Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.

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.

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Decreased Bone Mineral Density in Forearm vs Loaded Skeletal Sites in Professional Ballet Dancers.

AIMS: To compare the differences in bone mineral density (BMD) at loaded and non-loaded skeletal sites in professional ballet dancers. We hypothesized that in both male and female elite ballet dancers, a significant difference in BMD will be observed between impact and non-impact sites. METHODS: 44 elite ballet dancers, 22 men (age 26.4±5.9 yrs) and 22 women (age 24.9±5.3 yrs), were examined. BMD measurements were performed using dual-energy x-ray absorptiometry at three skeletal sites-forearm (FA), lumbar spine (LS), and femoral neck (FN)-and analyzed using t-tests, ANOVA, and linear regression models. Information about career duration, training volume, health habits, and menstrual disorders (women) was collected. RESULTS: Z-scores for LS and FN were significantly higher in men than in women. However, Z-scores for FA were similar in men and women and fell below the expected range for age (<-2.0), and they were significantly lower than those for LS and FN. With longer career duration, a trend was observed towards lower Z-scores for FN in men and towards higher Z-scores for FA in women. CONCLUSION: In ballet dancers, FA mineralization is extremely low compared to loaded skeletal sites. Male dancers may have lowered forearm BMD despite the absence of risk factors present in female dancers (menstrual disorders). Professional ballet dancers may be at risk of local osteopenia due to the "local non-impact" characteristics of ballet dance, and use of the 33% distal radius region for the accurate assessment of bone mineral status should be investigated further in this population.

Morphological, hemodynamic, and clinical independent risk factors for anterior communicating artery aneurysms.

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 (Vm), 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, Vm, 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°.

Radiological findings in relation to the neurodevelopmental outcome in hydrocephalic children treated with shunt insertion or endoscopic third ventriculostomy.

PURPOSE: The aim of the study was to compare the radiological indicators of effectiveness for hydrocephalus treatment in children operated on under the third year of age with the use of shunt insertion (SI) and endoscopic third ventriculostomy (ETV). The effectiveness was considered in terms of postoperative neurodevelopment in correlation to pre- and postoperative radiological findings. METHODS: The examined group consisted of 46 children operated on for hydrocephalus in the Division of Pediatric Neurosurgery in Katowice, Poland. There were 21 children treated with SI and 25 with ETV. The radiographic assessment was carried out on the basis of MRI and CT examinations with the use of a linear estimate known as frontal and occipital horn ratio (FOR). The FOR values were calculated for the entire group and in correlation to the treatment method and to the children neurodevelopment evaluated with The Denver Developmental Screening Test. RESULTS: No differences were recognized between initial FOR value in terms of the postoperative children neurodevelopment. In the successful ETV-treated subgroup, the mean change in FOR was 0.05 and in the SI-treated subgroup, the mean change in FOR 0.13. The patients with BFOR >0.1, developed normally more often than those in whom BFOR was lower than 0.1. CONCLUSIONS: The initial FOR value probably does not affect the postoperative developmental outcome. Long-term change in ventricles size after surgery can correlate with psychomotor development of hydrocephalic children. Presumably, there are no differences between two treatment options according to initial FOR values and to changes in FOR values.

A European multicenter outcome study on the different perioperative airway management policies following midface surgery in syndromic craniosynostosis: a proposal for a Standard Operating Procedure.

BACKGROUND: Perioperative airway management following midface advancements in children with Apert and Crouzon/Pfeiffer syndrome can be challenging, and protocols often differ. This study examined airway management following midface advancements and postoperative respiratory complications. METHODS: A multicenter, retrospective cohort study was performed to obtain information about the timing of extubation, perioperative airway management, and respiratory complications after monobloc / le Fort III procedures. RESULTS: Ultimately, 275 patients (129 monobloc and 146 Le Fort III) were included; 62 received immediate extubation and 162 delayed extubation; 42 had long-term tracheostomies and nine perioperative short-term tracheostomies. Short-term tracheostomies were in most centers reserved for selected cases. Patients with delayed extubation remained intubated for three days (IQR 2 - 5). The rate of no or only oxygen support after extubation was comparable between patients with immediate and delayed extubation, 58/62 (94%) and 137/162 (85%) patients, respectively. However, patients with immediate extubation developed less postoperative pneumonia than those with delayed, 0/62 (0%) versus 24/161 (15%) (P = 0.001), respectively. Immediate extubation also appeared safe in moderate/severe OSA since 19/20 (95%) required either no or only oxygen support after extubation. The odds of developing intubation-related complications increased by 21% with every extra day of intubation. CONCLUSIONS: Immediate extubation following midface advancements was found to be a safe option, as it was not associated with respiratory insufficiency but did lead to fewer complications. Immediate extubation should be considered routine management in patients with no/mild OSA and should be the aim in moderate/severe OSA after careful assessment.

Stereotactic linac radiosurgery and hypofractionated stereotactic radiotherapy for pediatric arteriovenous malformations of the brain: experiences of a single institution.

PURPOSE: The aim of our study was to evaluate treatment results and toxicity of stereotactic irradiation for arteriovenous malformations (AVMs) in children. METHODS: A group of ten consecutive children (four boys and six girls) irradiated between 2002 and 2010 at our institution was included into the study. The mean age at the time of treatment was 15.4 and ranged between 8 and 18 years. There were two Spetzler-Martin grade IV, four grade III, and four grade II lesions. Mean AVM volume was 13.2 cm(3) and varied from 0.6 to 36.8 cm(3). In five patients, the planned dose of 16-20 Gy was delivered in single fraction, in five the total dose of 16-24 Gy was delivered in two to three fractions. One patient was reirradiated with a dose of 15 Gy, 7 years after the initial treatment. RESULTS: The median follow-up was 38.5 months. The treatment resulted in total obliteration in eight patients and partial in one. The median time to obliteration was 22 months; actuarial total obliteration rates were 20, 54, 54, and 83 % after 1, 2, 3, and 4 years of follow-up, respectively. No patient bled after the treatment. In one patient, new epileptic seizures developed after the treatment; in magnetic resonance imaging, focal necrosis was revealed. In five patients, asymptomatic imaging abnormalities were seen during follow-up. CONCLUSIONS: Stereotactic radiotherapy appears to be an effective method of treatment for pediatric AVMs, the patients however require meticulous follow-up because of relative high incidence of radiation-induced imaging abnormalities.

Hypofractionated stereotactic radiotherapy for large or involving critical organs cerebral arteriovenous malformations.

BACKGROUND: The treatment of large arteriovenous malformations (AVMs) or AVMs involving eloquent regions of the brain remains a challenge. For inoperable lesions, observation, volume-staged radiosurgery or hypofractionated stereotactic radiotherapy (HFSRT) are proposed. The aim of our study was to assess the safety and efficiency of HFSRT for large AVMs located in eloquent areas of the brain. MATERIALS AND METHODS: An analysis of records of 49 patients irradiated for cerebral AVMs with a mean dose of 19.9 Gy (12-28 Gy) delivered in 2-4 fractions with planned gap (at least one week) between fractions. Actuarial obliteration rates and annual bleeding hazard were calculated using Kaplan-Meier survival analysis and life tables. RESULTS: Annual bleeding hazard rates were 4.5% and 1.6% after one and two years of the follow-up, respectively. Actuarial total obliteration rates were 7%, 11%, and 21% and total response rate (total and partial obliterations) 22%, 41%, and 55% after one, two and three years of the follow-up, respectively. There was a trend towards larger total obliteration rate in patients irradiated with fraction dose ≥ 8 Gy and total dose > 21 Gy for lesions of volume ≤ 8.18 cm(3) which was not observed in case of partial obliterations. CONCLUSIONS: HFSRT results with relatively low obliteration rate but is not associated with a significant risk of permanent neurological deficits if both total and fraction doses are adjusted to size and location of the lesion. Predictive factors for total and partial obliterations can be different; this observation, however, is not firmly supported and requires further studies.

The Effectiveness and Toxicity of Frameless CyberKnife Based Radiosurgery for Parkinson's Disease-Phase II Study.

Frame-based stereotactic radiosurgery (SRS) has an established role in the treatment of tremor in patients with Parkinson's disease (PD). The low numbers of studies of frameless approaches led to our prospective phase 2 open-label single-arm clinical trial (NCT02406105), which aimed to evaluate the safety and efficacy of CyberKnife frameless SRS. Twenty-three PD patients were irradiated on the area of the thalamic ventral nuclei complex with gradually increasing doses of 70 to 105 Gy delivered in a single fraction. After SRS, patients were monitored for tremor severity and the toxicity of the treatment. Both subjective improvement and dose-dependent efficacy were analysed using standard statistical tests. The median follow-up was 23 months, and one patient died after COVID-19 infection. Another two patients were lost from follow-up. Hyper-response resulting in vascular toxicity and neurologic complications was observed in two patients irradiated with doses of 95 and 100 Gy, respectively. A reduction in tremor severity was observed in fifteen patients, and six experienced stagnation. A constant response during the whole follow-up was observed in 67% patients. A longer median response time was achieved in patients irradiated with doses equal to or less than 85 Gy. Only two patients declared no improvement after SRS. The efficacy of frameless SRS is high and could improve tremor control in a majority of patients. The complication rate is low, especially when doses below 90 Gy are applied. Frameless SRS could be offered as an alternative for patients ineligible for deep brain stimulation; however, studies regarding optimal dose are required.

A Computational Framework to Predict Calvarial Growth: Optimising Management of Sagittal Craniosynostosis.

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.

Management of sagittal craniosynostosis: morphological comparison of eight surgical techniques.

The aim of this study was to carry out a retrospective multicentre study comparing the morphological outcome of 8 techniques used for the management of sagittal synostosis versus a large cohort of control patients. Computed tomographic (CT) images were obtained from children CT-scanned for non-craniosynostosis related events (n = 241) and SS patients at preoperative and postoperative follow-up stages (n = 101). No significant difference in morphological outcomes was observed between the techniques considered in this study. However, the majority of techniques showed a tendency for relapse. Further, the more invasive procedures at older ages seem to lead to larger intracranial volume compared to less invasive techniques at younger ages. This study can be a first step towards future multicentre studies, comparing surgical results and offering a possibility for objective benchmarking of outcomes between methods and centres.

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects.

Background: Craniosynostosis (CS) represents a highly heterogeneous genetic condition whose genetic background has not been yet revealed. The abnormality occurs either in isolated form or syndromic, as an element of hundreds of different inborn syndromes. Consequently, CS may often represent a challenging diagnostic issue. Methods: We investigated a three-tiered approach (karyotyping, Sanger sequencing, followed by custom gene panel/chromosomal microarray analysis, and exome sequencing), coupled with prioritization of variants based on dysmorphological assessment and description in terms of human phenotype ontology. In addition, we have also performed a statistical analysis of the obtained clinical data using the nonparametric test χ2. Results: We achieved a 43% diagnostic success rate and have demonstrated the complexity of mutations' type harbored by the patients, which were either chromosomal aberrations, copy number variations, or point mutations. The majority of pathogenic variants were found in the well-known CS genes, however, variants found in genes associated with chromatinopathies or RASopathies are of particular interest. Conclusion: We have critically summarized and then optimised a cost-effective diagnostic algorithm, which may be helpful in a daily diagnostic routine and future clinical research of various CS types. Moreover, we have pinpointed the possible underestimated co-occurrence of CS and intellectual disability, suggesting it may be overlooked when intellectual disability constitutes a primary clinical complaint. On the other hand, in any case of already detected syndromic CS and intellectual disability, the possible occurrence of clinical features suggestive for chromatinopathies or RASopathies should also be considered.

Predicting and comparing three corrective techniques for sagittal craniosynostosis.

Sagittal synostosis is the most occurring form of craniosynostosis, resulting in calvarial deformation and possible long-term neurocognitive deficits. Several surgical techniques have been developed to correct these issues. Debates as to the most optimal approach are still ongoing. Finite element method is a computational tool that's shown to assist with the management of craniosynostosis. The aim of this study was to compare and predict the outcomes of three reconstruction methods for sagittal craniosynostosis. Here, a generic finite element model was developed based on a patient at 4 months of age and was virtually reconstructed under all three different techniques. Calvarial growth was simulated to predict the skull morphology and the impact of different reconstruction techniques on the brain growth up to 60 months of age. Predicted morphology was then compared with in vivo and literature data. Our results show a promising resemblance to morphological outcomes at follow up. Morphological characteristics between considered techniques were also captured in our predictions. Pressure outcomes across the brain highlight the potential impact that different techniques have on growth. This study lays the foundation for further investigation into additional reconstructive techniques for sagittal synostosis with the long-term vision of optimizing the management of craniosynostosis.

Is neuroradiological imaging sufficient for exclusion of intracranial hypertension in children? Intracranial hypertension syndrome without evident radiological symptoms.

There are still many important questions about algorithms and clinical scenarios in the context of children with clinical intracranial hypertension symptoms (IHS) without radiological findings. Such conditions could appear in different clinical situations, including slit ventricle syndrome, overdrainage syndrome, normal volume hydrocephalus, or idiopathic intracranial hypertension. Many articles have defined specific treatment strategies for various forms of IHS, including ventriculoperitoneal shunting, medication for shunt-related migraine, steroids, and valve upgrades with antisiphoning devices or programmable systems. This study is an attempt to define the proper diagnostic procedures and treatment options for patients with various forms of IHS without evident neuroradiological findings. The authors discuss possible pathological mechanisms leading to IHS in the pediatric population. The authors present six children treated in their center. All of the children presented clinical manifestation of intracranial hypertension without evident neuroradiological findings in CT and/or MRI examinations. In three cases, the final diagnosis was slit ventricle syndrome; in two cases, normal volume hydrocephalus; in another case, idiopathic intracranial hypertension. The treatment options included short-term steroid (dexamethasone) administration and ventriculoperitoneal shunting using programmable systems. In one case of idiopathic intracranial hypertension, ICP monitoring was also performed. The authors discuss possible diagnostic and treatment strategies for the aforementioned cases. There are still many controversies about management of children with clinical symptoms of intracranial hypertension that are not confirmed in neuroimaging. It seems that our understanding of intracranial hypertension in the pediatric population is not nearly as sophisticated or complete as we might have imagined. Ventriculoperitoneal shunting with antisiphoning devices and/or short-term dexamethasone administration seem to be the best treatment options in these cases.

Posterior fossa brain tissue injury: developmental, neuropsychological, and neurological consequences of brain tumors in children.

The aim of the study was the functional neurodevelopmental assessment of children with posterior fossa tumors, specifically examining whether tumor location in particular cerebellar structures determines particular neuropsychological deficits. The examined group consisted of 34 children treated between 1999 and 2007 at the Division of Pediatric Neurosurgery Silesian University Medical School in Katowice, Poland. Twelve girls and 22 boys between 5 and 21 years of age were examined. The mean age was 12.3 years. There were 21 total and 8 subtotal resections of tumor, and marsupialization was performed in cases of arachnoid cysts. Hydrocephalus in 19 patients was fixed surgically. Histopathological diagnoses of tumors were as follows: 4 medulloblastomas, 8 pilocytic astrocytomas, 6 fibrillary astrocytomas, 1 anaplastic astrocytoma, 2 oligodendrogliomas, 4 anaplastic ependymomas, 1 choroid plexus papilloma, and 5 arachnoid cysts. The children were assessed by age-appropriate tests that examine higher mental functions such as cognitive processes, visual-spatial functions, verbal fluency, planning, sequential memory, and emotions. Additionally, speech examination and tests were performed. The clinical state of all patients was also evaluated, including a full neurological examination. Posterior fossa tumors can disturb normal development of higher mental functions, especially in the development of linguistic and emotional traits. Our study aimed to better understand the functional anatomy of the cerebellum in the context of behavioral changes. Exploration of the consequences of damage to posterior fossa structures may lead to a better understanding of their function in the emotional and cognitive development of children. Moreover, this work may enable the prediction of neurobehavioral disorders and offer appropriate strategies for rehabilitation, qualification, and surgical procedures.

MR spectroscopic evaluation of brain tissue damage after treatment for pediatric brain tumors.

PURPOSE: The aim of this study was to evaluate the metabolic profile of uninvolved brain tissue after treatment for pediatric brain tumors. MATERIAL: A group of 24 patients aged 4-18 years was analyzed after combined treatment for brain tumors. In this group, there were nine medulloblastomas, seven low-grade gliomas, three high-grade gliomas, two ependymomas and three children with conservatively treated diffuse brainstem gliomas. METHODS: Short echo-time (TE = 30 ms) point-resolved spectra were acquired using a 2 T clinical scanner (Elscint Prestige). The ratios of signal intensities for N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), lactate (Lac), and lipids (Lip) were calculated using the creatine (Cr) signal as an internal reference. The spectra were acquired both from the tumor bed and from contralateral uninvolved brain tissue; only control spectra were analyzed. The first examination was made between the third and sixth month after therapy (24 spectra), the second examination occurred 8-12 months after treatment (15 spectra available), and the third was performed approximately 18 months after completion of therapy (eight spectra available). The results were compared using the t-test for dependent samples. RESULTS: At all time points, the metabolite ratios showed alterations indicating brain tissue damage. The most important were the decrease of NAA/Cr and increase of Lac/Cr and Lip/Cr ratios. The mean NAA/Cr values were 0.91, 0.91, and 0.86, respectively, for the three examinations, while the Lac/Cr and Lip/Cr values were 1.66, 2.11, 1.19 and 12.24, 12.05, 5.69, respectively. Interestingly, in children with supratentorial tumors, a significant increase in NAA/Cr value was observed (from 0.82 to 1.11 in the first and second examinations, respectively; p = 0.0487), which may be indicative of neuronal function recovery. CONCLUSIONS: MRS examinations of uninvolved brain tissue indicate long-lasting metabolic disturbances. However, the NAA/Cr ratio increase may be a sign of at least partial recovery of metabolic function of the brain.

The incidence of imaging abnormalities after stereotactic radiosurgery for cerebral arteriovenous and cavernous malformations.

OBJECTIVE: The aim of the study was to evaluate the incidence of postirradiation imaging changes after stereotactic radiosurgery for arteriovenous malformations (AVM) and cerebral cavernous malformations (CCM). MATERIAL AND METHODS: A group of 85 patients treated for arteriovenous malformations (62 patients, 73%) and cavernomas (23 patients, 27%) between October 2001 and December 2005 was analyzed. All patients were treated with stereotactic radiosurgery with doses ranging from 8-28 Gy. After the irradiation, magnetic resonance imaging (MRI) or computed tomography (CT) was performed at 6 to 12-month intervals to assess the effects of the treatment. The mean follow-up time for the whole group was 27.3 months; AVM group -- 26 months; CCM group -- 30.9 months. All the imaging data were carefully reviewed to identify the radiological symptoms of postradiosurgical damage. T2 or FLAIR hyperintensity, T1-hypointensity and contrast enhancement on MRI and the presence of hypodense areas and contrast enhancement on CT examinations were assessed. RESULTS: Imaging abnormalities were found in 28 (33%) patients. The symptoms of postradiosurgical damage were observed in 21 (33.9%) patients in the AVM group and 7 (30.4%) patients in the CCM group. Radiological symptoms of radiation necrosis associated with neurological deterioration were identified in two patients with cavernomas, while no radiation necrosis was found in the AVM group. Patients in whom radiological signs of focal brain edema or gliosis existed were asymptomatic. CONCLUSIONS: Radiological symptoms of postradiosurgical damage affected about one third of the irradiated patients, typically without any clinical manifestations. Patients irradiated for CCMs seem to be more prone to develop symptomatic postradiosurgical necrosis; this observation, however, requires further investigation.

Alterations of upper airway volume caused by Le Fort III osteodistraction in children.

PURPOSE: The aim of the study was to assess changes in the upper respiratory tract and sleep quality in patients who were suffering from midfacial hypoplasia and treated with the movement of underdeveloped middle segment of the face with an Le Fort III osteotomy and distraction. METHODS: In this study patients aged 7-19, suffering from Crouzon syndrome, Apert syndrome, or other craniosynostosis were treated with Le Fort III osteotomy and midface distraction. Patients were subjected to radiological examination and polysomnography before and after the treatment. Typical anthropometric points were identified on lateral cephalograms, and were used to take linear and angular measurements. The surface and the volume of the upper respiratory tract were measured with the Dolphin Imaging software. Apnoea Hypopnea Index (AHI) was used to assess the sleep quality. RESULTS: In all 18 patients the analysis showed statistically significant changes of the AHI and in the linear, angular and volumetric measurements. Mean change of the volume of the upper respiratory tract was 12,4 ± 11,3cm3(p = 0,0001) and of the surface was 615 ± 521 mm2 (p = 0,0000000002). Mean improvement of AHI was 9 ± 6,2 (p = 0,00006). In three cases patients had tracheostomy prior to operation and none of them required tracheostomy after the operation. CONCLUSIONS: The use of distraction osteogenesis of the middle segment of the face combined with Le Fort III osteotomy results in dilation of the upper respiratory tract at the nasopharyngeal level and at the soft palate level resulting in elimination of sleep and respiration disorders. Further studies with polysomnography are necessary, as well as observation of patients over time and monitoring of treatment stability.

Adapting SureSelect enrichment protocol to the Ion Torrent S5 platform in molecular diagnostics of craniosynostosis.

Obtaining reliable and high fidelity next-generation sequencing (NGS) data requires to choose a suitable sequencing platform and a library preparation approach, which both have their inherent assay-specific limitations. Here, we present the results of successful adaptation of SureSelect hybridisation-based target enrichment protocol for the sequencing on the Ion Torrent S5 platform, which is designed to work preferably with amplicon-based panels. In our study, we applied a custom NGS panel to screen a cohort of 16 unrelated patients affected by premature fusion of the cranial sutures, i.e. craniosynostosis (CS). CS occurs either as an isolated malformation or in a syndromic form, representing a genetically heterogeneous and clinically variable group of disorders. The approach presented here allowed us to achieve high quality NGS data and confirmed molecular diagnosis in 19% of cases, reaching the diagnostic yield similar to some of the published research reports. In conclusion, we demonstrated that an alternative enrichment strategy for library preparations can be successfully applied prior to sequencing on the Ion Torrent S5 platform. Also, we proved that the custom NGS panel designed by us represents a useful and effective tool in the molecular diagnostics of patients with CS.

Compound craniosynostosis, intellectual disability, and Noonan-like facial dysmorphism associated with 7q32.3-q35 deletion.

OBJECTIVE: Craniosynostosis (CS) is the premature fusion of the cranial sutures, occurring either in isolated or syndromic form. Syndromic CS, which was described in over 180 genetic syndromes, accounts for 15-30% of all CS cases and usually originates from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. However, causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this article, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability and compound CS, involving coronal, sagittal, and squamous sutures. METHODS: We applied karyotyping, copy number variations analysis using array comparative genomic hybridization, and microarray-based genes expresion analysis. RESULTS: We have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3-q35 (HG38 - chr7:131837067-144607071). The aberration comprised 109 protein-coding genes, including BRAF, that encodes serine/threonine-protein kinase B-Raf, being a part of the RAS/MAPK signaling pathway. DISCUSSION: The RAS/MAPK pathway plays an essential role in human development; hence, its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency of BRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.