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Human-directed selective breeding has modified the phenotype of the modern Persian cat towards an extreme brachycephalic phenotype (‘peke-face’ Persian), which originates from a spontaneous mutation that first appeared in the 1950s in traditional Persian types. It was suggested that the peke-face phenotype results from pathologic skull development and might represent a craniosynostosis of the coronal sutures. We followed this hypothesis and investigated the time dependent status of the neurocranial sutures and synchondroses in an ontogenetic series of doll-faced and peke-faced Persian cats compared to Domestic Shorthair cats (DSHs). Cranial suture closure was assessed by examining an ontogenetic series of formalin-fixed head specimens (n = 55) and dry skulls (n = 32) using micro-computed tomography. Sagittal, metopic, coronal and lambdoid sutures as well as intersphenoidal, spheno-occipital and spheno-ethmoid synchondroses were examined. Logistic regression analysis was performed to test the global effect of age on suture closure within a group of peke-face Persians, doll-face Persians and DSHs and the 50% probability of having a closed suture was calculated and compared between groups. Age was a perfect predictor for the condition of the coronal sutures in peke-face Persians. Coronal sutures were found to be closed at 0–0.3 months. In doll-face and DSHs, coronal sutures were open throughout the lifetime with the exception of a few very old cats. Results of this study confirmed a coronal craniosynostosis that likely causes the extreme brachycephalic skull morphology in the peke-face Persian.

Craniosynostosis is characterized by the premature fusion of one or more major cranial sutures at birth or soon after. Single-suture non-syndromic craniosynostosis (NSC) is the most common form of craniosynostosis and includes the sagittal, metopic, unicoronal and unilambdoid subtypes. Characterized by an abnormal head shape specific to the fused suture type, NSC can cause increased intracranial pressure. Cranial sutures either originate from the neural crest or arise from mesoderm-derived mesenchymal stem cells. A mixture of environmental and genetic factors contributes to NSC, with genetic causes following a largely polygenic model. Physical examination is used to identify the majority of patients, but accompanying radiographic imaging can be confirmatory. The three major surgical techniques in use to treat NSC are cranial vault remodelling, strip craniectomy and spring-assisted cranioplasty. Surgical intervention is ideally performed in the first year of life, with a mortality of <1%. Health-care disparities contribute to delayed initial presentation and timely repair. Optimal timing of surgery and comparative outcomes by surgical technique remain under active study. School-age children with treated NSC on average have subtle, but lower cognitive and behavioural performance. However, patient-reported quality of life outcomes are comparable to those in control individuals. Craniosynostosis is characterized by the premature fusion of one or more major cranial sutures at birth or soon after. In this Primer, Alperovich and colleagues discuss the epidemiology, mechanisms, diagnosis and management of single-suture non-syndromic craniosynostosis, which is the most common form, and highlight quality of life of patients.

Craniosynostosis is a birth defect where calvarial sutures close prematurely, as part of a genetic syndrome or independently, with unknown cause. This study aimed to identify differences in gene expression in primary calvarial cell lines derived from patients with four phenotypes of single-suture craniosynostosis, compared to controls. Calvarial bone samples (N = 388 cases/85 controls) were collected from clinical sites during reconstructive skull surgery. Primary cell lines were then derived from the tissue and used for RNA sequencing. Linear models were fit to estimate covariate adjusted associations between gene expression and four phenotypes of single-suture craniosynostosis (lambdoid, metopic, sagittal, and coronal), compared to controls. Sex-stratified analysis was also performed for each phenotype. Differentially expressed genes (DEGs) included 72 genes associated with coronal, 90 genes associated with sagittal, 103 genes associated with metopic, and 33 genes associated with lambdoid craniosynostosis. The sex-stratified analysis revealed more DEGs in males (98) than females (4). There were 16 DEGs that were homeobox (HOX) genes. Three TFs (SUZ12, EZH2, AR) significantly regulated expression of DEGs in one or more phenotypes. Pathway analysis identified four KEGG pathways associated with at least one phenotype of craniosynostosis. Together, this work suggests unique molecular mechanisms related to craniosynostosis phenotype and fetal sex.

Findings on the cognitive, behavioral, and psychological functioning of individuals with sagittal synostosis (SS) are highly disparate, limiting their clinical utility. To identify and review research on individuals with SS and to determine whether, and to what extent, they experience cognitive, behavioral, and psychological difficulties compared with their healthy peers or normative data for each measure. PubMed, Scopus, Embase, and PsycINFO were searched through January 2021 with no date restrictions. Scopus citation searches and manual checks of the reference lists of included studies were conducted. Studies included participants of any age who had received a diagnosis of single-suture (isolated or nonsyndromic) SS or scaphocephaly and who had been assessed on cognitive, behavioral, and psychological outcomes. Data were independently extracted by 2 reviewers. Case-control outcomes (individuals with SS vs healthy peers or normative data) were compared using random-effects models with 3 effect sizes calculated: weighted Hedges g (gw), odds ratios (ORs), and mean prevalence rates. This study follows the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Findings were categorized by surgical status (conservatively managed, presurgery, postsurgery, or combined); domain (eg, general cognition); type of cognitive, behavioral, or psychological measure (objective or subjective); and source of comparison data (peers or normative data). Data from 32 studies, involving a pooled sample of 1422 children and adults with SS (mean [SD] age at assessment, 5.7 [6.6] years; median [interquartile range] age, 3.3 [0.5-10.3] years), were analyzed. Data on sex were available for 824 participants, and 642 (78%) were male. Individual study results varied substantially. Objective tests identified significant moderate group differences on 3 of 16 examined domains: presurgical motor functioning (3 studies; gw = -0.42; 95% CI, -0.67 to -0.18; P < .001), postsurgical short-term memory (2 studies; gw = -0.45; 95% CI, -0.72 to -0.17; P < .001), and postsurgical visuospatial ability (6 studies; gw = 0.31; 95% CI, 0.18 to 0.44; P < .001). Prevalence estimates and ORs varied widely, with 15 studies showing prevalence estimates ranging from 3% to 37%, and 3 studies showing ORs ranging from 0.31 (95% CI, 0.01 to 6.12) for processing speed in the conservatively managed sample to 4.55 (95% CI, 0.21 to 98.63) for postsurgical visuospatial abilities. In this meta-analysis, findings for the functioning of participants with SS were highly disparate and often of low quality, with small samples sizes and control groups rarely recruited. Nonetheless, the findings suggest that some individuals with SS experience negative outcomes, necessitating routine assessment.

PurposeIncisive suture is a suture classically described on the oral face of the palate in fetuses and young children. The aim of our study was to describe the evolution of the incisive suture in human fetuses and to evaluate the incidence of this suture in a population of young children under 4 years, to determine if there is a possibility of improving the anterior growth of the maxilla, by stimulation of this suture.MethodsOne hundred and thirty CT scan images of patients aged from birth to 48 months have been studied and nine fetal palates aged from 18 to 26 weeks of development, have been scanned using high-resolution X-ray micro-computed tomographyResultsThe CT scan images of patients showed that an incisive suture was present in 33/130 cases (25,4%). All the patients with a suture were under 2 years old. The fetal palate study showed that the suture was present in the inferior aspect of the palate (oral cavity) in all cases. The incisive suture increased from 18 to 24 weeks. At 26 weeks it stopped growing although the intercanine length increased. Considering the closure of the suture in a vertical plane, our study on fetuses has shown that the incisive suture is closing from its superior side (nasal side) to its inferior side.ConclusionsConsidering all these results it appears to us that the incisive suture is partially ossified after birth, it cannot be stimulated by orthodontic appliances.

The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.

Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures); in males, hypertelorism is the only typical manifestation. Here, we show that the classical female CFNS phenotype is caused by heterozygous loss-of-function mutations in EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases. In mice, the orthologous Efnb1 gene is expressed in the frontonasal neural crest and demarcates the position of the future coronal suture. Although EFNB1 is X-inactivated, we did not observe markedly skewed X-inactivation in either blood or cranial periosteum from females with CFNS, indicating that lack of ephrin-B1 does not compromise cell viability in these tissues. We propose that in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males deficient in ephrin-B1, an alternative mechanism maintains the normal boundary. This is the only known mutation in the ephrin/Eph receptor signaling system in humans and provides clues to the biogenesis of craniosynostosis.

Objective We defined parameters that could differentiate between positional and synostotic plagiocephaly and defined a diagnostic chart for decision making. Design Prospective study. Setting We examined 411 children with non-syndromic skull abnormalities between January 2011 and December 2012. Participants A total of 8 infants under 1 year of age with proven unilateral non-syndromic lambdoid synostosis (LS) and 261 children with positional deformity were examined to outline the specific clinical features of both diagnoses. After clinical examination, an ultrasound revealed either a closed suture suggestive of LS or a patent lambdoid suture suggestive of positional deformity. For patients with synostosis, plain radiographs, MR imaging and follow-up examinations were performed. In cases of open sutures, only follow-ups were completed. Main outcome measure Clinical, imaging, genesis and treatment differences between positional plagiocephaly and LS. Results In all 8 cases of unilateral LS and 258 cases of positional plagiocephaly, the diagnosis was established by clinical examination alone. In three cases of positional plagiocephaly, diagnosis was determined after an additional ultrasonography. MR imaging revealed a unilateral tonsillar herniation in five of the eight children with LS and hydrocephalus in one child. Conclusions We have suggested a list of clinical features that specify the underlying cause of posterior plagiocephaly. An additional ultrasound scanning confirmed the diagnosis without any risks of ionising radiation or sedation as in a CT scan.

•Accessory skull sutures are rare developmental anomalies, usually without any clinical signs.•Accessory skull sutures can mimic skull fractures in post-mortem radiography.•The misinterpretation of accessory skull sutures as fractures can lead to serious adverse events.•Radiology alone may not suffice to differentiate between accessory skull sutures and fractures. This paper describes an investigation of the sudden and unexpected death of a five-and-a-half-month-old boy. As in every Dutch case of sudden unexpected death in infancy (SUDI), a multidisciplinary diagnostic approach was used. This included post-mortem radiography, showing a linear discontinuity of the parietal bone. Originally this was interpreted as a skull fracture, but autopsy indicated no signs of mechanical trauma. Instead the defect was defined as a unilateral accessory suture of the parietal bone. The initial erroneous diagnosis had severe adverse consequences and thus every health care professional or forensic specialist dealing with paediatric mechanical traumas should be cautious of this rare anomaly.

PurposeTo describe the manifestations, surgical treatment, and potential complications of Hajdu–Cheney syndrome (HCS), and the management of these complications.MethodsThe clinical presentation, management and outcome of HCS with severe osteoporosis and open skull sutures is presented, together with a literature review.ResultsA 20-year-old female with HCS underwent posterior occipitocervical fusion for symptoms of progressive basilar invagination. Because of delayed lambdoid suture closure, the stiff fusion construct lead to increased suture distraction, most notably in the upright (suture-open) position, with relief in the supine (suture-closed) position. This was successfully remedied with extension of the fusion construct anteriorly over the skull vertex to the frontal bones.ConclusionsIn patients with HCS and other conditions with delayed suture closure, the surgeon must be cognizant of the presence of mobility at the suture lines, and consider extending the fusion construct anteriorly over the skull vertex up to the frontal bones. Because of significant osteoporosis in these syndromes, multiple fixation points and augmentation with bone graft are important principles.