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.

Sex

All

Minimum age

4 Weeks

* ELIGIBILITY CRITERIA PATIENT

INCLUSION CRITERIA:

1. Age:

   * \<= 35 years of age for all new patients (except NF1-GIST) 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. No upper age limit for patients with NF1-GIST.
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 two or more diagnostic criteria for NF1 listed below (NIH Consensus Conference):
   1. Six or more cafe-au-lait spots (\>=0.5 cm in prepubertal subjects or \>=1.5 cm in postpubertal subjects)
   2. \>= 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 subjects 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 \<= 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 patients is\<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 protocolrelated studies are performed. When appropriate, pediatric subjects will be included in all discussions.

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.

• BACKGROUNDFerner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007 Apr;6(4):340-51. doi: 10.1016/S1474-4422(07)70075-3. PMID 17362838
• BACKGROUNDKorf BR. Clinical features and pathobiology of neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):573-7; discussion 602-4, 646-51. doi: 10.1177/088307380201700806. PMID 12403555
• BACKGROUNDKim A, Gillespie A, Dombi E, Goodwin A, Goodspeed W, Fox E, Balis FM, Widemann BC. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009 Oct 20;73(16):1273-9. doi: 10.1212/WNL.0b013e3181bd1326. PMID 19841379
• DERIVEDAl Ghriwati N, Little P, Martin S, Tamula MA, Widemann BC, Wolters PL. Parent-child discrepancies in reports of child psychosocial functioning in neurofibromatosis type 1. J Fam Psychol. 2025 Feb;39(1):99-106. doi: 10.1037/fam0001256. Epub 2024 Oct 17. PMID 39418437
• DERIVEDCurry BP, Alvarez R, Widemann BC, Johnson M, Agarwal PK, Lehky T, Valera V, Chittiboina P. Robotic Nerve Sheath Tumor Resection With Intraoperative Neuromonitoring: Case Series and Systematic Review. Oper Neurosurg. 2022 Feb 1;22(2):44-50. doi: 10.1227/ONS.0000000000000051. PMID 35007270
• DERIVEDAkshintala S, Baldwin A, Liewehr DJ, Goodwin A, Blakeley JO, Gross AM, Steinberg SM, Dombi E, Widemann BC. Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: growth analysis of plexiform neurofibromas and distinct nodular lesions. Neuro Oncol. 2020 Sep 29;22(9):1368-1378. doi: 10.1093/neuonc/noaa053. PMID 32152628
• DERIVEDDagalakis U, Lodish M, Dombi E, Sinaii N, Sabo J, Baldwin A, Steinberg SM, Stratakis CA, Widemann BC. Puberty and plexiform neurofibroma tumor growth in patients with neurofibromatosis type I. J Pediatr. 2014 Mar;164(3):620-4. doi: 10.1016/j.jpeds.2013.10.081. Epub 2013 Dec 8.