OBJECTIVE: Previous work identified an association between genetics and neurodevelopmental delays in patients with nonsyndromic craniosynostosis. The authors investigated the role of genetic mutations on behavioral outcomes of patients with treated sagittal synostosis.
METHODS: Parents of children aged 6-18 years with surgically corrected sagittal synostosis were recruited to complete the Child Behavioral Checklist (overall behavioral problems), Conners 3rd Edition-Parent (attention-deficit/hyperactivity disorder), Social Responsiveness Scale 2nd Edition (autism spectrum disorder [ASD]), and Behavior Rating Inventory of Executive Function 2nd Edition (executive function). Genomic analysis was completed, and patients were identified if they had mutations in high probability of loss of function intolerant (pLI) genes (high pLI vs nonhigh pLI). Genetic burden was assessed relative to controls. Multivariate linear regression determined the association of mutations in high pLI genes with behavioral scores, while controlling for sociodemographic factors, age at surgery, surgery type, and IQ.
RESULTS: Sixteen of 45 patients were in the high pLI group. There were no differences between the groups in terms of sociodemographic factors. A greater proportion of children in the high pLI group scored at or above borderline clinical levels for aggression (18.8% vs 0.0%, p = 0.05) and externalizing problems (31.3% vs 3.7%, p = 0.02). Among children in the nonhigh pLI group, older age at surgery was associated with worse scores on the rule-breaking, aggression, and externalizing problems domains and four out of five ASD domains.
CONCLUSIONS: Children with treated nonsyndromic sagittal synostosis and mutations in high pLI genes had worse behavioral problems in externalizing behaviors and aggression, whereas older age at surgery was a significant predictor of worse behavioral outcomes in patients without mutations in high pLI genes.

The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).

OBJECTIVE: As many as 5% of normocephalic children may have a prematurely fused sagittal suture, yet the clinical significance and best course of management of this finding remain unclear. Providers in the Synostosis Research Group were surveyed to create a multicenter consensus on an optimal treatment and monitoring algorithm for this condition.
METHODS: A four-round modified Delphi method was utilized. The first two rounds consisted of anonymous surveys distributed to 10 neurosurgeons and 9 plastic surgeons with expertise in craniosynostosis across 9 institutions, and presented 3 patients (aged 3 years, 2 years, and 2 months) with incidentally discovered fused sagittal sutures, normal cephalic indices, and no parietal dysmorphology. Surgeons were queried about their preferred term for this entity and how best to manage these patients. Results were synthesized to create a treatment algorithm. The third and fourth feedback rounds consisted of open discussion of the algorithm until no further concerns arose.
RESULTS: Most surgeons preferred the term \"premature fusion of the sagittal suture\" (93%). At the conclusion of the final round, all surgeons agreed to not operate on the 3- and 2-year-old patients unless symptoms of intracranial hypertension or papilledema were present. In contrast, 50% preferred to operate on the 2-month-old. However, all agreed to utilize shared decision-making, taking into account any concerns about future head shape and neurodevelopment. Panelists agreed that patients over 18 months of age without signs or symptoms suggesting elevated intracranial pressure (ICP) should not undergo surgical treatment.
CONCLUSIONS: Through the Delphi method, a consensus regarding management of premature fusion of the sagittal suture was obtained from a panel of North American craniofacial surgeons. Without signs or symptoms of ICP elevation, surgery is not recommended in patients over 18 months of age. However, for children younger than 18 months, surgery should be discussed with caregivers using a shared decision-making process.

Craniosynostosis is characterized by congenital absence or premature closure of skull sutures. The most common form of craniosynostosis is synostosis of sagittal suture followed by scaphocephaly. There are some head deformities similar to scaphocephaly such as positional and constitutional dolichocephaly, etc. These patients have no sagittal suture synostosis. However, there are difficulties in differential diagnosis between these deformities and scaphocephaly.
To develop differential diagnostic criteria between dolichocephalic head deformities and true scaphocephaly following sagittal synostosis.
The study included 33 patients with dolichocephaly (25 (75.8%) boys and 8 (24.2%) girls) between December 2013 and August 2022. The inclusion criterion was available CT or ultrasound data confirming or excluding sagittal synostosis. Age of patients was 8.62±7.71 (1.77-36) months. We analyzed anamnestic, clinical and radiological data. Radiological data was compared with diagnostic findings in 20 patients with scaphocephaly. Both groups were comparable in age, gender and cranial index.
We present clinical and radiological signs, as well as algorithm for differential diagnosis between scaphocephaly and dolichocephaly.
There are objective difficulties in differential diagnosis between scaphocephaly following sagittal synostosis and dolichocephalic head deformities. In most cases, we cannot establish the cause of congenital forms of dolichocephaly. The most likely causes may be pre- and postnatal compressive and positional effects. Ultrasound of skull sutures is preferable for differential diagnosis between these abnormalities. Correction of dolichocephaly can be carried out according to aesthetic indications with individual cranial orthoses.
Краниосиностозы (КС) — группа заболеваний, которые развиваются вследствие врожденного отсутствия или преждевременного закрытия швов черепа. Самой частой формой КС является синостоз сагиттального шва (СШ), проявляющийся деформацией головы — скафоцефалией (СЦ). Существует ряд состояний со схожими с СЦ деформациями головы, к которым относятся: позиционная долихоцефалия (ДЦ), конституциональная ДЦ, деформация по типу «тазовой головки». У пациентов этой группы не выявляется синостоза СШ, однако возникают трудности с проведением дифференциального диагноза между этими состояниями и СЦ.
Разработка дифференциально-диагностических критериев между состояниями, сопровождающимися ДЦ-деформациями головы и истинной СЦ, развивающейся вследствие сагиттального синостоза (СС).
В исследование включено 33 пациента с ДЦ: 25 (75,8%) мальчиков и 8 (24,2%) девочек, консультированных в период с декабря 2013 г. по август 2022 г. в ФГАУ «Национальный медицинский исследовательский центр нейрохирургии им. акад. Н.Н. Бурденко» Минздрава России. Критерием включения было наличие инструментального обследования (компьютерная томография головы или ультразвуковое исследование (УЗИ) швов черепа), позволявшего объективно подтвердить или исключить СС. Возраст пациентов составил 8,62±7,71 (1,77—36) мес. Выполнен анализ анамнестических, клинических и рентгенологических данных. Сравнение рентгенологических данных произведено с группой из 20 больных СЦ, сопоставимой по возрасту и полу с равноценными показателями краниального индекса.
В работе представлены клинические и рентгенологические признаки, позволяющие провести дифференциальную диагностику между СЦ и ДЦ, разработан алгоритм.
Исследование продемонстрировало объективные сложности клинической дифференциальной диагностики между СЦ, развивающейся вследствие синостоза СШ, и долихоцефалическими деформациями головы. В большинстве наблюдений не удается выяснить причину врожденных форм ДЦ, наиболее вероятными поводами развития которой могут быть пре- и постнатальные компримирующие и позиционные воздействия. УЗИ швов черепа является методом выбора инструментальной дифференциальной диагностики между этими состояниями. Коррекция ДЦ может быть проведена по эстетическим показаниям при помощи индивидуальных краниальных ортезов.

This study aimed to determine the cognitive profile of preschool children undergoing surgery to correct non-syndromic craniosynostosis, compare them with typically developing children, and analyze possible cognitive deficits in the most prevalent subtypes: sagittal and unicoronal. Thirty-one children aged 3 years to 5 years and 11 months with non-syndromic craniosynostosis (11 sagittal, 9 unicoronal, 4 metopic, 3 lambdoid, 4 multisutural) who underwent surgery were compared with thirty-one typically developing children. The Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III) was used to assess cognitive function. Children with non-syndromic craniosynostosis scored below the typically developing children in the Verbal Intelligence Quotient (VIQ) and Full-Scale Intelligence Quotient (FISQ). When specific subtypes were compared, children with sagittal synostosis scored similarly to the typically developing children; in contrast, children with unicoronal synostosis had lower performance in the Processing Speed Quotient and FISQ. The proportion of participants scoring below one standard deviation on the VIQ, General Language Composite, and FISQ was greater in the non-syndromic craniosynostosis group. This study supports the finding that children with non-syndromic craniosynostosis, particularly those with unicoronal synostosis, have more cognitive difficulties than those with normal development. Assessing cognition at preschool age in children with non-syndromic craniosynostosis is important in order to detect difficulties before they become more apparent at school age.

Study Design: A Case Report. Objective: Craniosynostosis is a craniofacial condition defined by premature fusion of at least one cranial suture. Resynostosis or secondary craniosynostosis of a previously patent adjacent suture following primary repair is a relatively common complication. While studies have assessed the rates of secondary craniosynostosis and subsequent reoperation, extremely limited data regarding reoperation techniques is available. Methods: We present a unique case of a pediatric patient with sagittal craniosynostosis who previously underwent a modified pi procedure and later developed resynostosis of the sagittal suture and secondary synostosis of the bicoronal sutures. We subsequently performed total cranial vault reconstruction with virtual surgical planning (VSP). Results: At his 31-month postoperative follow-up, he displayed normal head shape and denied any clinical signs of elevated intracranial pressures with a normal ophthalmological exam. Conclusions: The reoperation was successful with no significant postoperative complications noted. Performing geometric expansion with VSP to manage fusion of a previously open suture following primary treatment of sagittal synostosis should be considered within the armamentarium of operative options.

Early suturectomy with a rigid endoscope followed by orthotic cranial helmet therapy is an accepted treatment option for single-suture craniosynostosis. To the authors\' knowledge, flexible endoscope-assisted suture release (FEASR) has not been previously described. Presented herein is their experience with FEASR for the treatment of isolated sagittal craniosynostosis.
A retrospective analysis of the health records of patients who had undergone FEASR between March 2018 and December 2020 was performed. Patients under the age of 6 months who had been diagnosed with isolated sagittal synostosis were considered eligible for FEASR. Exclusion criteria included syndromic synostosis or multiple-suture synostosis. The cephalic index, the primary measure of the cosmetic endpoint, was calculated at prespecified intervals: immediately preoperatively and 6 weeks and 12 months postoperatively. Parental satisfaction with the cosmetic outcome was determined throughout the clinical follow-up and documented according to a structured questionnaire for the first 12 months.
A total of 18 consecutive patients met the criteria for study inclusion. The mean patient age at the time of surgery was 3.4 months (range 2-6 months). All patients underwent a wide craniectomy with no need to convert to an open procedure. The mean craniectomy width was 3.61 cm. Estimated blood loss ranged from 5 to 30 ml. The mean operative time was 75 minutes. No intraoperative complications were observed. The average length of stay was 2.6 days. The mean cephalic index was 67.7 preoperatively, 77.1 at 6 weeks postoperatively, and 76.3 at 1 year postoperatively. The mean percentage change in the cephalic index from preoperatively to the 12-month follow-up was 10.44 (p < 0.001). The mean follow-up was 17 months (range 12-28 months). All parents were satisfied with the cosmetic outcome of the procedure. No patients developed symptoms of raised intracranial pressure (ICP) or needed invasive ICP monitoring during the follow-up period. No patients required reoperation.
In this modest single-hospital series, the authors demonstrated the feasibility of FEASR in treating sagittal synostosis with favorable cosmetic outcomes. The morbidity profile and resource utilization of the procedure appear similar to those of procedures conducted via traditional rigid endoscopy.

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.
CONCLUSIONS: 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.

OBJECTIVE: Surgical treatment of sagittal craniosynostosis is challenging in older patients. This study aimed to assess the effect of increasing age on open surgical technique selection and patient outcomes using the multi-institutional Synostosis Research Group (SynRG) collaboration.
METHODS: Surgeons in SynRG were surveyed for key influences on their preferred open calvarial vault remodeling techniques at various patient ages: < 6, 6-12, and > 12 months. The SynRG database was then queried for open repairs of nonsyndromic sagittal craniosynostosis performed for patients older than 12 months of age. Perioperative measures, complications, and preoperative and postoperative cephalic indices were reviewed.
RESULTS: All surgeons preferred to treat patients at an earlier age, and most (89%) believed that less-optimal outcomes were achieved at ages older than 12 months. The modified pi procedure was the dominant technique in those younger than 12 months, while more involved open surgical techniques were performed for older patients, with a wide variety of open calvarial vault remodeling techniques used. Forty-four patients met inclusion criteria, with a mean (± SD) age at surgery of 29 ± 16 months. Eleven patients underwent parietal reshaping, 10 parietal-occipital switch, 9 clamshell craniotomy, 7 geometric parietal expansion, 6 modified pi procedure, and 1 parietal distraction. There were no readmissions, complications, or mortality within 30 days postoperatively. Patients\' cephalic indices improved a mean of 6.4% ± 4.0%, with a mean postoperative cephalic index of 74.2% ± 4.9%. Differences in postoperative cephalic index (p < 0.04) and hospital length of stay (p = 0.01) were significant between technique cohorts. Post hoc Tukey-Kramer analysis identified the parietal reshaping technique as being significantly associated with a reduced hospital length of stay.
CONCLUSIONS: Patient age is an important driver in technique selection, with surgeons selecting a more involved calvarial vault remodeling technique in older children. A variety of surgical techniques were analyzed, with the parietal reshaping technique being significantly associated with reduced length of stay; however, multiple perioperative factors may be contributory and require further analysis. When performed at high-volume centers by experienced pediatric neurosurgeons and craniofacial surgeons, open calvarial vault techniques can be a safe method for treating sagittal craniosynostosis in older children.

The neonate skull consists of several bony plates, connected by fibrous soft tissue called sutures. Premature fusion of sutures is a medical condition known as craniosynostosis. Sagittal synostosis, caused by premature fusion of the sagittal suture, is the most common form of this condition. The optimum management of this condition is an ongoing debate in the craniofacial community while aspects of the biomechanics and mechanobiology are not well understood. Here, we describe a computational framework that enables us to predict and compare the calvarial growth following different reconstruction techniques for the management of sagittal synostosis. Our results demonstrate how different reconstruction techniques interact with the increasing intracranial volume. The framework proposed here can be used to inform optimum management of different forms of craniosynostosis, minimising the risk of functional consequences and secondary surgery.