Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Natural History Study of Patients With Neurofibromatosis Type I

Summary: 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.

Detailed description: 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: -  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.

Relevance to patient case: not relevant