- and Physical summary of the patients with SS was similar to the general population. In the distinct CHQ scales, "Family cohesion" ( P =0.02) was higher, and "Mental health" ( P =0.05) was lower compared with the general population. The type and timing of surgery did not affect the HR-QoL. Thirty-two patients (47.1%) reported having headache complaints at least once a month. The CHQ scores of SS patients with frequent headaches had a significantly lower score of mild to large effect than those without headaches., Conclusion: Patients with SS have a slightly lower to similar HR-QoL compared with the general population. In all, 47.1% of SS patients have frequent headaches, resulting in lower average HR-QoL. The type and timing of surgery did not affect the results. Clinicians should be aware of lower HR-QoL in some subgroups of patients with SS., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

Background: Metopic synostosis patients have a high prevalence of orthoptic anomalies, including hyperopia, astigmatism, and amblyopia. We hypothesized altered orbital anatomy contributes to suboptimal visual outcomes by adversely affecting eye anatomy and growth from early life onward. Therefore, we aimed to investigate eye and orbital anatomy in metopic synostosis., Methods: We conducted a retrospective study in nonsyndromic metopic synostosis patients (n = 134, median age 0.43 years [IQR 0.45]) with nonsyndromic sagittal synostosis patients (n = 134, median age 0.27 years [IQR 0.23]) as controls. Primary analyses focused on eye dimensions (axial length, width, and globe height) and orbital dimensions, correcting for sex and age. Measurements were obtained from preoperative computed tomography scans., Results: Axial length and width in metopic synostosis patients did not differ from sagittal synostosis patients, but globe height was significantly smaller ( P = 0.0002). Lateral wall interorbital length, lateral orbital wall length, anterior medial interorbital length, and maximal medial interorbital length were significantly smaller, and anterior vertical orbital height and maximal vertical orbital height were significantly larger ( P < 0.001). The central orbital axis and interorbital angle were significantly narrower, and medial-to-lateral orbital wall angle was wider ( P < 0.001)., Conclusions: Metopic synostosis patients have more shallow, wider, and higher orbits. Eye dimensions are similar in sagittal synostosis patients, although globe height was smaller. Altered orbital and eye dimensions in metopic synostosis probably have a causal relation with an unknown order of development. How these dimensions relate to future orthoptic anomalies (eg, refractive error) needs further investigation., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Objective: A scoping review of literature about mechanisms leading to intracranial hypertension (ICH) in syndromic craniosynostosis (sCS) patients, followed by a narrative synopsis of whether cognitive and behavioral outcome in sCS is more related to genetic origins, rather than the result of ICH., Methods: The scoping review comprised of a search of keywords in EMBASE, MEDLINE, Web of science, Cochrane Central Register of Trials, and Google scholar databases. Abstracts were read and clinical articles were selected for full-text review and data were extracted using a structured template. A priori, the authors planned to analyze mechanistic questions about ICH in sCS by focusing on 2 key aspects, including (1) the criteria for determining ICH and (2) the role of component factors in the Monro-Kellie hypothesis/doctrine leading to ICH, that is, cerebral blood volume, cerebrospinal fluid (CSF), and the intracranial volume., Results: Of 1893 search results, 90 full-text articles met criteria for further analysis. (1) Invasive intracranial pressure measurements are the gold standard for determining ICH. Of noninvasive alternatives to determine ICH, ophthalmologic ones like fundoscopy and retinal thickness scans are the most researched. (2) The narrative review shows how the findings relate to ICH using the Monro-Kellie doctrine., Conclusions: Development of ICH is influenced by different aspects of sCS: deflection of skull growth, obstructive sleep apnea, venous hypertension, obstruction of CSF flow, and possibly reduced CSF absorption. Problems in cognition and behavior are more likely because of genetic origin. Cortical thinning and problems in visual function are likely the result of ICH., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Craniosynostosis may present in isolation, 'non-syndromic', or with additional congenital anomalies/neurodevelopmental disorders, 'syndromic'. Clinical focus shifted from confirming classical syndromic cases to offering genetic testing to all craniosynostosis patients. This retrospective study assesses diagnostic yield of molecular testing by investigating prevalences of chromosomal and monogenic (likely) pathogenic variants in an 11-year cohort of 1020 craniosynostosis patients. 502 children underwent genetic testing. Pathogenic variants were identified in 174 patients (35%). Diagnostic yield was significantly higher in syndromic craniosynostosis (62%) than in non-syndromic craniosynostosis (6%). Before whole exome sequencing (WES) emerged, single-gene testing was performed using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). Diagnostic yield was 11% and was highest for EFNB1, FGFR2, FGFR3, and IL11RA. Diagnostic yield for copy number variant analysis using microarray was 8%. From 2015 onwards, the WES craniosynostosis panel was implemented, with a yield of 10%. In unsolved, mainly syndromic, cases suspected of a genetic cause, additional WES panels (multiple congenital anomalies (MCA)/intellectual disability (ID)) or open exome analysis were performed with an 18% diagnostic yield. To conclude, microarray and the WES craniosynostosis panel are key to identifying pathogenic variants. in craniosynostosis patients. Given the advances in genetic diagnostics, we should look beyond the scope of the WES craniosynostosis panel and consider extensive genetic diagnostics (e.g. open exome sequencing, whole genome sequencing, RNA sequencing and episignature analysis) if no diagnosis is obtained through microarray and/or WES craniosynostosis panel. If parents are uncomfortable with more extensive diagnostics, MCA or ID panels may be considered., (Copyright © 2023. Published by Elsevier Masson SAS.)

Objective: To reflect upon our non-surgical respiratory management by evaluating clinical outcomes regarding airway, feeding, and growth during the first year of life in patients with Robin Sequence., Design: Prospective study., Setting: Sophia Children's Hospital, Rotterdam, the Netherlands., Patients/ Participants: 36 patients with Robin Sequence who were treated between 2011 and 2021., Interventions: Positional therapy and respiratory support ., Main Outcome Measure(s): Data on respiratory outcomes included polysomnography characteristics and capillary blood gas values. Feeding outcomes were based on the requirement of additional tube feeding. Outcomes on growth were expressed as standard-deviation-scores (SDS) for weight-for-age (WFA) and height-for-age (HFA)., Results: Twenty patients were treated with positional therapy (PT), whilst the other 16 patients required respiratory support. Twenty-two patients presented with non-isolated Robin Sequence (RS). During the first year of life, obstructive apnea hypopnea index decreased, oxygen levels enhanced, and capillary blood gas values improved. Eighty-six percent (31/36) experienced feeding difficulties, which completely resolved in 71% (22/31) during their first year of life. From start treatment, to stop treatment, to the age of 1 year, the SDS WFA worsened from -0.40 to -0.33 to -1.03, respectively., Conclusions: Non-surgical respiratory treatment resulted in an improvement of respiratory outcomes to near normal during the first year of life in patients with RS. These patients often experience feeding difficulties and endure impaired weight gain up to 1 year of age, despite near normalization of breathing. The high prevalence of feeding difficulties and impaired weight for age indicate the urgency for early recognition and adequate treatment to support optimal growth.

Background: Headaches are the most common complaints among pediatric populations. Determining the cause and appropriate treatment for headaches may be challenging and costly, and the impact of headaches on the lives of patients and their families is not well understood., Objective: A systematic literature review was conducted to examine what PROMs are currently used, and to identify quality of life (QoL) concepts important to children suffering from headaches and any known determinants of QoL., Methods: Embase, Medline, Web of Science, CINAHL, EBSCOhost, PsychINFO, Cochrane CENTRAL and Google Scholar were searched from their inception through to June 2021. Studies investigating QoL, using a validated outcome measure in pediatric patients with headaches, were included. Relevant studies were identified through title and abstract screening and full text review by two independent reviewers. A citation review of included studies was performed. QoL concepts were extracted from the outcome measures that were used in each study to develop a preliminary conceptual model of QoL in children suffering from headaches. Determinants of QoL were also identified and categorized., Results: A total of 5421 studies were identified in the search. Title and abstract screening resulted in the exclusion of 5006 studies. Among the 415 studies included for full text review, 56 were eligible for final analysis. A citation review resulted in the addition of five studies. Most studies were conducted in high-income countries and included a patient-sample accordingly (n = 45 studies). Sixteen different PROMs were identified in the included studies, of which the PedsQL was used the most often (n = 38 studies). The most common health concepts reported were physical functioning (n = 113 items), social and psychological wellbeing (N = 117, n = 91 resp.). Twenty-five unique determinants of QoL were extracted from the included studies., Conclusion: There is a need for a condition-specific PROM to facilitate the measurement of QoL outcomes in the pediatric headache population. A conceptual model was developed based on the findings from the health concepts. Findings from this review could be used for future qualitative interviews with pediatric patients with headaches to elicit and refine important QoL concepts., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

The care and treatment of patients with craniosynostosis and the new developments were described for health care professionals involved in this in the guideline "Treatment and Management of Craniosynostosis", which was revised in 2020. A patient version was written based on the professional guideline to make the information accessible to patients and parents too. In this patient version, each chapter consists of several sections. Firstly, an introduction and background information is provided in each chapter. Various questions are then answered based on scientific literature. Finally, the recommendations indicate the importance of the literature for care in practice and how this care should be provided in practice. This patient version is an abbreviated and simplified representation of the professional guideline. The introduction, conclusions, and recommendations sections of each chapter were revised and, where necessary, rewritten. With some surgical techniques, links to animation videos (recognizable by underlined references) have been added in the text for clarification. An attempt was made to stay as close as possible to the original guideline in terms of content, questions, numbering, and classification. The patient version can therefore easily be read side by side with the professional guideline if more information is required about a specific subject. As this patient version is a summary and does not deal with all aspects in detail, no rights can be derived from its content and the professional guideline takes precedence at all times. Originally, this patient version has been written in response to the established Dutch guideline on craniosynostosis for health care professionals.2 This professional guideline has been specifically tailored to the Dutch health care setting and policy. There are however differences between health care systems and national health policies of other countries and the Netherlands. It is important to keep in mind that this may, at some points, result in the management of care in your country and/or hospital different from outlined here., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

Introduction: Neurofibromatosis Type 1 (NF-1) is a genetic disorder that occurs in 1:2500-3000 live births and may involve multiple organs. An uncommon but well-known phenomena is sphenoid dysplasia, which appears in 3-11% of the patients, and may result in significant lowering of the orbit. Understanding the cause and development of this process might predict its course and its treatment., Methods: The records of 29 patients with PNF in the head and neck region were searched for location of the PNF and type of surgery. Photographs were studied for facial disturbances, including vertical dystopia, hypertelorism, ptosis, exophthalmos and enophthalmos. MR and CT scans were studied for the presence of PNF, aspect of the sphenoid bone, alteration in the CSF circulation, and other tumour involvement., Results: Fourteen of 29 patients with PNF in the head and neck presented with sphenoid dysplasia. All 14 patients had their PNF located in the periorbital region. Increased locoregional CSF collections were seen in almost all of these patients. Besides glioma of the optical nerve or hamartomas in the cerebrum and cerebellum, there were no other tumours found. Surgical treatment varies from simple excision to excessive debulking of the PNF, reconstruction of the orbit and even enucleation., Conclusion: Although sphenoid dysplasia is uncommon in NF-1 patients, early recognition is important to prevent facial disfigurement and vision loss. Clinicians should be aware that abnormalities in the periorbital region and especially vertical dystopia might be the first sign of sphenoid dysplasia. Performing a CT or black-bone MR scan would be the next step to confirm or exclude sphenoid dysplasia and abnormal CSF dynamics., Competing Interests: Declaration of competing interest None., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Objective: Stagnation of skull growth is correlated with papilledema in craniosynostosis. In this retrospective cohort study, we describe the postoperative skull growth after surgical correction for sagittal synostosis and its relation to the development of papilledema., Methods: Patients with isolated sagittal synostosis at our center between 2005 and 2012 were included. Occipitofrontal circumference (OFC) was analyzed, at 3 time points (preoperative, 2 years postoperative, and last OFC measurement) and 3 phases (initial postoperative growth, long-term growth, and overall growth), and related to papilledema on fundoscopy., Results: In total, 163 patients were included. The first time interval showed a decline in skull growth, with subsequent stabilization at long term. Papilledema occurred postoperatively in 10 patients. In these patients, the OFC at 2 years and at last follow-up (T3) were significantly smaller than in patients without papilledema. A larger OFC resulted in a decreased odds of developing papilledema at both postoperative time points (at T2 (OR = 0.40, p = 0.01) and at T3 (OR 0.29, p < 0.001)). Sensitivity and specificity analysis indicated that an OFC below 0.25 SD at T2 (sensitivity 90%, specificity 65%) and below 0.49 at T3 (sensitivity 100%, specificity 60%) are related to the occurrence of papilledema., Conclusion: A small OFC is correlated with the occurrence of papilledema. A decline in OFC within 2 years postoperatively is common in sagittal synostosis and is acceptable up to a value of 0.25SD. Patients with an OFC at last follow-up of less than 0.5SD are at risk for developing papilledema., (© 2022. The Author(s).)

Given the high prevalence of OSA in children with syndromic and complex craniosynostosis (SCC) and the consequences of untreated OSA, it is important to assess their nutritional status and growth. Yet, literature regarding growth in children with SCC remain scarce. Therefore, this study aimed to (1) illustrate the growth pattern in SCC, (2) determine the impact of OSA on this growth pattern, and (3) evaluate the effect of surgical treatment of OSA on growth over time. A retrospective study was performed in children with SCC, who were treated at the Dutch Craniofacial Center (Rotterdam, Netherlands). Growth variables (height, weight, weight-for-age standard-deviation-score (SDS), weight-for-height SDS, and height-for-age SDS) and degree of OSA (obstructive apnea-hypopnea index) were assessed. Of the 153 children with SCC, 38 (25%) were acutely malnourished at some point during follow-up, of whom 21 had disease-related acute malnutrition. Children with moderate-severe OSA had significant lower weight-for-height SDS compared to children without OSA (p = 0.0063). Growth parameters (weight-for-age SDS, weight-for-height SDS, height-for-age SDS) in children with SCC without OSA were not impaired as they did not differ from the normal healthy population, with exception of the patients with Saethre-Chotzen syndrome (SCS) who had a significantly lower SDS for height-for-age.   Conclusion: Children with SCC have a substantial chance of developing acute malnutrition at some point during growth. Additionally, in children with moderate-severe OSA, a significant lower SDS for weight-for-height is present, indicating the importance of assessing the weight and growth pattern in children who are clinically suspected for OSA. What is Known: • Obstructive sleep apnea is seen in up to two-thirds of the children with syndromic and complex craniosynostosis. • Presence of obstructive sleep apnea is associated with intracranial hypertension and an increased risk of metabolic, cardiovascular, and neurocognitive consequences later in life. Untreated obstructive sleep apnea may lead to impaired growth and weight gain, which can result in growth failure. What is New: • Craniosynostosis patients with moderate-severe obstructive sleep apnea had significant lower weight-for-height standard deviation scores (SDS), compared to children without obstructive sleep apnea.  • Children with syndromic and complex craniosynostosis without OSA did not significantly differ from the normal healthy population in regard to weight-for-age SDS, weight-for-height SDS, and height-for-age SDS., (© 2022. The Author(s).)

Purpose: In 7 to 15-year-old operated syndromic craniosynostosis patients, we have shown the presence of microstructural anomalies in brain white matter by using DTI. To learn more about the cause of these anomalies, the aim of the study is to determine diffusivity values in white matter tracts in non-operated syndromic craniosynostosis patients aged 0-2 years compared to healthy controls., Methods: DTI datasets of 51 non-operated patients with syndromic craniosynostosis with a median [IQR] age of 0.40 [0.25] years were compared with 17 control subjects with a median of 1.20 [0.85] years. Major white matter tract pathways were reconstructed with ExploreDTI from MRI brain datasets acquired on a 1.5 T MRI system. Eigenvalues of these tract data were examined, with subsequent assessment of the affected tracts. Having syndromic craniosynostosis (versus control), gender, age, frontal occipital horn ratio (FOHR), and tract volume were treated as independent variables., Results: ʎ 2 and ʎ 3 of the tracts genu of the corpus callosum and the hippocampal segment of the cingulum bundle show a ƞ 2  > 0.14 in the comparison of patients vs controls, which indicates a large effect on radial diffusivity. Subsequent linear regressions on radial diffusivity of these tracts show that age and FOHR are significantly associated interacting factors on radial diffusivity (p < 0.025)., Conclusion: Syndromic craniosynostosis shows not to be a significant factor influencing the major white matter tracts. Enlargement of the ventricles show to be a significant factor on radial diffusivity in the tracts corpus callosum genu and the hippocampal segment of the cingulate bundle., Clinical Trial Registration: MEC-2014-461., (© 2022. The Author(s).)

Background: Multiple pregnancy is a known predisposing factor for sagittal suture synostosis, and intrauterine constraint has been suggested as a potential cause. This study evaluates prenatal images of single and multiple pregnancies of children with sagittal suture synostosis to assess the possible pathogenesis., Materials and Methods: Prenatal ultrasound data of scaphocephaly twins treated at Erasmus MC was retrieved retrospectively. The head circumference, cephalic index (CI), and biparietal diameter (BPD) were analyzed. Data were compared with the nonaffected sibling, singletons with scaphocephaly, and to general fetal growth reference values., Results: Data of 8 twin pregnancies with 10 cases of scaphocephaly was gathered. For the head circumference no difference was found between affected fetuses and reference values throughout pregnancy. For the BPD a reduced growth was found, compared with control values. The growth curve for the CI of the affected twins is lower from the start and declines over time. When comparing affected fetuses to nonaffected fetuses, the same differences for the BPD and CI were found as compared with controls. No differences in growth parameters were found between the nonaffected siblings and reference values, nor between the affected scaphocephaly twins and singletons with scaphocephaly., Conclusions: Scaphocephaly in twin pregnancy develops early on in pregnancy, similar to singleton pregnancy, making the theory of constraint as a cause less likely. The development of scaphocephaly in twins is likely to be attributed to the same disturbed developmental processes in suture development as in singletons, and not to mechanical constraint., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Study Objectives: Obstructive sleep apnea (OSA) is seen in up to two-third of the patients with syndromic craniosynostosis. Gold standard to diagnose OSA is the hospital-based polysomnography, although alternatively ambulatory home sleep apnea devices are available. Aim of this study was to assess (1) accuracy of ambulatory sleep studies, (2) clinical decision making following sleep studies, and (3) course of OSA during long-term follow-up., Materials and Methods: A retrospective cohort study was performed in children with syndromic craniosynostosis, of whom polysomnographies and home sleep apnea device recordings were collected. Measurements of apnea-hypopnea index, respiratory event index, total sleep/recording time, heart rate, oxygen saturation, and oxygen desaturation index were derived from the sleep studies. Primary clinical care subsequent to the sleep studies was determined using electronic patient files., Results: In total, 123 patients were included, with 149 polysomnographies and 108 ambulatory studies. Performing an ambulatory study was associated with increased age at time of measurement (OR=1.1, 95% CI=1.02 to 1.17, P =0.01). No significant difference was found between the 2 types of sleep studies regarding sleep study parameters. Subsequent to sleep studies, patients with no-mild OSA had expectant care whereas patients with moderate-severe OSA underwent OSA-related treatment. OSA was most prevalent up to the age of 5 years, but also noticeable after the age of 10 years in patients with the Crouzon syndrome., Conclusions: Ambulatory sleep studies are reliable for diagnosing OSA in older children and can be used to determine clinical decision-making. Hence, we recommend implementing ambulatory sleep studies in a protocolized management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants., Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments., Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity., Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping., Competing Interests: Conflict of Interest H.Z.E. and K.G.M. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To obtain pediatric normative reference values and determine whether optical coherence tomography (OCT) corresponds better with clinical signs of intracranial hypertension (ICH) compared to the traditional screening method fundoscopy in a large cohort of one type of single suture craniosynostosis., Methods: Control subjects without optic nerve diseases and isolated sagittal synostosis patients aged 3-10 years who underwent fundoscopy and OCT were included in this prospective cohort study. Normative reference values were obtained through bootstrap analysis. Main outcome was the association between peripapillary total retinal thickness (TRT) and total retinal volume (TRV) and appearance on fundoscopy. Signs and symptoms suggestive of ICH, including skull growth arrest, fingerprinting, and headache, were scored., Results: Sixty-four healthy controls and 93 isolated sagittal synostosis patients were included. Normative cut-off values for mean TRT are < 256 μm and > 504 μm and for mean TRV < 0.21 mm 3 and > 0.39 mm 3 . TRT was increased in 16 (17%) and TRV in 15 (16%) of 93 patients, compared to only 4 patients with papilledema on fundoscopy (4%). Both parameters were associated with papilledema on fundoscopy (OR = 16.7, p = 0.02, and OR = 18.2, p = 0.01). Skull growth arrest was significantly associated with abnormal OCT parameters (OR = 13.65, p < 0.01)., Conclusions: The established cut-off points can be applied to screen for ICH in pediatrics. The present study detected abnormalities with OCT more frequent than with fundoscopy, which were associated with skull growth arrest. Therefore, a combination of OCT, fundoscopy, and skull growth arrest can improve clinical decision-making in craniosynostosis., (© 2022. The Author(s).)

Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding these outcomes following mandibular distraction. The aim of this study was to evaluate the effect of mandibular distraction on feeding and swallowing function. A retrospective study was performed on 22 patients with non-isolated mandibular hypoplasia and severe upper airway obstruction treated with mandibular distraction. Median age at first mandibular distraction was 3.1 years (interquartile range 2.3-6.0 years) and the median follow-up time was 3.5 years (interquartile range 2.0-9.4 years). Prior to mandibular distraction, feeding difficulties were present in 18 patients. Swallowing difficulties were present in 20 patients, all of whom had problems in the oral phase of swallowing, while 11 patients had additional problems in the pharyngeal phase. Following mandibular distraction, at the time of follow-up, feeding difficulties persisted in 13 patients. Swallowing difficulties in the oral phase remained present in all 20 patients, while pharyngeal phase problems persisted in seven patients. In conclusion, feeding and swallowing difficulties are highly prevalent in non-isolated patients and often persist following mandibular distraction. Moreover, these can be the reason that decannulation cannot be accomplished. Hence, awareness and close follow-up by a specialized speech therapist is of paramount importance., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Children with trigonocephaly are at risk for neurodevelopmental disorders. The aim of this study is to investigate white matter properties of the frontal lobes in young, unoperated patients with metopic synostosis as compared to healthy controls using diffusion tension imaging (DTI)., Methods: Preoperative DTI data sets of 46 patients with trigonocephaly with a median age of 0.49 (interquartile range: 0.38) years were compared with 21 controls with a median age of 1.44 (0.98) years. White matter metrics of the tracts in the frontal lobe were calculated using FMRIB Software Library (FSL). The mean value of tract-specific fractional anisotropy (FA) and mean diffusivity (MD) were estimated for each subject and compared to healthy controls. By linear regression, FA and MD values per tract were assessed by trigonocephaly, sex, and age., Results: The mean FA and MD values in the frontal lobe tracts of untreated trigonocephaly patients, younger than 3 years, were not significantly different in comparison to controls, where age showed to be a significant associated factor., Conclusions: Microstructural parameters of white matter tracts of the frontal lobe of patients with trigonocephaly are comparable to those of controls aged 0-3 years., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adolescents with a visible difference can experience difficult social situations, (e.g., people staring or making unwanted comments) and are at risk for mental health problems. Unfortunately, interventions for adolescents with a visible difference experiencing appearance-related distress are scarce and lack an evidence-base. This study tests the acceptability and feasibility of YP Face IT, an innovative online psychological intervention using social skills training and cognitive behavioural therapy, to Dutch adolescents. Adolescents aged 12-17 with a visible difference and access to an internet-enabled computer or tablet participated. They completed YP Face IT (eight sessions) and questionnaires were administered pre- and post-intervention. After completing YP Face IT, participants were interviewed to assess the acceptability and feasibility of YP Face IT and study procedures. Overall, 15 adolescents consented to participation, one person dropped out after one session. Most adolescents appreciated the intervention and all would recommend it to other adolescents experiencing appearance-related distress. Everyone reported learning experiences after following the sessions. Some struggled with motivation, but reminders by the website and research team were helpful. The Dutch YP Face IT intervention may be acceptable and the current study design is feasible to use. An RCT should be conducted to assess the effectiveness of the intervention., Competing Interests: Conflicts of interests None declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes., Materials and Methods: This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8-16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian's index of dental maturity. The control group included 451 children without a syndrome., Results: Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis., Conclusions: Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes., Implications: Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society.)