Significance: Craniosynostosis is a common congenital malformation resulting from premature fusion of the bones that comprise the cranial vault, requiring surgery in infancy to prevent adverse neurologic outcomes. Eighty-five percent of cases are non-syndromic and of unknown cause. By exome sequencing of families with non-syndromic midline craniosynostosis, we show that 5% of cases have de novo damaging mutations in negative regulators of the Wnt, bone morphogenetic protein (BMP), and Ras/ERK signaling pathways, developmental cascades that converge on common nuclear targets to promote bone formation. Another 5% have transmitted mutations in these pathways. Common variants nearBMP2show genetic interaction with these rare mutations. The results provide insight into pathophysiology and have immediate implications for the diagnosis and genetic counseling of families with craniosynostosis.

Background and Purpose—: The pathogenesis of cerebral aneurysms still raises some controversies. The aim of this study was to identify morphological, hemodynamic, and clinical independent risk factors for anterior communicating artery (ACoA) aneurysm development. Methods—: Computed tomography angiography and transcranial color-coded sonography were performed in 77 patients with a nonbleeding ACoA aneurysm and in 73 controls. Symmetry of A1 segments of the anterior cerebral arteries, angles between A1 and A2 segments, tortuosity, diameter, mean velocity ( V _m ), pulsatility index, and volume flow rate in both A1 segments were determined. Moreover, all study participants completed a survey on their medical history. Multivariate backward stepwise logistic regression analysis was performed to identify independent risk factors for ACoA aneurysm development. Results—: Smoking, hypertension, asymmetry of A1 segments, the angle between A1 and A2 segments, A1 segment diameter, V _m , pulsatility index, and volume flow rate turned out to be associated with the occurrence of ACoA aneurysms on univariate analysis. Multivariate analysis identified smoking (odds ratio, 2.036; 95% confidence interval, 1.277–3.245), asymmetry of A1 segments >40% (odds ratio, 2.524; 95% confidence interval, 1.275–4.996), pulsatility index (odds ratio, 0.004; 95% confidence interval, 0.000–0.124), and the angle between A1 and A2 segments ≤100° (odds ratio, 4.665; 95% confidence interval, 2.247–9.687) as independent strong risk factors for ACoA aneurysm development. Conclusions—: The risk of ACoA aneurysm formation is determined by several independent clinical, morphological, and hemodynamic factors. The strongest independent risk factors include smoking, asymmetry of A1 segments >40%, low blood flow pulsatility, and the angle between A1 and A2 segments ≤100°.

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation ( P = 4.0 × 10 ⁻⁸ ); additionally, a rare damaging mutation in SOX11 , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant ( P = 8.2 × 10 ⁻¹² ). Three probands had rare damaging mutations in GLI2 , SOX11 , or GPC4 , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A , and CTNNA1 , encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

We investigated the putative benefits of simultaneous teleradiotherapy and anti-epidermal growth factor receptor (EGFR) 125I monoclonal antibody (MAb) 425 radioimmunotherapy, when applied after neurosurgery in high-grade gliomas, over teleradiotherapy alone. In comparison to previous studies which have reported good results with this type of radioimmunotherapy, we advanced the adjuvant radioimmunotherapy step, that is, gave it during, not after, teleradiotherapy. The randomized prospective study examined two groups: simultaneous postoperative teleradiotherapy and radioimmunotherapy (TRT + RIT; eight patients) versus teleradiotherapy alone (TRT; 10 patients). Patients who after primary operation of grade III (6 cases) or IV glioma (12 cases), showed no or less than 2 mL of remnant tumor on post-operative magnetic resonance (MR) study and were not treated postoperatively by chemotherapy were enrolled and randomized. Anti-EGFR 125IMAb 425 RIT was started during week 4 of radiotherapy, not later than 8 weeks after neurosurgery, and was repeated three times at 1-week intervals. Total activity given was 5026 + 739 MBq/patient. The tolerance of TRT was good. No immediate side effects of concomitant anti-EGRF 125I RIT were observed. Observation showed a median total survival (as evaluated from the primary neurosurgical treatment) of 14 months (range 3.5-28 months). There was no improvement in disease-free or total survival in the group of patients treated by TRT + RIT after neurosurgery. In addition, an immunohistochemical analysis of EGFR expression in gliomas was performed in a group of 100 cases and was distinctly positive in 50% grade IV gliomas and 68% grade III gliomas. We conclude that simultaneous radiotherapy and radioimmunotherapy with anti-EGFR 125I-MAb 425 is not beneficial over radiotherapy alone in adjuvant treatment of high-grade gliomas after neurosurgery. We also recommend individual confirmation of EGFR expression in further anti-EGFR radioimmunotherapy trials.