Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies

Recruiting

• Conditions: RASopathy; Cardiofaciocutaneous Syndrome; Legius Syndrome; Noonan Syndrome; Costello Syndrome; Capillary Arteriovenous Malformation Syndrome

• Registration Number: NCT04888936
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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.

Detailed Description

Study Description:\<TAB\>

The RASopathies are a clinically defined group of disorders caused by pathogenic germline variants in genes encoding components of the Ras/mitogen-activated-protein kinase (Ras/MAPK) pathway. These disorders have overlapping clinical features due to Ras/MAPK dysfunction, including a predisposition to the development of certain malignancies. The aims of this prospective longitudinal cohort study are to determine the incidence of malignancy in patients with RASopathies and determine the underlying differences in those who develop tumors as compared to those who do not, in order to inform cancer screening recommendations. In addition, this longitudinal cohort study will provide a better understanding of non-tumor RASopathy manifestations.

Objectives:

Primary Objectives:

* 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).

* To study the lifetime rates of cancer development in participants with a RASopathy.

* To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations.

Secondary Objectives:

* To create a biospecimen repository of carefully annotated tissue samples for use in subsequent etiologically oriented translational research projects.

* To describe novel phenotypes associated with germline Ras/MAPK pathway genetic variation.

Endpoints:\<TAB\>

* Number of participants meeting enrollment criteria for inclusion in the RASopathy cohort.

* Development of RASopathy-associated neoplasms in patients with RASopathies other than neurofibromatosis type 1 (NF1).

* Longitudinal standardized quantitative evaluations of specific RASopathy manifestations.

Study Timeline

• Study First Submitted: 2021-05-14
• Study First Submitted QC: 2021-05-14
• Study First Posted: 2021-05-17
• Study Start: 2022-04-25
• Status Verified: 2025-05-02
• Last Update Submitted: 2025-05-03
• Last Update Posted: 2025-05-06
• Primary Completion: 2031-01-31
• Study Completion: 2035-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Genetic and Environmental Interactions	ongoing	To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations.
Clinical Phenotype	ongoing	To study the lifetime rates of cancer development in participants with a RASopathy and their unaffected family members.
RASopathy Syndromes	ongoing	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).

Secondary Outcome Measures

Name	Time	Method
Biospecimen Repository	ongoing	To create a biospecimen repository of carefully annotated tissue samples for use in subsequent etiologically oriented translational research projects.
Novel Phenotype	ongoing	To describe novel phenotypes associated with germline Ras/MAPK pathway genetic variation.

Trial Locations

Locations (2)

National Cancer Institute - Shady Grove; 🇺🇸 Rockville, Maryland, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States