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Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.

ABSTRACT: We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy.

SUBMITTER: Taylor MD

PROVIDER: S-EPMC1288204 | biostudies-literature | 2000 Apr

REPOSITORIES: biostudies-literature

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Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.

Taylor M D MD Gokgoz N N Andrulis I L IL Mainprize T G TG Drake J M JM Rutka J T JT

American journal of human genetics 20000314 4

We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show l ...[more]

PMID: 10739763

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Project description:Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined.This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles.Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Project description:PurposeProspective and longitudinal neuroimaging studies of posterior fossa tumors are scarce. Here we evaluate the early changes in white matter and intellectual outcome up to 3 years after diagnosis.Patients and methodsTwenty-two children with posterior fossa tumors and 24 similarly-aged healthy children participated. Patients included: (a) 12 individuals who received surgery, cranial-spinal radiation (CSR), and focal radiation to the tumor bed (CSR group) and (b) 10 individuals who received local therapy, either surgery only or surgery and focal radiation to the tumor bed (Local group). Diffusion tensor imaging (DTI) and intelligence measures were obtained an average of 3 months after diagnosis and then at 12, 24, and 36 months later. DTI tractography and voxel-wise approaches were employed. The Neurological Predictor Scale was used to summarize the type and amount of treatment for PF tumor patients. Linear mixed modelling was used to evaluate group differences at baseline and changes over time in DTI metrics for both the specific white matter tracts and voxel-wise, as well as for intelligence measures.ResultsBased on tractography, patients treated with CSR had significantly higher Axial and Mean diffusivity in the cortical-spinal tracts (CST) 3 month after diagnosis - particularly on the right side, p < .003, compared to healthy children. Mean diffusivity in right CST decreased over time in this group of patients, p = .001. No differences compared to controls were evident in specific tracts for the Local group, p > .10. Voxel-wise analyses revealed multiple areas of white matter compromise in both patients groups. Notably, both patient groups had lower scores on intelligence measures compared to the Control group: The CSR group displayed lower performance 3 months following diagnosis, ps < 0.001, and their performance remained stable over time ps > 0.10, whereas the Local group displayed no differences at 3 months, ps> 0.10, but their performance declined over time, ps < 0.01. At baseline, higher MD in right CST predicted lower Perceptual Reasoning scores across all participants, p = .001. Furthermore, lower FA in left IFOF at baseline predicted decline in Processing Speed over time, p = .001. In patients, more aggressive treatment protocols and presence of mutism were related to lower performance on intelligence measures at baseline, ps < 0.04.ConclusionsChildren treated with CSR displayed diffuse white matter compromise and poor intellectual outcome shortly after radiation treatment. There was evidence of subsequent growth of white matter structure, but stable intellectual insult. Conversely, in children treated with either surgery only or surgery and focal radiation to the tumor bed we observed less compromise of white matter early following treatment and no intellectual insult compared to healthy children. However, declines in intellectual function were evident for these children, though their performance remained within the average normative range. Overall, results suggest that early intervention is necessary to circumvent these deficits.

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Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.

Publications

Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.

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