TUBG1, a tubulin gene, plays an important role in neurodevelopment. Here we describe a case of a novel TUGB1 mutation (NM_001070.4:c.821C>T) (p.Thr274Ile). This patient presented similarly to previous cases with features including microcephaly, epilepsy, and speech and motor delay. Unique characteristics were also present such as trigonocephaly, tethered frenulum, scoliosis, nystagmus, and a concurrent FBXW7 mutation. This case expands our breadth of knowledge on TUBG1 genotypic and phenotypic variation. However, further work is needed to fully understand this rare mutation and the associations between TUBG1 and FBXW7 mutations.

Duplication 20p or partial trisomy 20 is a rare chromosomal anomaly characterized by duplication of the short arm of chromosome 20, with various clinical abnormalities. Despite complete trisomy 20, which usually leads to prenatal death, partial trisomy 20 can manifest with variable phenotypes, from mild to severe manifestations. Here, we present a rare case of an 8-year-old boy diagnosed with trisomy 20, epilepsy with focal seizures of genetic origin, craniosynostosis, type 1 diabetes, and autism spectrum disorder. Duplication 20p is a complex diagnostic and presents a therapeutic challenge due to its diverse clinical manifestations. To succeed in the intricacy of such a unique and challenging case, a comprehensive clinical and genetic assessment must be performed.

Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human NINEIN gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.

Titanium continues to be the gold standard in the field of osteosynthesis materials. This also applies to pediatric craniofacial surgery. Various resorbable materials have already been developed in order to avoid costly and risky second operations to remove metal in children. However, none of these resorbable materials have been able to completely replace the previous gold standard, titanium, in a satisfactory manner. This has led to the need for a new resorbable osteosynthesis material that fulfills the requirements for biocompatibility, stability, and uniform resorption. In our previous in vitro and in vivo work, we were able to show that molybdenum fulfills these requirements. To further confirm these results, we conducted a proof of concept in four domestic pigs, each of which was implanted with a resorbable molybdenum implant. The animals were then examined daily for local inflammatory parameters. After 54 days, the animals were euthanized with subsequent computer tomography imaging. We also removed the implants together with the surrounding tissue and parts of the spleen, liver, and kidney for histopathological evaluation. The molybdenum implants were also analyzed metallographically and using scanning electron microscopy. A blood sample was taken pre- and post-operatively. None of the animals showed clinical signs of inflammation over the entire test period. Histopathologically, good tissue compatibility was found. Early signs of degradation were observed after 54 days, which were not sufficient for major resorption. Resorption is expected with longer in situ residence times based on results of similar earlier investigations.

BACKGROUND: Trigonocephaly occurs due to the premature fusion of the metopic suture, leading to a triangular forehead and hypotelorism. This condition often requires surgical correction for morphological and functional indications. Metopic ridges also originate from premature metopic closure but are only associated with mid-frontal bulging; their surgical correction is rarely required. Differential diagnosis between these two conditions can be challenging, especially in minor trigonocephaly.
METHODS: Two hundred seven scans of patients with trigonocephaly (90), metopic rigdes (27), and controls (90) were collected. Geometric morphometrics were used to quantify skull and orbital morphology as well as the interfrontal angle and the cephalic index. An innovative method was developed to automatically compute the frontal curvature along the metopic suture. Different machine-learning algorithms were tested to assess the predictive power of morphological data in terms of classification.
RESULTS: We showed that control patients, trigonocephaly and metopic rigdes have distinctive skull and orbital shapes. The 3D frontal curvature enabled a clear discrimination between groups (sensitivity and specificity > 92%). Furthermore, we reached an accuracy of 100% in group discrimination when combining 6 univariate measures.
CONCLUSIONS: Two diagnostic tools were proposed and demonstrated to be successful in assisting differential diagnosis for patients with trigonocephaly or metopic ridges. Further clinical assessments are required to validate the practical clinical relevance of these tools.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.

Sagittal craniosynostosis (SC) is a congenital condition whereby the newborn skull develops abnormally owing to the premature ossification of the sagittal suture. Spring-assisted cranioplasty (SAC) is a minimally invasive surgical technique to treat SC, where metallic distractors are used to reshape the newborn\'s head. Although safe and effective, SAC outcomes remain uncertain owing to the limited understanding of skull-distractor interaction and the limited information provided by the analysis of single surgical cases. In this work, an SC population-averaged skull model was created and used to simulate spring insertion by means of the finite-element analysis using a previously developed modelling framework. Surgical parameters were varied to assess the effect of osteotomy and spring positioning, as well as distractor combinations, on the final skull dimensions. Simulation trends were compared with retrospective measurements from clinical imaging (X-ray and three-dimensional photogrammetry scans). It was found that the on-table post-implantation head shape change is more sensitive to spring stiffness than to the other surgical parameters. However, the overall end-of-treatment head shape is more sensitive to spring positioning and osteotomy size parameters. The results of this work suggest that SAC surgical planning should be performed in view of long-term results, rather than immediate on-table reshaping outcomes.

UNASSIGNED: Fontanelles, membranous gaps in the infant skull, are integral for accommodating the expansion of the skull by the growing brain postnatally. The anterior fontanelle, situated at the frontal-parietal bone intersection, typically closes gradually within the first two years. Fontanellar bone, an exceedingly rare ossification anomaly of the anterior fontanelle, clinically mimics craniosynostosis.
UNASSIGNED: We present the case of a 22-day-old male with an almost closed anterior fontanelle who underwent evaluation. Prenatal and postnatal history were unremarkable. Physical examination revealed a well-nourished infant with a nearly closed fontanelle but no other anomalies. The initial diagnosis was craniosynostosis; however, a head computed tomography scan revealed fontanellar bone. Consequently, a conservative management approach with regular follow-ups was adopted.
UNASSIGNED: This case provides valuable insights into fontanellar bone, emphasizing its consideration in differential diagnoses for almost closed anterior fontanelles. The report aims to enhance awareness and understanding of this rare condition, promoting accurate diagnosis and optimal patient outcomes.

Sagittal craniosynostosis, a rare but fascinating craniofacial anomaly, presents a unique challenge for both diagnosis and treatment. This condition involves premature fusion of the sagittal suture, which alters the normal growth pattern of the skull and can affect neurological development. Sagittal craniosynostosis is characterised by a pronounced head shape, often referred to as scaphocephaly. Asymmetry of the face and head, protrusion of the fontanel, and increased intracranial pressure are common clinical manifestations. Early recognition of these features is crucial for early intervention, and understanding the aetiology is, therefore, essential. Although the exact cause remains unclear, genetic factors are thought to play an important role. Mutations in genes such as FGFR2 and FGFR3, which disrupt the normal development of the skull, are suspected. Environmental factors and various insults during pregnancy can also contribute to the occurrence of the disease. An accurate diagnosis is crucial for treatment. Imaging studies such as ultrasound, computed tomography, magnetic resonance imaging, and three-dimensional reconstructions play a crucial role in visualising the prematurely fused sagittal suture. Clinicians also rely on a physical examination and medical history to confirm the diagnosis. Early detection allows for quick intervention and better treatment outcomes. The treatment of sagittal craniosynostosis requires a multidisciplinary approach that includes neurosurgery, craniofacial surgery, and paediatric care. Traditional treatment consists of an open reconstruction of the cranial vault, where the fused suture is surgically released to allow normal growth of the skull. However, advances in minimally invasive techniques, such as endoscopic strip craniectomy, are becoming increasingly popular due to their lower morbidity and shorter recovery times. This review aims to provide a comprehensive overview of sagittal craniosynostosis, highlighting the aetiology, clinical presentation, diagnostic methods, and current treatment options.