• Age: \> 1 (\>12 months) and ≤8 years of age at the time of study enrollment.

• Diagnosis: Participants with a diagnosis of NF1 based on the 2021 revised consensus criteria \[52\] and

• No known PN (prior to enrollment on Part 1). Participants for whom there is clinical suspicion for a PN (e.g., subtle facial asymmetry or large overlying hyperpigmented area) may be included in the study after discussion with the Study Chair so long as they have not previously had an MRI of the region of concern and are otherwise asymptomatic.

• Physical exam at your institution within 1 year prior to consent.

• Written informed consent must be obtained from the legal guardians of all participants \<18 years of age.

• Enrolled on Part 1 of this study and completed baseline WBMRI within 6 weeks of planned enrollment on Part 2.

• A measurable (≥3 mL) PN in a high-risk location as defined below (this must be confirmed by Study Chair or a member of the Study Committee prior to enrollment on Part 2).

‣ In the head or neck (with the exception of isolated scalp lesions) OR

⁃ Within the brachial or lumbosacral plexus OR

⁃ Adjacent to high-risk structure(s), defined as:

⁃ Major (named) blood vessel OR

• Major (named) airway OR

• Hollow viscus OR

• Spinal cord and foramina OR

• Vital Organs (including heart, lungs, liver, spleen, etc.)

• Body Surface Area (BSA): BSA ≥ 0.55 m2 \[pending availability of granule formulation\].

• Performance status: Lansky performance ≥70%. Participants who are wheelchair bound because of paralysis or immobility secondary to a non-PN related manifestation of NF1 (such as tibial pseudarthrosis or severe scoliosis) should be considered ambulatory when they are in their wheelchair.

• Able to swallow whole capsules \[Pending availability of granule formulation\].

• Hematologic Function: Absolute neutrophil count ≥1200/µL, hemoglobin ≥9g/dL, and platelets ≥100,000/µL (without transfusions).

• Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with the exception of those with Gilbert syndrome, and AST/ALT within ≤ 3 x upper limit of normal.

• Renal Function: Creatinine clearance or radioisotope GFR ≥60ml/min/1.73 m2 or a normal serum creatinine based on age, described in the table below.

• Age (years) Maximum Serum Creatinine (mg/dL)

• ≤5 0.8 \>5 to ≤10 1.0 \>10 to ≤15 1.2 \>15 1.5

• Cardiac Function:

∙ Normal ejection fraction (ECHO or cardiac MRI) ≥ 53% (or the institutional normal; if a range is given then the upper value of the range will be used).

‣ EKG with QTC or QTcF ≤450 msec.

⁃ Adequate Blood Pressure defined as:

⁃ A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequate blood pressure can be achieved using medication for treatment of hypertension. Participants must be on stable antihypertensive regimen for at least 30 days prior to study entry.

⁃ Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated.

⁃ Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g., grapefruit juice or marmalade) during the study, as these may affect selumetinib metabolism.

• Enrolled on Part 2 of this study and had PN growth \>20% OR development of PN related symptom(s) while on observation portion of Part 2 (including the first 2 years for the observation arm OR during first year of observation after treatment with selumetinib).

• Body Surface Area (BSA): BSA ≥ 0.55 m2 \[pending availability of granule formulation\].

• Performance status: Lansky performance ≥70%. Participants who are wheelchair bound because of paralysis or immobility secondary to a non-PN related manifestation of NF1 (such as tibial pseudarthrosis or severe scoliosis) should be considered ambulatory when they are in their wheelchair.

• Able to swallow whole capsules \[Pending availability of granule formulation\].

• Hematologic Function: Absolute neutrophil count ≥1200/µL, hemoglobin ≥9g/dL, and platelets ≥100,000/µL (without transfusions).

• Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with the exception of those with Gilbert syndrome, and AST/ALT within ≤ 3 x upper limit of normal.

• Renal Function: Creatinine clearance or radioisotope GFR ≥60mL/min/1.73 m2 or a normal serum creatinine based on age, described in the table below.

• Age (years) Maximum Serum Creatinine (mg/dL)

• ≤5 0.8 \>5 to ≤10 1.0 \>10 to ≤15 1.2 \>15 1.5

• Cardiac Function:

∙ Normal ejection fraction (ECHO or cardiac MRI) ≥ 53% (or the institutional normal; if a range is given then the upper value of the range will be used).

‣ EKG with QTC or QTcF ≤450 msec.

• Adequate Blood Pressure defined as:

• A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequate blood pressure can be achieved using medication for treatment of hypertension. Participants must be on stable antihypertensive regimen for at least 30 days prior to study entry.

⁃ Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated.

⁃ Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g., grapefruit juice or marmalade) during the study, as these may affect selumetinib metabolism.