Association between Brachycephaly, Chiari Malformation, and Basilar Invagination

Background There is evidence that Chiari malformation (CM) and basilar invagination (BI) are largely due to disproportion between the content and volume of the posterior fossa. A recent study identified an increased association between brachycephaly and BI. In several types of craniosynostosis, the posterior fossa volume is smaller than normal, and this is more pronounced in coronal synostosis. The aim of this study is to evaluate the association between CM and BI. Methods The cephalic index (CI) measured on magnetic resonance imaging (MRI) from a sample of patients with craniocervical malformation was compared with that of normal subjects. Results The average CI in the craniovertebral junction malformation (CVJM) group was significantly higher in BI patients than in normal subjects. The BI patients also had the highest CI among the whole sample of patients (p = 0.009). Conclusions In this study, BI patients had the highest CI among patients with CVJM and a significantly higher CI than those in the control group. Our data confirm the association between BI and brachycephaly.

Embryonic requirements for Tcf12 in the development of the mouse coronal suture

A major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in either of the basic HLH transcription factors TWIST1 and TCF12. While compound heterozygous Tcf12; Twist1 mice display severe coronal synostosis, the individual role of Tcf12 had remained unexplored. Here we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement for Tcf12 in suture formation, as combined deletion of Tcf12 in embryonic neural crest and mesoderm, but not in postnatal suture mesenchyme, disrupts the coronal suture. We also detect asymmetric distribution of mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. In Tcf12 mutants, reduced asymmetry is associated with bones meeting end-on-end, possibly contributing to synostosis. Our results support embryonic requirements of Tcf12 in proper formation of the overlapping coronal suture.

Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel EFNB1 Gene Mutation

Craniofrontonasal syndrome (CFNS) is a rare X-linked genetic disorder which is characterized by coronal synostosis, widely spaced eyes, a central nasal groove, and various skeletal anomalies. Mutations in the <i>EFNB1</i> gene in Xq13.1 are responsible for familial and sporadic cases. In the present study, we aimed to evaluate the clinical characteristics and molecular results of 4 patients with CFNS. Genomic DNA was extracted from the peripheral blood lymphocytes of all patients and their parents, and Sanger sequencing of the <i>EFNB1</i> gene was performed. A novel <i>EFNB1</i> gene mutation (c.65delG; p.Cys22SerfsTer24) was detected in a newborn who had only dysmorphic facial features and bicornuate uterus. The other 3 patients (2 familial cases and 1 sporadic case) shared the same mutation (c.196C&#x3e;T; p.R66X). However, the clinical features of these patients were highly variable. Additionally, central (meso-axial) polydactyly and deep palmar creases were detected, which have not been previously reported. CFNS has a wide clinical spectrum, but there is no clear genotype-phenotype correlation. However, central (meso-axial) polydactyly and deep palmar creases may be part of the clinical spectrum seen in CFNS. In addition, our findings expand the mutational spectrum in patients with CFNS.

The developing mouse coronal suture at single-cell resolution

Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. To uncover the cellular diversity within sutures, we generated single-cell transcriptomes and performed extensive expression validation of the embryonic murine coronal suture. We identify Erg and Pthlh as markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. In the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones. In the dura mater underlying the suture, we detect a chondrocyte-like signature potentially linked to cartilage formation under pathological conditions. Genes mutated in coronal synostosis are preferentially expressed in proliferative osteogenic cells, as well as meningeal layers, suggesting discrete cell types that may be altered in different syndromes. This single-cell atlas provides a resource for understanding development of the coronal suture, the suture most commonly fused in monogenic craniosynostosis.

Occipitofrontal switch for correction of anterior plagiocephaly planned through virtual mock surgery

Background: Unilateral coronal synostosis causing anterior plagiocephaly can result in restricted brain development and severe facial deformities. Various surgical procedures have been described for the correction of this deformity. Cranial vault remodeling, however, is associated with several complications. Occipitofrontal switching is a novel technique which utilizes a part of the contralateral occipital bone to reconstruct the frontal area. This is the first such case reported from India and first report where virtual mock surgery has been utilized for precision and improving outcome in this elegant procedure. Case Description: A 5-year-old girl presented with left anterior plagiocephaly. 3D image of her skull was reconstructed using Geomagic Freeform software (3D Systems, Rock Hill, SC). Measurements were accurately drawn and the procedure was practised virtually before performing the occipitofrontal switch on the patient. There were minimal blood loss and postoperative morbidity. One year follow-up of the patient showed optimal correction of the defect in the forehead region, symmetrical shape of the frontal and occipital region and symmetrical brows. Conclusion: The technique of occipitofrontal switch for correction of anterior plagiocephaly is an elegant procedure with good functional and aesthetic outcome.

Open craniofacial reconstruction for coronal craniosynostosis

Here the authors demonstrate open craniofacial reconstruction for the correction of craniosynostosis, using techniques refined by Dr. James T. Goodrich at Montefiore Medical Center. They present the operative management of a case of unilateral coronal synostosis in a 12-month-old child, who presented with right forehead prominence and calvarial asymmetry. The patient had an excellent correction of her head shape with an uneventful postoperative course. This video highlights the authors’ multidisciplinary approach to complete cranial vault remodeling, utilizing a Marchac bandeau construct and split calvarial graft mosaic technique. The video can be found here: https://vimeo.com/519489422.

Embryonic requirements forTcf12in the development of the mouse coronal suture

A major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in the basic HLH transcription factorsTWIST1andTCF12. While compound heterozygousTcf12; Twist1mice display severe coronal synostosis, the individual role ofTcf12has remained unexplored. Here we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement forTcf12in suture formation, as combined deletion ofTcf12in the embryonic neural crest and mesoderm, but not in the postnatal suture mesenchyme, disrupts the coronal suture. We also detect asymmetric distribution of Grem1 + mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. InTcf12mutants, reduced asymmetry correlates with lack of bone overlap. Our results indicate a largely embryonic function of Tcf12 in controlling the rate and asymmetrical growth of calvarial bones and establishment of suture boundaries, which together ensure the proper formation of the overlapping coronal suture.