Natural History Study of Patients With Neurofibromatosis Type I
Natural History Study of Patients With Neurofibromatosis Type I
Background:

 Neurofibromatosis Type 1 (NF1) is a genetic disorder in which patients are at increased risk
 of developing tumors (usually non-cancerous) of the central and peripheral nervous system.
 The disease affects essentially every organ system.

 The natural course of NFI over time is poorly understood. For most patients the only
 treatment option is surgery. A better understanding of NF1 may be helpful for the design of
 future treatment studies.

 Objectives:

 To evaluate people with NF1 over 10 years in order to better understand the natural history
 of the disease.

 To characterize the patient population and to examine how NFI affects patients quality of
 life and function.

 Eligibility:

 Children, adolescents, and adults with NF1.

 Design:

 Participants have a comprehensive baseline evaluation including genetic testing, tumor
 imaging, pain and quality-of-life assessments, and neuropsychological, motor and endocrine
 evaluations.

 Patients are monitored every 6 months to every 3 years, depending on their individual
 findings at the baseline study. Tests may include the following, as appropriate:

 -  Medical history, physical examination and blood tests.

 -  Whole body and face photography to monitor visible deformities.

 -  Neuropsychological testing, quality-of-life evaluations, motor function tests,
 endocrinologic evaluations, heart and lung function tests, hearing tests, bone density
 scans and other bone evaluations.

 -  MRI and PET scans to detect and assess plexiform neurofibromas (tumors that arise from
 nerves and can cause serious problems), paraspinal neurofibromas (tumors that arise from
 nerves around the spine and can cause problems by compressing the spinal cord), and
 malignant peripheral nerve sheath tumors (a type of cancer that arises from a peripheral
 nerve or involves the sheath covering the nerve).

 -  Eye exams, MRI scans and PET scans to evaluate optic pathway gliomas (tumors arising
 from the vision nerves or the brain areas for vision) and the chemicals within the tumor
 and brain.

 -  Eye exams and photographs to evaluate the development of Lisch nodules (non-cancerous
 tumors on the eye).

 -  Photographs of dermal neurofibromas (tumors of the skin), cafe-au-lait spots (dark or
 pigmented areas on the skin that are often the first signs of NF1) and other skin
 problems.

 -  Pain evaluations to monitor the different types of pain patients experience, causes of
 the pain, how often the pain occurs, effect of the pain on quality of life, and what
 pain medications and alternative treatments, such as acupuncture, are effective.
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.