NF1-like optic pathway gliomas in children: clinical and molecular characterization of this specific presentation.

Background: Pediatric neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) exhibit different clinico-radiological features, treatment, and outcome compared with sporadic OPGs. While NF1-associated OPGs are caused by complete loss-of-function of the gene, other genetic alterations of the RAS-MAPK pathway are frequently described in the sporadic cases. We identified a group of patients who presented OPGs with typical radiological features of NF1-associated OPGs but without the NF1 diagnostic criteria. We aim to investigate into the possible molecular mechanisms underlying this "NF1-like" pediatric OPGs presentation.

Methods: We analyzed clinico-radiological features of 16 children with NF1-like OPGs and without NF1 diagnostic criteria. We performed targeted sequencing of the gene in constitutional samples ( = 16). The RAS-MAPK pathway major genes were sequenced in OPG tumor samples ( = 11); BRAF FISH and IHC analyses were also performed.

Results: In one patient's blood and tumor samples, we identified a nonsense mutation (exon 50: c.7285C>T, p.Arg2429*) with ~8% and ~70% VAFs, respectively, suggesting a mosaic mutation limited to the brain (segmental NF1). This patient presented signs of neurodevelopmental disorder. We identified a somatic alteration of the RAS-MAPK pathway in eight tumors: four activating p.Val600Glu mutations, three oncogenic fusions, and one putative gain-of-function complex indel inframe mutation.

Conclusions: NF1-like OPGs can rarely be associated with mosaic NF1 that needs specific constitutional DNA analyses for diagnosis. Further studies are warranted to explore unknown predisposition condition leading to the NF1-like OPG presentation, particularly in patients with the association of a neurodevelopmental disorder.