Inclusion Criteria:

all patients (stratum 1 and 2):

- All patients must have the clinical diagnosis of NF1 using the NIH Consensus
Conference criteria.

- Six or more café-au-lait spots (greater than or equal to 0.5 cm in prepubertal
subjects or greater than or equal to 1.5 cm in postpubertal subjects).

- Freckling in the axilla or groin.

- Optic glioma.

- Two or more Lisch nodules.

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
long bone cortex).

- A first-degree relative with NF1.

- Patients must have plexiform neurofibroma(s) that have the potential to cause
significant morbidity, such as (but not limited to) head and neck lesions that could
compromise the airway or great vessels, brachial or lumbar plexus lesions that could
cause nerve compression and loss of function, lesions that could result in major
deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the
extremity that cause limb hypertrophy or loss of function, and painful lesions.
Patients with paraspinal plexiform neurofibromas will be eligible for this trial.
Histologic confirmation of tumor is not necessary in the presence of consistent
clinical and radiographic findings, but should be considered if malignant
degeneration of a plexiform neurofibroma is clinically suspected.

- Age: Patients must be greater than or equal to 3 years of age at the time of study
entry.

- Durable Power of Attorney: Adults evaluated for this study will be offered a durable
power of attorney. Adults who are unable to provide informed consent will have to
have a durable power of attorney in order to participate in this trial.

- Disease status: Measurable disease: Patients must have measurable plexiform
neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, a
measurable lesion will be defined as a lesion of at least 3 cm measured in one
dimension.

- Performance Level: Karnofsky greater than or equal to 50% for patients > 10 years of
age and Lansky greater than or equal to 50 for patients less than or equal to 10
years of age (Appendix IV). Note: Patients who are unable to walk because of
paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score.

- Prior Therapy: Patients who underwent surgery for a progressive plexiform
neurofibroma will be eligible to enter the study after the surgery, provided the
plexiform neurofibroma was incompletely resected and is measurable. Patients are only
eligible if complete resection of a plexiform neurofibroma with acceptable morbidity
is not feasible, or if a patient with surgical option refuses surgery. Patients may
have been previously treated for a plexiform neurofibroma but must have fully
recovered from the acute toxic effects of all prior chemotherapy or radiotherapy
prior to entering this study.

- a. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
this study.

- b. Hematopoietic growth factors: At least 7 days since the completion of therapy with
a growth factor that supports platelet, red or white cell number or function.

- c. Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy
with a biologic agent. For agents that have known adverse events occurring beyond 14
days after administration, this period must be extended beyond the time during which
adverse events are known to occur. These patients must be discussed with the Study
Chair on a case-by-case basis.

- d. Investigational Drugs: Patients must not have received an investigational drug
within 4 weeks.

- e. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic
or stress doses of steroids if necessary.

- f. CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of
CYP3A4, and may not have received these medications within 1 week of entry. These
include: Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin,
troleandomycin; Gastrointestinal prokinetic agents: cisapride, metoclopramide;
Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole;
Calcium channel blockers: verapamil, diltiazem, nicardipine; and, Other drugs:
rifampin, bromocriptine, cimetidine, danazol, cyclosporine oral solution.

- Grapefruit juice.

- g. CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4 and may not
have received these medications within 1 week of entry. These include:
Anticonvulsants: carbamazepine, phenobarbital, phenytoin; Antibiotics: rifabutin,
rifapentine; Herbal preparations: St. John's wort (Hypericum perforatum, hypericine).

- h. Enzyme inducing anticonvulsants : Patients may not be taking enzyme - inducing
anticonvulsants, and may not have received these medications within 1 week of entry,
as these patients may experience different drug disposition. These medications
include: Carbamazepine (Tegretol), Felbamate (Felbtol), Phenobarbitol, Phenytoin
(Dilantin), Primidone (Mysoline), Oxcarbazepine (Trileptal), and, Herbal
preparations: St. John's wort (Hypericum perforatum, hypericine).

- i. XRT: Greater than or equal to 6 months from involved field radiation to index
plexiform neurofibroma(s); greater than or equal to 6 weeks must have elapsed if
patient has received radiation to areas outside index plexiform neurofibroma(s).

- j. Surgery: At least 2 weeks since undergoing any major surgery.

- Organ Function Requirements; Adequate Bone Marrow Function Defined as: Peripheral
absolute neutrophil count (ANC)greater than or equal to 1500/μL; Platelet count
greater than or equal to 100,000/μL (transfusion independent); and Hemoglobin greater
than or equal to 10.0 gm/dL (may receive RBC transfusions).

- Adequate Renal Function Defined as: A serum creatinine based on age, OR a creatinine
clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2

- Adequate Liver Function Defined As: Bilirubin (sum of conjugated + unconjugated) < or
equal to 1.5 x upper limit of normal (ULN) for age, and SGPT (ALT)< or equal to 5 x
upper limit of normal (ULN) for age, and Serum albumin > or equal to 2 g/dL.

- Fasting LDL Cholesterol: Patients must have a fasting LDL cholesterol of < 160 mg/dL;
Patients taking a cholesterol lowering agent must be on a single medication and on a
stable dose for at least 4 weeks

Specific eligibility criteria stratum 1 Disease status:

- Patients must have a progressive plexiform neurofibroma(s). Progression at the time of
study entry is defined as: Presence of new plexiform neurofibromas on MRI or CT, OR A
measurable increase of the plexiform neurofibroma (> or equal to 20% increase in the
volume, or a > or equal to 13% increase in the product of the two longest perpendicular
diameters, or a > or equal to 6% increase in the longest diameter) over the last two
consecutive scans (MRI or CT), or over the time period of approximately one year prior to
evaluation for this study.

Specific eligibility criteria stratum 2 Disease status:

- Radiographic disease progression as defined in Section 4.2.1 is not required for trial
entry.

Exclusion Criteria:(Both Strata):

- Chronic treatment with systemic steroids or another immunosuppressive agent.

- Patients with endocrine deficiencies are allowed to receive physiologic or stress
doses of steroids if necessary.

- Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve
sheath tumor, or other cancer requiring treatment with chemotherapy or radiation
therapy. Patients not requiring treatment are eligible for this protocol.

- Dental braces or prosthesis that interfere with volumetric analysis of the
neurofibroma(s).

- Other concurrent severe and/or uncontrolled medical disease which could compromise
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,
severe infection, severe malnutrition, chronic liver or renal disease, active upper
GI tract ulceration).

- A known history of HIV seropositivity or known immunodeficiency. HIV testing will not
be required as part of this trial, unless HIV is clinically suspected.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of sirolimus (e.g. ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection). A nasogastric tube (NG tube) is allowed.

- Women who are pregnant or breast feeding.

- Males or females of reproductive potential may not participate unless they have
agreed to use an effective contraceptive method during the period they are receiving
the study drug and for 3 months thereafter. Abstinence is an acceptable method of
birth control. Women of childbearing potential will be given a pregnancy test within
7 days prior to administration of sirolimus and must have a negative urine or serum
pregnancy test.

- Patients who have received prior treatment with an mTOR inhibitor.

- History of noncompliance to medical regimens.

- Patients unwilling to or unable to comply with the protocol, or who in the opinion of
the investigator may not be able to comply with the safety monitoring requirements of
the study.

- Patients who have an uncontrolled infection.