The Development of a European Multidisciplinary Cleft Lip and Palate Registry by the European Reference Network CRANIO: Experiences, Barriers, And Facilitators.

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.

Child-Patient Perspective on Results After Correction of Sagittal Synostosis and the Difference Between Child-Patient and Parent's Perspectives.

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.

Quantifying dysmorphologies of the neurocranium using artificial neural networks.

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.

Severe obstructive sleep apnea in children with syndromic craniosynostosis: analysis of pulse transit time.

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: Retrospective study of children (age <18 years) with SCS and moderate-to-severe OSA (i.e., obstructive apnea-hypopnea index [oAHI] ≥ 5), or no OSA (oAHI < 1) who underwent overnight polysomnography (PSG). Children without SCS and normal PSG were included as controls. Reference intervals (RIs) for PTT were computed by non-parametric bootstrap analysis. Based on RIs 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 SCS with OSA, 30 SCS without OSA, 19 controls), obstructive events occurred throughout all sleep stages, most prominently during rapid eye movement sleep (REM) and non-REM sleep stages N1 and N2, with evident PTT changes. Greatest reductions were observed 4 - 8 s after an event (p < 0.05). In SCS with OSA, PTT RIs were lower during all sleep stages compared to SCS without OSA. The highest sensitivity was observed during N1 (55.5%), and the highest specificity during REM (76.5%). 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.

3D Analysis of the Cranial and Facial Shape in Craniosynostosis Patients: A Systematic Review.

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.

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.

Most Efficient and Meaningful Patient-Reported Appearance Assessment in Different Cleft Types and Age Groups with CLEFT-Q.

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.

Automated three-dimensional analysis of facial asymmetry in patients with syndromic coronal synostosis: A retrospective study.

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.

What is the optimal assessment of speech? A multicentre, international evaluation of speech assessment in 2500 patients with a cleft.

OBJECTIVES: Speech problems in patients with a cleft palate are often complex and multifactorial. Finding the optimal way of monitoring these problems is challenging. The International Consortium of Health Outcomes Measurement (ICHOM) has developed a set of standardised outcome measures at specific ages for patients with a cleft lip and/or palate, including measures of speech assessment. This study evaluates the type and timing of speech outcome measures currently included in this ICHOM Standard Set. Additionally, speech assessments in other cleft protocols and initiatives are discussed. DESIGN, SETTING AND PARTICIPANTS: An international, multicentre study was set up including centres from the USA and the Netherlands. Outcomes of clinical measures and Patient Reported Outcome Measures (PROMs) were collected retrospectively according to the ICHOM set. PROM data from a field test of the CLEFT-Q, a questionnaire developed and validated for patients with a cleft, were collected, including participants from countries with all sorts of income statuses, to examine the value of additional moments of measurement that are used in other cleft initiatives.Data from 2500 patients were included. Measured outcomes contained univariate regression analyses, trend analyses, t-tests, correlations and floor and ceiling effects. RESULTS: PROMs correlated low to moderate with clinical outcome measures. Clinical outcome measures correlated low to moderate with each other too. In contrast, two CLEFT-Q Scales correlated strongly with each other. All PROMs and the Percent Consonants Correct (PCC) showed an effect of age. In patients with an isolated cleft palate, a ceiling effect was found in the Intelligibility in Context Scale. CONCLUSION: Recommendations for an optimal speech outcome assessment in cleft patients are made. Measurement moments of different cleft protocols and initiatives are considered in this proposition. Concerning the type of measures, adjustment of the current PCC score outcome seems appropriate. For centres with adequate resources and specific interest in research, translation and validation of an upcoming tool, the Cleft Audit Protocol for Speech Augmented, is recommended.

Quantitative detection and follow-up of intracranial hypertension in craniosynostosis: an optical coherence tomography study.

BACKGROUND/PURPOSE: To evaluate in craniosynostosis: 1) the diagnostic accuracy of fundoscopy and optical coherence tomography (OCT) to detect intracranial hypertension (ICH); 2) the time course of retinal thickness after treatment of ICH; and 3) the relation between high hyperopia (HH) and fundoscopy/OCT scan findings. METHODS: Syndromic, multisuture, unicoronal, unilambdoid and sagittal synostosis patients visiting our national center were included in this longitudinal cohort study and formed a consecutive series. Retinal layers on OCT, OCT fundus image and fundoscopy 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: 577 OCT scans in 307 patients were included. ICH was found in 7.2%. Combining total retinal thickness (TRT), OCT fundus image and fundoscopy resulted in a sensitivity of 76% and 81% specificity to detect signs of ICH. TRT was increased in patients who have had signs of ICH versus patients who never had signs of ICH (ß+44.9 µm in patients who have had ICH, 95%CI 9.0-80.8,P=0.01). TRT decreased to normal in the years after surgery (ß -3.6 µm/year, 95%CI -7.2 - -0.05, P=0.047). There were greater odds of having increased TRT in patients with HH (OR 2.9, 95%CI 1.1-7.6,P=0.03). CONCLUSIONS: The correlation between TRT, OCT fundus image, fundoscopy and particularly for the combination of these parameters with ICP surrogate markers is fair. Increased TRT in the presence of a clinical suspicion of ICH warrants further screening.

Eye and Orbital Anatomy in Metopic Synostosis.

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.

Health-related Quality of Life in Children and Adolescents With Sagittal Synostosis.

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.

Genetic diagnostic yield in an 11-year cohort of craniosynostosis patients.

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.

Non-Surgical Respiratory Management in Relation to Feeding and Growth in Patients with Robin Sequence; a Prospective Longitudinal Study.

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.

What We Know About Intracranial Hypertension in Children With Syndromic Craniosynostosis.

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.

Reliability and Agreement of Automated Head Measurements From 3-Dimensional Photogrammetry in Young Children.

This study aimed to assess the reliability and agreement of automated head measurements using 3-dimensional (3D) photogrammetry in young children. Specifically, the study evaluated the agreement between manual and automated occipitofrontal circumference (OFC) measurements (n = 264) obtained from 3D images of 188 patients diagnosed with sagittal synostosis using a novel automated method proposed in this study. In addition, the study aimed to determine the interrater and intrarater reliability of the automatically extracted OFC, cephalic index, and volume. The results of the study showed that the automated OFC measurements had an excellent agreement with manual measurements, with a very strong regression score ( R2 = 0.969) and a small mean difference of -0.1 cm (-0.2%). The limits of agreement ranged from -0.93 to 0.74 cm, falling within the reported limits of agreement for manual OFC measurements. High interrater and intrarater reliability of OFC, cephalic index, and volume measurements were also demonstrated. The proposed method for automated OFC measurements was found to be a reliable alternative to manual measurements, which may be particularly beneficial in young children who undergo 3D imaging in craniofacial centers as part of their treatment protocol and in research settings that require a reproducible and transparent pipeline for anthropometric measurements. The method has been incorporated into CraniumPy, an open-source tool for 3D image visualization, registration, and optimization, which is publicly available on GitHub ( https://github.com/T-AbdelAlim/CraniumPy ).

Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance.

PURPOSE: Studies have previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the preosteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function (LoF) variants in PRRX1 associated with craniosynostosis. METHODS: Trio-based genome, exome, or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. RESULTS: Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis, who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9 of 1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, 7 additional individuals (4 families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multisuture synostosis was present in 11 of 17 cases (65%). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. CONCLUSION: This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis.

Sagittal Craniosynostosis: Comparing Surgical Techniques Using 3D Photogrammetry.

BACKGROUND: The aim of this study was to compare three surgical interventions for correction of sagittal synostosis-frontobiparietal remodeling (FBR), extended strip craniotomy (ESC), and spring-assisted correction (SAC)-based on three-dimensional (3D) photogrammetry and operation characteristics. METHODS: Patients who were born between 1991 and 2019 and diagnosed with nonsyndromic sagittal synostosis who underwent FBR, ESC, or SAC and had at least one postoperative 3D photogrammetry image taken during one of six follow-up appointments until age 6 were considered for this study. Operative characteristics, postoperative complications, reinterventions, and presence of intracranial hypertension were collected. To assess cranial growth, orthogonal cranial slices and 3D photocephalometric measurements were extracted automatically and evaluated from 3D photogrammetry images. RESULTS: A total of 322 postoperative 3D images from 218 patients were included. After correcting for age and sex, no significant differences were observed in 3D photocephalometric measurements. Mean cranial shapes suggested that postoperative growth and shape gradually normalized with higher occipitofrontal head circumference and intracranial volume values compared with normal values, regardless of type of surgery. Flattening of the vertex seems to persist after surgical correction. The authors' cranial 3D mesh processing tool has been made publicly available as a part of this study. CONCLUSIONS: The findings suggest that until age 6, there are no significant differences among the FBR, ESC, and SAC in their ability to correct sagittal synostosis with regard to 3D photocephalometric measurements. Therefore, efforts should be made to ensure early diagnosis so that minimally invasive surgery is a viable treatment option. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.