Abstract
The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5’ tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher’s exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni’s correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype–phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.
Highlights
Neurofibromatosis type 1 (NF1) is a multi-system, tumour-prone disorder that is diagnosed on the basis of established clinical criteria [1,2]
The youngest patients in familial cases in order to include patients with a more expressed phenotype and to avoid any confounding effects due to shared polymorphisms in possible modifying genes in family members; patients in whom the entire neurofibromatosis type 1 (NF1) gene and flanking genes were deleted because it is not possible to study the correlation between the localisation of the mutation and phenotype in such patients; patients harbouring more than one variant of the NF1 gene because the role of each variant needs to be tested separately;
We looked for NF1 patients who had not been described in previous studies of genotype–phenotype correlations in relation to the development of optic pathway gliomas (OPGs) [27,28,29]
Summary
Neurofibromatosis type 1 (NF1) is a multi-system, tumour-prone disorder that is diagnosed on the basis of established clinical criteria [1,2] It is one of the most frequently inherited genetic conditions (its worldwide prevalence is about 1/3000 people), and it is characterised by complete and age-related penetrance and highly variable expression [3,4,5]. It is caused by constitutional dominant loss-of-function intragenic mutations or the deletion of the NF1 gene (OMIM 613113) located on the long arm of human chromosome 17. The gene encodes for neurofibromin, a ubiquitous 2818 amino acid protein with various domains, the most widely known of which is the GTPase-activating protein (GAP)-related domain (GRD), which exerts tumour suppressing activity by down-regulating the Ras signalling pathway [8].
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