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

  • STATUS
    Recruiting
  • End date
    Jan 31, 2025
  • participants needed
    300
  • sponsor
    National Cancer Institute (NCI)
Updated on 5 July 2022
Accepts healthy volunteers

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.

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.

Details
Condition Costello Syndrome, Noonan Syndrome, Cardiofaciocutaneous Syndrome, Legius Syndrome, Capillary Arteriovenous Malformation Syndrome
Clinical Study IdentifierNCT04888936
SponsorNational Cancer Institute (NCI)
Last Modified on5 July 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
All types and amounts of prior therapies are allowed
with a clinical diagnosis of a RASopathy who are not found to carry a corresponding
There is no age restriction
pathogenic or likely pathogenic variant in a known RASopathy gene will be considered
There is no restriction related to organ and marrow function
for exome analysis for identification of potentially novel RASopathy germline
variation
performed
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
SPRED1,57. 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
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
performed
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
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 nonblood-related family members) are controls. Carriers and
controls in this study are referred to as "participants," "individuals," or "patients
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
Research Eligibility Evaluation: This is solely a function of meeting the inclusion
criteria described above and not fulfilling any of the exclusion criteria in section 0
below

Exclusion Criteria

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
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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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