Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the 'RASopathies', including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation-arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway.

OBJECTIVES:The goal of this study was to review and present neurosurgical related activity within a multidisciplinary nationally commissioned specialty neurofibromatosis type I (NF1) center.PATIENTS & METHODS:We reviewed all NF1 Neurosurgical MDTs, NF1 Neurosurgical clinics and all neurosurgical procedures carried out in NF1 patients over an 8-year period.RESULTS:Since the inception of the service in 2009, 1505 cases were discussed at our NF-1 multidisciplinary meeting, 171 clinic appointments in complex NF1 patients with neurosurgical pathologies and 43(cranial and spinal) operations were performed.CONCLUSIONS:The formation of a supraregional multidisciplinary team allows for a better understanding of the disease, a comprehensive evaluation of neuroimaging findings and a steep learning curve in the management of NF1 surgical conditions. We provide holistic treatment for these patients via direct care, specialist advice and liaison with local units.

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Background The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for Health (NIH) criteria which include ≥6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria. Methods We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009–12/2015 on 361 NF1 patients. Findings A presumed causative NF1 mutation was found in 166/171 (97.08%–95% CI 94.56–99.6%) of familial cases and 182/190 (95.8%–95% CI 92.93–98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p=0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥6 CAL and no non-pigmentary criterion aged 0–20years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis. Interpretation RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.