Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.

BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.

The current understanding of germline predisposition in non-syndromic sagittal craniosynostosis: a systematic review.

PURPOSE: The objective of this literature review was to provide a comprehensive and up-to-date overview of the current understanding of the genetic etiology for non-syndromic sagittal craniosynostosis. METHODS: Using the PubMed database and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we systematically reviewed relevant records on germline genetics in children with non-syndromic sagittal craniosynostosis. RESULTS: Two hundred two records were identified, of which 25 were included following title and abstract screening and subsequent full-text review. The 25 records in combination included 829 children with non-syndromic sagittal craniosynostosis. A likely pathogenic or pathogenic germline variant was reported for 9.8% of the 827 patients for whom germline genetic testing was performed. The reported variants were distributed across 50 different genes, with more than one variant detected in 13 genes. CONCLUSION: Based on the existing literature, genetic predisposition is likely to play a role in at least 9% of children with non-syndromic sagittal craniosynostosis. Future studies will benefit from international consensus in terms of diagnostic nomenclature and a higher level of standardization across study methodologies and bioinformatic approaches.

CNS infection in children with brain tumors: adding ventriculostomy to brain tumor resection increases risk more than 20-fold.

PURPOSE: To investigate the risk of central nervous system (CNS) infections in children undergoing neurosurgery for brain tumors. METHODS: Single-center retrospective cohort study including all children with brain tumors undergoing neurosurgical treatment over an 11-year period. RESULTS: A total of 274 patients undergoing 733 neurosurgical procedures were included. Overall, 12.8% of patients were diagnosed with a CNS infection during their course of treatment. CNS infections were more frequent among children treated with CSF diversion (p < 0.001) and independently associated with low age (OR/y 0.9 (CI 95% 0.769-0.941), intraventricular (OR 2.8, CI 95% 1.2-6.5), and high-grade tumors (OR 2.7, CI 95% 1.1-6.5). The majority of CNS infections occurred within 30 days of surgery, resulting in a postoperative CNS infection rate of 5.3%. Postoperative CNS infections were significantly more frequent following adjunct EVD placement during tumor resection compared to a stand-alone craniotomy (30.4% vs. 1.5%, RR 20.6, CI 95% 5.7-72.2). CONCLUSION: CNS infections affect at least 12% of children with brain tumors and are associated with age, tumor location, and grade. Adding EVD to tumor surgery increases the risk of postoperative CNS infection, and reconsidering routine adjunct EVD placement is therefore advocated.

Assessment of the Milan Complexity Scale for prediction of postoperative morbidity in pediatric neuro-oncological surgery.

PURPOSE: To assess the performance of the risk-predicting Milan Complexity Scale (MCS) on postoperative morbidity in pediatric neuro-oncological surgery. METHODS: A retrospective dual-center review of children undergoing primary brain tumor resection in Denmark over a 10-year period. MCS scoring was performed based on preoperative imaging, blinded to individual outcomes. Surgical morbidity was registered according to existing complication scales and dichotomized as significant or nonsignificant morbidity. The MCS was evaluated using logistic regression modeling. RESULTS: 208 children (50% female, mean age 7.9 y, and SD 5.2) were included. Of the original "Big Five" predictors included in the MCS, only posterior fossa (OR: 2.31, 95% CI: 1.25-4.34, p-value = 0.008) and eloquent area (OR: 3.32, 95% CI: 1.50-7.68, p-value = 0.004) locations were significantly associated with increased risk of significant morbidity in our pediatric cohort. The absolute MCS score correctly classified 63.0% of cases. Its accuracy increased to 69.2% when mutually adjusting for each of the "Big Five" predictors with corresponding positive and negative predictive values of 66.2% and 71.0%, using a predicted probability cutoff of 0.5. CONCLUSION: The MCS is predictive of postoperative morbidity also in pediatric neuro-oncological surgery, although only two of its original five variables were significantly associated with poor outcome in children. The clinical value of the MCS is likely limited for the experienced pediatric neurosurgeon. Future clinically impactful risk-prediction tools should include a larger number of relevant variables and be tailored to the pediatric population.

Genetic predisposition to central nervous system tumors in children - what the neurosurgeon should know.

BACKGROUND: Historically, few pediatric central nervous system (CNS) tumors were thought to result from genetic predisposition. However, within the last decade, new DNA sequencing methods have led to an increased recognition of high-risk cancer predisposition syndromes in children with CNS tumors. Thus, genetic predisposition is increasingly impacting clinical pediatric neuro-oncology. METHODS: In this narrative review, we discuss the current understanding of genetic predisposition to childhood CNS tumors and provide a general overview of involved research methodologies and terminology. Moreover, we consider how germline genetics may influence neurosurgical practice. RESULTS: Introduction of next-generation DNA sequencing has greatly increased our understanding of genetic predisposition to pediatric CNS tumors by enabling whole-exome/-genome sequencing of large cohorts. To date, the scientific literature has reported germline sequencing findings for more than 2000 children with CNS tumors. Although varying between tumor types, at least 10% of childhood CNS tumors can currently be explained by rare pathogenic germline variants in known cancer-related genes. Novel methodologies continue to uncover new mechanisms, suggesting that a much higher proportion of children with CNS tumors have underlying genetic causes. Understanding how genetic predisposition influences tumor biology and the clinical course in a given patient may mandate adjustments to neurosurgical treatment. CONCLUSION: Germline genetics is becoming increasingly important to clinicians, including neurosurgeons. This review provides an updated overview of genetic predisposition to childhood CNS tumors with focus on aspects relevant to pediatric neurosurgeons.

Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci.

INTRODUCTION: Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease. METHOD: A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls. RESULTS: For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10-7 and 9.668 × 10-8, respectively). PAPPA2 regulates local bioavailability of insulin-like growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10-7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors. DISCUSSION: This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways.

Intracranial pressure, brain morphology and cognitive outcome in children with sagittal craniosynostosis.

BACKGROUND: Patients with sagittal craniosynostosis are at increased risk of developing raised intracranial pressure (ICP) and neurocognitive deficiencies such as reduced attention, planning, speech, behavioural and learning disabilities. AIM: To determine if the existing literature supports a correlation between elevated ICP and negative cognitive outcome in patients with sagittal craniosynostosis. Secondly, to investigate if the risk of developing neurocognitive deficiencies can be explained by changes in brain morphology in this patient category. METHODS: Systematic literature review in PubMed. RESULTS: A total of 190 publications were reviewed to determine a possible correlation between raised ICP and cognitive outcome, of which four were included in the study. No significant association was found. Forty-four publications on brain morphology in sagittal craniosynostosis were identified, of which 11 were included in the review. Clear evidence of morphologic changes in multiple areas of the brains of sagittal craniosynostosis patients was found in the literature. CONCLUSION: The existing literature does not support an association between increased ICP and negative global cognitive outcome measures in patients with sagittal craniosynostosis. Brain morphology is altered in areas related to neurocognition and language in the same patient group. These changes might play a role in the development of neurocognitive deficiencies, though no definitive link is yet established, and further investigation is warranted.

Thirty-day surgical morbidity and risk factors in pediatric brain tumor surgery: a 10-year nationwide retrospective study.

OBJECTIVE: Pediatric neuro-oncological surgery is often associated with significant risk; however, comprehensive data on surgical morbidity remain limited. The purpose of this study was therefore to provide national population-based data on both the incidence and characteristics of poor postoperative outcomes following pediatric intracranial neuro-oncological surgery. Additionally, the authors aimed to evaluate key risk factors for poor postoperative outcomes including overall morbidity, significant morbidity, and the most frequent types of morbidity. METHODS: The authors conducted a registry-based, nationwide, retrospective study including all children receiving surgical treatment for a CNS tumor over a 10-year period. Patients were identified using the Danish Childhood Cancer Registry, and 30-day morbidity was assessed through manual review of electronic health records. Significant morbidity was defined as complications in need of treatment under general anesthesia, ICU admission, or persistent neurological deficits at 30 days following surgery or death. Risk factors including sex, age, tumor location, tumor malignancy grade, and preoperative hydrocephalus were investigated using multivariate logistic regression analysis. RESULTS: A total of 349 children undergoing 473 tumor procedures were included, with an overall morbidity rate of 66.0% and a significant morbidity rate of 34.2%. The most frequent complications included neurological deficits (41.4%) and CSF-related morbidity consisting of CSF leaks, pseudomeningoceles, and postoperative hydrocephalus. Highly significant associations between infratentorial tumor location and both significant morbidity (OR 1.26, 95% CI 1.11-1.43; p < 0.001) and neurological deficits (OR 1.38, 95% CI 1.21-1.57; p < 0.001) were identified. In addition, younger age was revealed as a major risk factor of both postoperative CSF leakage and CSF-related morbidity in general. CONCLUSIONS: In this large, population-based cohort, the authors show that postoperative morbidity is frequent, occurring in about two-thirds of all patients, largely driven by neurological deficits and CSF-related complications. In addition, infratentorial tumor location and younger age emerged as key risk factors for poor postoperative outcomes.

The evolutionary impact of childhood cancer on the human gene pool.

Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.

Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus.

BACKGROUND: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. METHODS: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. RESULTS: Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). CONCLUSIONS: In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.

BACKGROUND: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. METHODS: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. RESULTS: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected. CONCLUSIONS: Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.

Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

[Topical haemostatic agents in neurosurgery].

Haemostasis is of fundamental significance in neurosurgery, and insufficient control of bleeding is associated with morbidity and mortality. Topical haemostatic agents play an important role, as the characteristics of neuronal tissue limit the use of classical surgical haemostasis techniques. Appropriate choice of agent depends on the location and type of bleeding, but also on knowledge of the products' mechanisms of action, indications, price and accessibility. Biological products are superior to the mechanical in efficacy but require more preparation and are significantly more cost-intensive.

Transient global amnesia after cerebral angiography still occurs: Case report and literature review.

Transient global amnesia is considered a very rare complication of diagnostic cerebral angiography, and has been reported only in a limited number of case reports more than 15 years ago. We describe a patient experiencing transient global amnesia following cerebral digital subtraction angiography. While the condition by definition is self-limiting, its differential diagnoses may cause severe morbidity and/or mortality if left untreated. It is therefore important to build and maintain awareness of transient global amnesia as a possible complication of cerebral angiography.

Childhood hydrocephalus - is radiological morphology associated with etiology.

BACKGROUND: Clinicians use a non-standardized, intuitive approach when correlating radiological morphology and etiology of hydrocephalus. OBJECTIVE: To investigate the possibility of categorizing hydrocephalus in different groups based on radiological morphology, to analyze if these proposed groups relate to the location and type of underlying pathology, and if this can be of use in clinical practice. METHODS AND MATERIAL: A retrospective cohort study including 110 hydrocephalus patients below age seven seen at Rigshospitalet University Hospital, Denmark. Their neuro-imaging was analyzed and categorized based on radiological morphology. Patient charts were reviewed and possible association between the underlying cause of hydrocephalus and the proposed groups of radiological morphology was evaluated. RESULTS: Radiological appearance varied distinctively between patients. A classification system was created based on the morphology of the lateral ventricles from axial sections at the level of maximal ventricular width. No statistically significant association was found between the suggested groups of morphology and the location and type of pathology. CONCLUSION: Distinguishable patterns of radiological morphology exist. The proposed classification system cannot in its current form indicate type and location of the underlying cause of hydrocephalus. A clear need exists for a standardized approach when evaluating etiology and treatment options based on radiological results.