Natural History Study of Patients With Neurofibromatosis Type I

BACKGROUND:

Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder
characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of
developing tumors of the central and peripheral nervous system including plexiform
neurofibromas (PN), dermal neurofibromas, optic pathway tumors, brain tumors, malignant
peripheral nerve sheath tumors (MPNST), juvenile myelomonocytic leukemia, and
pheochromocytomas. In addition, NF1 manifests in essentially every organ system, with for
example, skeletal and vascular abnormalities, and cognitive deficits. Thus, the care for
individuals with NF1 requires a multidisciplinary approach. The natural history of NF1
related tumor and other manifestations is poorly understood, and for most NF1 related tumor
manifestations the only standard treatment option is surgery. The NIH Clinical Center
provides the ideal infrastructure for evaluation of the natural history of rare diseases. A
better understanding of the natural history of NF1 related tumor and other manifestations
will be helpful for the design of treatment studies. The NCI, POB has an active clinical
trials program for NF1 related tumor manifestations including PN, MPNST, and in collaboration
with Dr. Douglas Stewart from the NHGRI, dermal neurofibromas. Unlike individuals with
refractory solid cancers, individuals with NF1 have near normal life expectancy, and their
benign tumors progress more slowly than solid cancers. Individuals with NF1 may thus
participate in multiple treatment trials.

OBJECTIVES:

The overall purpose of this descriptive NF1 Natural History study is to serve as an umbrella
protocol for the ongoing NF1 clinical trials program to allow the longitudinal evaluation of
individuals with NF1 for NF1 related tumor and non tumor manifestations irrespective whether
they are currently enrolled on a treatment study or not, and to develop a better
understanding of the biology of NF1 related manifestations. Following these patients
longitudinally will allow investigators to develop a better understanding of the natural
history of these manifestations, provide the basis for the development of endpoints for
clinical trials and to potentially develop more effective treatments. NF1 manifestations,
which will be followed longitudinally, include PN, MPNST, optic pathway tumors, dermal
neurofibromas, NF1 associated pain, and neuropsychological, motor, and endocrine function. A
comprehensive treatment plan and recommendations will be developed and communicated with the
patient and primary caregivers.

ELIGIBILITY:

Children, adolescents, and adults with a confirmed clinical diagnosis of NF1 or a confirmed
NF1 mutation.

DESIGN:

Attempts will be made to have all individuals undergo a comprehensive baseline evaluation
including clinical phenotyping, genotyping, imaging of tumor manifestations, and pain,
quality of life, neuropsychological, motor, and endocrine evaluations. The NF1 manifestations
will be longitudinally monitored with a frequency of every year to every three years, with
the extent and timing of follow-up evaluations depending on the findings at baseline.

- ELIGIBILITY CRITERIA PATIENT

INCLUSION CRITERIA:

1. Age:

- Less than or equal to 35 years of age for new patients evaluated at NIH.

- No upper age limit for patients previously enrolled on clinical trials at NIH or
for patients diagnosed with MPNST, or with clinical concern for MPNST, or with
infrequent or unusual NF1 related manifestations.

2. Diagnosis: Patients who are diagnosed with NF1 using the NIH Consensus Conference
criteria or have a confirmed NF1 mutation with analysis performed in a CLIA-certified
laboratory. NF1 mutation testing to confirm eligibility will not be performed on this
protocol, but as part of a separate screening study. Histologic confirmation of NF1
related benign tumors is not necessary in the presence of consistent clinical and
radiographic findings, but is required for individuals with MPNST who enroll on this
study.

For the clinical diagnosis of NF1 all study subjects must have at least two or more
diagnostic criteria for NF1 listed below (NIH Consensus Conference):

1. Six or more cafe-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).

2. Greater than or equal to 2 neurofibromas or 1 plexiform neurofibroma.

3. Freckling in the axilla or groin.

4. Optic glioma.

5. Two or more Lisch nodules.

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

7. A first-degree relative with NF1.

3. Prior and current therapy: For NF1 related benign tumor manifestations there is no
standard effective medical treatment, and surgery is the only standard treatment.
Chemotherapy and radiation therapy are additional treatment options for malignant NF1
related tumors. For the purpose of this study, subjects who have not previously
received medical or surgical treatment, patients, who have previously received medical
or surgical treatment, and patients who are currently receiving medical treatment
and/or radiation for a NF1 related manifestation will be eligible. Prior and current
treatment for NF1 related manifestations will be recorded at trial entry and
throughout the study.

4. Performance Status: ECOG less than or equal to 3. Subjects who are wheelchair bound
because of paralysis will be considered ambulatory when they are up in their
wheelchair. Subjects have to be able to travel to the NIH for evaluations.

5. Informed Consent: All patients or their legal guardians (if the patient is less than
18 years old) must sign an IRB-approved document of informed consent to demonstrate
their understanding of the investigational nature and the risks of this study before
any protocol-related studies are performed. When appropriate, pediatric subjects will
be included in all discussions.

6. Durable Power of Attorney (DPA): All subjects greater than or equal to 18 years of age
will be offered the opportunity to assign DPA so that another person can make
decisions about their medical care if they become incapacitated or cognitively
impaired.

7. In addition, subjects participating in evaluation for variation in gene expression
must:

- Have at least 1 plexiform neurofibroma and be able to undergo MRI analysis of the
plexiform neurofibroma(s).

- If possible, but not absolutely required, have one or both biologic parents (NF1
affected or not) willing to donate a blood or cheek swab, or mouthwash sample for
DNA extraction. A separate informed consent will be obtained from biologic
parents.

EXCLUSION CRITERIA:

1. In the opinion of the investigator the patient is not able to return for follow-up
visits or obtain required follow-up studies.

2. In the opinion of the investigator the patient is not able to obtain an MRI scan.

3. Individuals who are pregnant or breast feeding or who become pregnant while enrolled
on this trial will not be excluded from participation, but will not undergo
radiographic evaluations or MRI scans requested for research purposes, or other
studies which might negatively impact on the pregnancy.

ELIGIBILITY CRITERIA PATIENT FOR OPTIONAL TUMOR / TISSUE BIOPSY FOR RESEARCH

INCLUSION CRITERIA:

1. Age greater than 12 years, and neurofibroma, cafe-au-lait macule, xanthogranuloma, or
other skin area, which is easily accessible, and sufficiently distant from vital
structures to allow for biopsy.

2. Platelet count has to be greater than or equal to 100,000/microL, and PT and PTT have
to be within normal limits within 1 week of each biopsy.

3. The subject or parent/guardian must sign a separate biopsy consent, and the
participant, if minor, must sign a separate assent describing the biopsy.

4. No medical treatment specifically directed at NF1 related tumor within six weeks prior
to collection of specimen.

EXCLUSION CRITERIA:

1. Biopsies will not be performed if the participant requires general anesthesia.

2. Requirement for medications, which interfere with platelet function, such as aspirin,
which cannot be stopped within 1 week prior to the biopsy.

ELIGIBILITY CRITERIA UNAFFECTED SIBLING (NEUROCOGNITIVE AND QOL EVALUATION)

INCLUSION CRITERIA:

1. Availability of a sibling not affected with NF1 for longitudinal evaluation of
neurocognitive function and quality of life evaluation. An assent form will be prepared for
unaffected minor siblings, and written informed consent will be obtained from siblings 18
years of age or older.

EXCLUSION CRITERIA:

1. A medical condition which would preclude the sibling from participation in the
evaluation of neurocognitive function or quality of life.

ELIGIBILITY CRITERIA PARENT(S) OF PATIENT (GENETIC MODIFIER STUDIES)

INCLUSION CRITERIA:

1. Biologic parents (one or both) of patients with NF1 will be eligible if they are willing
to provide a blood, cheek swab, saliva, or mouthwash sample for DNA extraction for analysis
of gene modifiers. These individuals may be of any gender and ethnicity. Written informed
consent will be obtained from each parent willing to participate in this part of the study.

EXCLUSION CRITERIA:

1. A medical condition, which would preclude the parent from providing a biologic sample.

ELIGIBILITY CRITERIA PARENT(S) OF PATIENT (QUESTIONNAIRES)

INCLUSION CRITERIA:

Parents (one or both) of patients with NF1 will be eligible if they are willing to t
complete the questionnaires for NF1 assessment itemized in Section 1.2.8.