Background:
RASopathies are a group of conditions caused by a genetic change. People with a RASopathy may have developmental issues, cognitive disability, poor growth, and birth defects. They may also have an increased risk for developing cancer. Researchers want to learn more.
Objective: To learn more about RASopathies, how genes and environmental factors contribute to cancer development in people with RASopathies, and the best way to find these cancers and other conditions early or prevent them.
Eligibility:
People of any age who have or may have a RASopathy, and their family members.
Design:
Participants will complete questionnaires about their personal and family medical history. Their medical records will be reviewed.
Participants will give blood and urine samples. They will give a saliva or cheek cell sample. Some samples will be used for genetic testing.
Participants may have a skin biopsy.
Participants may have a physical exam by the RASopathies study team. They may also have exams by additional specialists, such as dentists; urologists; ear, nose, and throat doctors; and neurologists.
Participants may have computed tomography of the face and mouth. They may have an ultrasound of the abdomen. They may have a bone density scan. They may have skeletal and/or spine x-rays. They may have magnetic resonance imaging of the brain, low back, chest, and/or heart. They may be photographed.
Participants may have other tests, such as sleep, brain and heart electrical activity, speech and swallow, metabolism, hearing, eye, and colon function tests.
Participants may sign separate consent forms for some tests.
Participation will last indefinitely. Participants may be contacted once in a while by phone or mail. They may have follow-up visits.
Individuals with a clinical diagnosis of a RASopathy, including Costello syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines, Cardiofaciocutaneous syndrome, Legius syndrome, capillary arteriovenous malformation syndrome, or others, are eligible. Published clinical diagnostic criteria exist for most of the clinical RASopathy syndromes and differ by syndrome. It will be uncommon for individuals to have a clinical diagnosis and not have had molecular genetic testing. All individuals considered by the study team to be at risk for a RASopathy who have not had prior genetic testing will have this completed as part of the study. The rare individuals with a clinical diagnosis of a RASopathy who are not found to carry a corresponding pathogenic or likely pathogenic variant in a known RASopathy gene will be considered for exome analysis for identification of potentially novel RASopathy germline variation.
Individuals with a germline variant (P/LP or a variant of uncertain significance but predicted bioinformatically to be damaging) in a RASopathy-associated gene are eligible. These include but are not limited to: BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1,
Individuals with NF1 only are not eligible for the study. However, individuals with a dual diagnosis of both NF1 and another RASopathy (via genetic testing and/or clinical diagnosis) are eligible for the study.
All types and amounts of prior therapies are allowed.
Individuals with only a diagnosis of NF1, or a newly identified germline pathogenic germline variant in NF1, and first-degree relatives of these patients are ineligible. However, individuals with a dual diagnosis of both NF1 and another RASopathy (via genetic testing and/or clinical diagnosis) are eligible for the study.
Individuals who, in the opinion of the investigator, are not able to return for follow-up visits or obtain required follow-up studies will be excluded from participation in the NIH Clinical Center Cohort.
A cohort of individuals with RASopathies (Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, Legius syndrome, capillary arteriovenous malformation syndrome, and others, excluding neurofibromatosis type 1, and their relatives (parents, siblings, grandparents, other affected individuals). Individuals with germline pathogenic variants in Ras/MAPK pathway genes (excluding NF1) with or without a clinically diagnosed RASopathy.
Family-based
Other
Not listed
RASopathy Syndromes
To establish a longitudinal cohort of participants with a clinical diagnosis of a RASopathy and/or a pathogenic germline variation in a Ras/MAPK pathway gene (excluding NF1).
Clinical Phenotype
To study the lifetime rates of cancer development in participants with a RASopathy and their unaffected family members.
Genetic and Environmental Interactions
To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations.
Biospecimen Repository
To create a biospecimen repository of carefully annotated tissue samples for use in subsequent etiologically oriented translational research projects.
Novel Phenotype
To describe novel phenotypes associated with germline Ras/MAPK pathway genetic variation.
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