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Background: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel., Methods: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients., Results: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism., Conclusions: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium "Care for CMMRD" (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1-2 years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting., (© 2024. The Author(s).)

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions., (© 2024. The Author(s).)

In paediatric oncology, genomics raises new ethical, legal and psychological issues, as somatic and constitutional situations intersect throughout the care pathway. The discovery of potential predisposition in this context is sometimes carried out outside the usual framework. This article focuses on the views of children, adolescents, and young adults (AYA) with cancer and their parents about their experience with genomic testing. Forty-eight semi-structured interviews were performed with children or AYAs with cancer and one of their parents, before and/or after receiving the genetic test results. The interviews were fully transcribed, coded and thematically analysed using an inductive method. This analysis revealed several themes that are key issues: perceived understanding and consenting, apprehension about the test outcomes (expectations and fears), perception and attitude towards incidental findings. The main expectation was an aetiological explanation. Children and AYAs also emphasised the altruistic meaning of genetic testing, while parents seemed to expect a therapeutic and preventive approach for their child and the rest of the family. Parents were more concerned about a family risk, while patients were more afraid of cancer relapse or transmission to their descendants. Both groups suggested possible feelings of guilt concerning family transmission and imaginary representations of what genomics may allow. Incidental findings were not understood by patients, while some parents perceived the related issues and hesitated between wanting or not to know. A multidisciplinary approach would be an interesting way to help parents and children and AYAs to better grasp the complexity of genetic and/or genomic testing., (© 2024. The Author(s).)

Background: Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas., Methods: Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma., Results: PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2 , TP53 , NF1 , EPHB2 , PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation., Conclusions: CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors., Competing Interests: The authors have no commercial association that might pose or create the appearance of a conflict of interest with the information presented in the submitted manuscript., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome., Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1 -mutated MB., Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1 -mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA ( n  = 26); moreover, all tested familial trio ( n  = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms., Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment., Design: Single-centre retrospective cohort study., Method: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation., Results: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001)., Conclusion: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objectives: Posterior fossa ependymoma group A (EPN&#95;PFA) and group B (EPN&#95;PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN&#95;PFA and EPN&#95;PFB at presentation., Methods: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests., Results: Fifty-six patients were categorized as EPN&#95;PFA and 12 as EPN&#95;PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN&#95;PFA tumoral volume was larger (57 vs 29 cm 3 , p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN&#95;PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN&#95;PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN&#95;PFA vs 40% of EPN&#95;PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN&#95;PFA, particularly the foramina of Luschka (p = 0.0008). EPN&#95;PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN&#95;PFB (p = 0.0008). All mainly cystic tumors were EPN&#95;PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN&#95;PFA (p = 0.02 and p = 0.01, respectively)., Conclusion: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively., Clinical Relevance Statement: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management., Key Points: • Posterior fossa ependymoma subtypes often have different imaging characteristics. • Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. • Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1 ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)