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An 11 year old boy presented with a three month history of progressive bilateral lower extremity weakness associated with recent intermittent incontinence. Spine MRI showed a right-sided T11-T12 paraspinal mass extending through the neural foramina into the epidural space and causing severe spinal cord compression. Skin showed a large macular lightly-hyperpigmented café au lait spot with irregular borders along the T10-T12 dermatome extending from the spine to approximately the anterior-axillary line. He was suspected to have segmental neurofibromatosis type 1 (NF1) as no additional clinical findings, radiographic features or family history of NF1 were identified. Patient underwent T10-12 laminectomy for resection of the epidural tumor component. Post-operative MRI showed resolution of the mass effect on the thecal sac and cord, with expected tumor residual lateral to the neural foramen. His residual spinal tumor and mild scoliosis remained stable over the two years of follow up to date. Pathological and molecular analysis of the resected tumor revealed a neurofibroma harboring an activating KRAS c.35G>A, p.Gly12Asp (KRAS-G12D) pathogenic variant at 27% variant allele frequency. Melanocytes cultured from two hyperpigmented skin biopsies showed the same KRAS-G12D pathogenic variant. This KRAS-G12D pathogenic variant was not found in leukocytes, indicating a post-zygotic origin. No NF1 pathogenic variant was identified in tumor tissue, melanocytes or leukocytes. The clinical findings were consistent with a mosaic KRASopathy due to a post zygotic KRAS-G12D pathogenic variant. The presence of the KRAS variant in the spinal neurofibroma and overlaying café au lait spot without an NF1 etiology in associated tissues demonstrates overlapping variability of presentations of RAS-MAPK pathway disorders. This case highlights the need for full clinical and genetic evaluation of patients presenting with segmental neurocutaneous disorders.

INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.

Plexiform neurofibromas (PNs) can cause significant disfigurement, compression of vital structures, neurologic dysfunction, and pain. MEK pathway inhibition results in significant PN shrinkage in neurofibromatosis type 1 (NF1) mouse models of PN. We evaluated the efficacy of the MEK inhibitor, PD0325901, in adolescents (≥ 16 years of age) and adults with symptomatic or growing NF1-PN in a phase II open label study. The primary aim was to assess tumor response by cycle 12 using centrally read MRI, defined as at least 20% decrease in tumor volume from baseline. Subjects received PD-0325901 by mouth twice daily at 2 mg/m2/dose (maximum dose 4 mg bid). Each course was 4 weeks, and subjects received drug on a 3 week on / 1 week off schedule. NF106 enrolled 19 subjects (7M;12F) in two stages with a median age of 24 years (range 16-39 years). The mean PN volume was 797.8 mL. Eight subjects (42.1%; 95% CI: 20%, 67%) had a response. PD0325901 was well tolerated, with the most common dose limiting toxicity being acneiform rash in 3/19 patients (16%). Five subjects (26.3%) developed Grade 3 toxicities, mostly pain (4/19; 21%). No subjects developed Grade 4 or higher toxicities. Five subjects (26.3%) had a dose reduction for toxicity: one for Grade 3 abdominal and back pain, the others for intolerable Grade 1-2 nausea, rash, or fatigue. This study demonstrated that PD0325901 is well tolerated and results in PN shrinkage in 42% of adolescent and adult subjects with NF1-PN. Supported by DOD Award W81XWH-12-1-0155.

Vestibular schwannomas (VSs) in patients with neurofibromatosis 2 (NF2) are associated with hearing loss. Recently published data from a prospective clinical trial showed that bevacizumab treatment at a fixed dose of 7.5 mg/kg every 3 weeks was associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. The optimal treatment dose and schedule, however, are unknown. The primary aim of this study was to determine the hearing response rate during induction therapy with bevacizumab at 10 mg/kg every 2 weeks; secondary aims included radiographic response rate. This multicenter, phase II, open label study evaluated children and adults (≥6 years of age) with NF2 and progressive VSs treated with bevacizumab. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (9M;13F) with a median age of 23 years (range 12-62 years). Nineteen subjects have completed induction therapy. 8/19 (42%) subjects had hearing response and 4/19 subjects (21%) had a radiographic response in the target VS. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 female subjects had elevated FSH and underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates at 6 months that are similar to previous studies using lower doses. Future analyses will address the durability of hearing and radiographic responses during 18 months of maintenance therapy.