Background
DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low‐to‐moderate penetrance of ...tumour development, which is sex‐ and age‐dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females.
Patients and Methods
We report a series of eight families referred for childhood‐onset of MNG or DICER1‐related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools.
Results
Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives.
Conclusions
Multinodular goitre is uncommon in children. Childhood‐onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.
We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve ...the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.
The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous ...system (CNS).
Patients aged <18 years with newly diagnosed CNS AT/RT who were treated in France between 1998 and 2008 were retrospectively identified. The study included all patients who had a diagnosis of AT/RT confirmed by pathologic review, including immunostaining for INI 1, tumor protein 53 (p53), β-catenin, claudin-6, and Ki-67 and analysis for SMARCB1/hSNF5/INI1 mutation.
Fifty-eight patients with confirmed AT/RT were eligible for the current analysis. The median age at diagnosis was 1.4 years (range, 14 days to 8.5 years). The site of the primary tumor was supratentorial in 26 patients, infratentorial in 28 patients and spinal in 4 patients. Loss of INI1 nuclear expression was observed in 49 of 50 evaluable tumors. Positive claudin-6 was observed in 37 of 42 assessed tumors and, in 12 of those tumors, the staining was strong and diffuse. Positive nuclear immunoreactivity for β-catenin was observed in 24 of 44 tumors, and P53 was overexpressed in 31 of 44 tumors. Primary adjuvant therapy included chemotherapy in 47 patients and radiotherapy in 16 patients. The median follow-up was 58 months (range, 9-125 months), and the median survival was 9 months. Multivariate analysis identified age <2 years (P = .01), metastasis at diagnosis (P = .03), and strong immunopositivity for claudin-6 (P = .03) as prognostic factors for the risk of death.
AT/RT tumors in children carry a dismal prognosis. Age <2 years, metastasis at diagnosis, and strong claudin-6 positivity appeared to be independent prognostic factors for outcome.
Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether ...maternal preconceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population‐based case‐control studies with similar designs conducted in 2003–2004 and 2010–2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of preconceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more; OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population‐based studies may provide further insight into findings by CBT subtypes.
What's new?
In the search for causes of childhood brain tumors (CBTs), birth weight, fetal growth and maternal behaviors have attracted significant interest. Despite extensive study, however, associations between those factors and CBTs remain unclear. This investigation of 510 CBT cases and over 3,000 controls from two French studies yields no evidence of an association between fetal growth and CBT risk. There also was little indication that maternal preconceptional folic acid supplementation or breastfeeding protect against CBTs. The findings highlight the importance of replicating analyses in different populations and the need for international consortiums to make full use of available data.
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•Posterior fossa tumors and surgery have an impact on cortico-cerebellar connectivity.•Irradiation has an adding impact on cortico-hippocampal and -striatal connectivity.•Atypical ...connectivities are linked with memory outcomes in irradiated patients.•Hippocampus, striatum and cerebellum can be considered as organ at risk for memory.
Memory is one of the main specific cognitive domains impaired with attention and processing speed after a pediatric brain tumor. This work explored the long-term impact of radiotherapy in children with posterior fossa tumor (PFT) on brain connectivity in neural circuits involved in memory using resting-state functional magnetic resonance imaging (rs-fMRI).
A total of 20 irradiated and 15 non-irradiated PFT survivors, and 21 healthy controls, prospectively included in the IMPALA study (NCT04324450), performed memory tests assessing episodic, procedural, and working memories and were subjected to an rs-fMRI. We manually contoured main structures involved in memory to explore connectivity at rest in a seed-to-voxel analysis. The groups were compared and differences in connectivity were correlated with behavioral scores and irradiation doses.
The performance of all mnesic tasks was lower in PFT survivors with a greater alteration in working and episodic memory in irradiated patients. Irradiated survivors had atypical connectivities in all memory circuits compared to controls and in cortico-caudate and cortico-cerebellar circuits compared to non-irradiated survivors. Non-irradiated survivors had only atypical connectivities in the cortico-cerebellar circuits compared to controls. In irradiated survivors, atypical connectivities in cortico-hippocampal circuits were linked with episodic memory scores and dose of irradiation to the left hippocampus and in cortico-striatal circuits with procedural memory scores and dose of irradiation to the striatum.
The results of this study highlight that irradiation has a long-term impact on brain connectivity in brain circuits involved in memory after pediatric PFT with a specific radiation-dose effect in supratentorial structures.
Background
Conservative treatments of intraocular retinoblastoma often consist of chemotherapy and focal treatments. The protocols vary and currently may combine two or three drugs, with different ...number of cycles, associated to the ocular treatments. In case of macular/paramacular involvement, tumor location and retinal scars induced by focal treatments often have a major negative impact on final visual outcome.
Methods
This study aimed to include children affected by bilateral intraocular macular/paramacular retinoblastoma in a prospective phase II study. The protocol consisted of six cycles of a three‐drug combination (vincristine, etoposide, carboplatin), and the addition of macula‐sparing transpupillary thermotherapy (TTT) to the third cycle. The primary endpoint was the local control rate without external beam radiotherapy (EBR) and/or enucleation.
Results
Nineteen patients (26 eyes) were included from July 2004 to November 2009. Thirteen eyes belonged to group V of the Reese‐Ellsworth classification and 10 to group D of the International Intraocular Retinoblastoma Classification. Macular/paramacular tumors were treated with chemotherapy alone in nine eyes, and with chemotherapy associated with macula‐sparing TTT in 17 eyes. Four eyes experienced macular relapse. At a median follow up of 77 months, 23 eyes (88.5%) were saved without EBR, two were enucleated and one received EBR. The median visual acuity of the 24 saved eyes was 20/50. No severe adverse effect was observed.
Conclusion
Six cycles of a three‐drug combination associated with macula‐sparing TTT achieved good tumor control, improved eye preservation rates without EBR, and decreased macular damage, often providing satisfactory visual results with long‐term follow up.
Some previous epidemiological studies have suggested that pesticide exposure during pregnancy may have a possible role in the development of childhood brain tumors (CBT). We pooled data from two ...French national population‐based, case–control studies to investigate the association between maternal residential use of pesticides during pregnancy and the risk of CBT. The mothers of 437 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency‐matched by age and gender, answered a structured telephone interview conducted by trained interviewers. Unconditional logistic regression was used to estimate pooled odds ratio (OR) and 95% confidence intervals (95% CI). CBT was significantly associated with the maternal home use of pesticides during pregnancy (OR 1.4, 95% CI 1.2–1.8) and, more specifically, with insecticide (OR 1.4, 1.2–1.8). We could not draw any conclusions about herbicides and/or fungicides because few women used them during pregnancy and most of these mothers also used insecticides. Although potential recall bias cannot be excluded, our findings of this pooled analysis support the hypothesis that residential maternal use of pesticides during pregnancy and particularly insecticides may increase the risk of CBT. Future investigations to verify these findings and to explore for CBT subtypes and dose–response are necessary to have a better understanding of the possible role of pesticides in etiology of CBT.
What's new?
The etiology of childhood brain tumor (CBT) remains unknown. Several perinatal factors are suspected to increase CBT risk, including maternal exposure to pesticides. In our study of malignant CBT, the authors found a positive association between maternal residential pesticide use (particularly of insecticides) during pregnancy, and malignant CBT. These results further implicate pesticides in the development of these cancers in children.
Craniopharyngioma is a rare condition in children, but it is the most frequent tumor that occurs in the hypothalamic pituitary region. Chemical meningitis has been described as an uncommon ...postoperative complication, but no chemical meningitis due to a spontaneous rupture leading to craniopharyngioma diagnosis in children has been reported.
This is a case of a 13-year-old boy presenting with fever, vomiting and headache for two days. The CT scan revealed a suprasellar lesion, and lumbar puncture showed aseptic meningitis. The cerebral MRI suggested a craniopharyngioma and the cerebrospinal fluid cholesterol concentration was abnormally high. A thorough medical history indicated some visual disturbance, which improved at the onset of meningitis, and an inflection of the growth curve. The anatomopathological analysis of the tumor confirmed the diagnosis of craniopharyngioma.
This case is the first to report the discovery of a craniopharyngioma with meningoencephalitis caused by the rupture of a craniopharyngioma cyst in a child. Diagnosis was facilitated by determining the cholesterol level in the cerebrospinal fluid, as well as fine anamnesis to identify visual and growth disturbances.
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