Costello SyndromeNCT04888936
Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
An observational study of Costello Syndrome and Noonan Syndrome, run by National Cancer Institute (NCI) at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 99 yearsHealthy volunteers can take part
- Conditions the study is for
- Costello Syndrome, Noonan Syndrome, Cardiofaciocutaneous Syndrome
- How many people
- 500 participants
- Where
- 2 sitesUnited States
- Study dates
- 25 Apr 2022to 31 Jan 2035
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 99 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: 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.
Who may be able to join
- Carriers: An individual who meets any of the following criteria will be eligible to participate in this study:
- 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,
- MAP2K2, MAP3K8, MRAS, NRAS, PPP1CB, PTPN11, RAF1, RASA1, RASA2, RIT1, RRAS, SHOC2, SOS1, SPRED1. From herein, we refer to 1) individuals with germline pathogenic variation in a RAS pathway gene AND 2) individuals with a clinical RASopathy diagnosis but in whom a genetic variant has not yet been identified as "carriers." The first member of a family to be identified is termed a "proband."
- 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.
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- There is no age restriction.
- There is no restriction related to organ and marrow function.
- Each carrier (or their appropriate surrogate if the carrier is unable) must sign an IRB-approved document of informed consent to demonstrate their understanding of the investigational nature and the risk of this study before any protocol-related studies are
- performed.
- Controls: Family members of carriers are eligible for enrollment. Genetic testing in a CLIA-certified lab will be offered to these blood-related family members to establish whether or not a variant may be segregating in a family with incomplete penetrance. As most of the RASopathy syndromes are sporadic, extensive testing and enrollment of extended family members (grandparents, aunts, uncles) will likely not be necessary in many pedigrees. Family members who have undergone genetic testing for the proband s RAS variant and do not harbor it (or non-blood-related family members) are controls. Carriers and controls in this study are referred to as "participants," "individuals," or "patients."
- All types and amounts of prior therapies are allowed.
- There is no age restriction.
- There is no restriction related to organ and marrow function.
- Each control (or their appropriate surrogate if the control is unable) must sign an IRB-approved document of informed consent to demonstrate their understanding of the investigational nature and the risk of this study before any protocol-related studies are
- performed.
- Research Eligibility Evaluation: This is solely a function of meeting the inclusion criteria described above and not fulfilling any of the exclusion criteria below.
Who cannot join
- Carriers: An individual who meets any of the following criteria will be excluded from participation in this study:
- 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.
- Controls: An individual who meets any of the following criteria will be excluded from participation in this 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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office, 888-624-1937
- Recruiting
National Cancer Institute - Shady Grove
Rockville, Maryland, 20850
About this study
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.
Read 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.
Read the 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.
- Conditions
- Costello Syndrome, Noonan Syndrome, Cardiofaciocutaneous Syndrome, Legius Syndrome, Capillary Arteriovenous Malformation Syndrome, RASopathy
- Keywords
- Ras/MAPK pathway, Natural History
- Medical subject headings
- Costello Syndrome, Noonan Syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, Capillary Malformation-Arteriovenous Malformation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| NCI RASopathies Clinical Center Cohort | includes Proband, Other carriers in family, Family Controls | |
| NCI RASopathies Field Cohort | includes Proband, Other carriers in family, Family Controls |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: ongoing
Clinical Phenotype
To study the lifetime rates of cancer development in participants with a RASopathy and their unaffected family members.
Measured: ongoing
Genetic and Environmental Interactions
To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations.
Measured: ongoing
Secondary outcomes (2)
Biospecimen Repository
To create a biospecimen repository of carefully annotated tissue samples for use in subsequent etiologically oriented translational research projects.
Measured: ongoing
Novel Phenotype
To describe novel phenotypes associated with germline Ras/MAPK pathway genetic variation.
Measured: ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 May 2021
- Study start25 Apr 2022
- Primary completion31 Jan 2031 (estimated)
- Study completion31 Jan 2035 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Costello SyndromeStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Family based
- Time perspective
- Other
- Enrolment
- 500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Douglas R Stewart, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04888936
- Sponsor's protocol ID
- 200107
- Other IDs
- 20-C-0107
- Status last verified
- 30 Sep 2026
- First submitted
- 14 May 2021
- Last updated
- 2 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
- ClinicalTrials.gov ID
- NCT04888936
- Acronym / sponsor ID
- 200107
- Conditions
- Costello Syndrome, Noonan Syndrome, Cardiofaciocutaneous Syndrome, Legius Syndrome, Capillary Arteriovenous Malformation Syndrome, RASopathy
- Keywords
- Ras/MAPK pathway, Natural History
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 500 participants (estimated)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 25 Apr 2022 (actual)
- Primary completion
- 31 Jan 2031 (estimated)
- Study completion
- 31 Jan 2035 (estimated)
- First posted
- 17 May 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Family based
- Time perspective
- Other
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| NCI RASopathies Clinical Center Cohort | – | –includes Proband, Other carriers in family, Family Controls |
| NCI RASopathies Field Cohort | – | –includes Proband, Other carriers in family, Family Controls |
Who may qualify
- Ages
- 1 month to 99 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- 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.
Key inclusion criteria (17 listed)
- Carriers: An individual who meets any of the following criteria will be eligible to participate in this study:
- 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,
- MAP2K2, MAP3K8, MRAS, NRAS, PPP1CB, PTPN11, RAF1, RASA1, RASA2, RIT1, RRAS, SHOC2, SOS1, SPRED1. From herein, we refer to 1) individuals with germline pathogenic variation in a RAS pathway gene AND 2) individuals with a clinical RASopathy diagnosis but in whom a genetic variant has not yet been identified as "carriers." The first member of a family to be identified is termed a "proband."
- 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.
Key exclusion criteria (5 listed)
- Carriers: An individual who meets any of the following criteria will be excluded from participation in this study:
- 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.
- Controls: An individual who meets any of the following criteria will be excluded from participation in this 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
RASopathy Syndromes
Time frame: 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).
Clinical Phenotype
Time frame: ongoing
To study the lifetime rates of cancer development in participants with a RASopathy and their unaffected family members.
Genetic and Environmental Interactions
Time frame: ongoing
To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations.
2 secondary outcomes
Biospecimen Repository
Time frame: ongoing
Novel Phenotype
Time frame: ongoing
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2026.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Related trials for Costello Syndrome
Not yet recruitingObservational study
Clinical Genetics Branch Eligibility Screening Survey
Melanoma, Li-Fraumeni Syndrome
Recruiting
Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
Neurofibromatosis 1, Noonan Syndrome
RecruitingObservational study
RASopathy Biorepository
RAS Mutation, Neurofibromatosis 1
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Douglas R Stewart, M.D. principal investigator
National Cancer Institute (NCI)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Costello Syndrome and Noonan Syndrome, run by National Cancer Institute (NCI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 2 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact NCI Family Study Referrals ((800) 518-8474, ncifamilystudyreferrals@mail.nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
RASopathy Syndromes (time frame: ongoing). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2026.