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Individuals with a confirmed or suspected diagnosis of Neurofibromatosis Type 1 (NF1). Diagnosis may be made clinically and/or confirmed through genetic testing. Clinical (non-genetic) diagnosis requires that individuals meet the National Institute of Health's (NIH) clinical diagnostic criteria for NF1.

Individuals with a confirmed or suspected diagnosis of Noonan Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Noonan Syndrome with Multiple Lentigines. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Noonan Neurofibromatosis Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Cardiofaciocutaneous Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Costello Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Legius Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a confirmed or suspected diagnosis of Smith-Kingsmore Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Individuals with a suspected or known mutation of GATOR-1.

Individuals with a suspected or known mutation of SYNGAP1.

Individuals with a suspected or known mutation of DLG4.

Individuals with a suspected or known mutation of MAPK1.

1. Individuals with a suspected or known mutation of a gene associated with the MTOR cellular pathway. Diagnosis may be made clinically and/or confirmed through genetic testing.
2. Unaffected relatives of individuals with a suspected or known mutation of a gene associated with the MTOR cellular pathway.

1. Individuals with a suspected or known mutation of a gene associated with the RAS/MAPK cellular pathway. Diagnosis may be made clinically and/or confirmed through genetic testing.
2. Unaffected relatives of individuals with a suspected or known mutation of a gene associated with the RAS/MAPK cellular pathway.

Lindsey Aschbacher-Smith, MS

Laurie Bailey, MS

Carlos E Prada, MD

Kathryn N Weaver, MD

The RASopathies are a group of developmental disorders caused by genetic changes in the genes that compose the Ras/mitogen activated protein kinase (MAPK) pathway. New RASopathies are being diagnosed frequently. This pathway is essential in the regulation of the cell cycle and the determination of cell function. Thus, appropriate function of this pathway is critical to normal development. Each syndrome in this group of disorders has unique phenotypic features, but there are many overlapping features including facial features, heart defects, cutaneous abnormalities, cognitive delays, and a predisposition to malignancies. This research study proposes to collect and store human bio-specimens from patients with suspected or diagnosed RASopathies. Once obtained, blood and/or tissue samples will be processed for: metabolic function studies, biomarkers, genetic studies, and/or the establishment of immortalized cell lines. In addition, data from the medical record (including neuropsychological evaluations) and surveys will be stored to create a longitudinal database for research conducted at CCHMC or at other research institutions.

Patients who are being evaluated for a RASopathy may have overlapping features, but the disorders individually can be exceedingly rare and many are not yet well characterized. Additionally, available clinical testing is not always diagnostic in this group of patients. The investigators propose to study disorders across the RAS/MAPK pathway, identifying both commonalities and differences, under one unified ongoing research protocol. The investigators propose:

1. To investigate the metabolic and molecular basis of established and suspected RASopathies.
2. Collect specimens derived from blood, buccal cells, sputum, urine, bone marrow, tumor tissue and residual specimens, including but not limited to pleural fluid, ascetic fluid, chyle, skin, lung, lymphatic or renal tissue and/or bronchoalveolar lavage fluid, tissue specimens, and/or cells that are left over from clinical procedures from enrolled patients for research purposes only.
3. Non-invasive or minimally invasive procedures to collect tissues for research purposes only, such as saliva, skin, or blood samples are also allowed. The collection of all samples from minor subjects will be done only if it is safe for the participant. Clinical studies will take precedence over research procedures.
4. Collect demographic information, medical history, and clinical test results to create a longitudinal research database of participants with suspected or diagnosed RASopathies. Participants will also complete surveys to be included in the research database (see "Research Database" section for details).
5. Provide a facility for long-term storage of bio-specimens and clinical data from participants with suspected or diagnosed RASopathies and their unaffected relatives.

Specimens derived from blood, buccal cells, sputum, urine, bone marrow, tumor tissue and residual specimens, including but not limited to pleural fluid, ascetic fluid, chyle, skin, lung, lymphatic or renal tissue and/or bronchoalveolar lavage fluid, tissue specimens, and/or cells that are left over from clinical procedures from enrolled patients for research purposes only.

RASopathy Biorepository

Investigation Into the Natural History and Metabolic and Molecular Basis of RASopathies.

Collect specimens derived from blood, buccal cells, sputum, urine, bone marrow, tumor tissue and residual specimens, including but not limited to pleural fluid, ascetic fluid, chyle, skin, lung, lymphatic or renal tissue and/or bronchoalveolar lavage fluid, tissue specimens, and/or cells that are left over from clinical procedures from enrolled patients for research purposes only.

Collect demographic information, medical history, and clinical test results to create a longitudinal research database of participants with suspected or diagnosed RASopathies. Participants will also complete surveys to be included in the research database (see "Research Database" section for details).

Release of fresh or frozen specimens and clinical data to both CCHMC and external investigators. Applications for use of bio-specimen and/or data must be approved by the Repository Use Committee through the completion of a specimen request form. Among other data, the specimen request form will require information concerning: Principal Investigator, funding sources, a research synopsis, Institutional Review Board (IRB) approval of the research project, and details about the required samples. At the time a de-identified sample is requested, the requesting investigator may also request de-identified clinical data if needed.

Children's Hospital Medical Center, Cincinnati

Quality of Life

Participants will begin their 1-week baseline EMA data collection period and then take part in intervention procedures immediately after enrollment to assess feasibility and acceptability.

Participants will begin their 1-week baseline EMA data collection period immediately after randomization and will begin receiving the 8-week intervention at the end of this week/beginning of the next week (depending on participant schedule).

After an initial 1-week baseline period for EMA data collection and 8 weeks of maintaining their usual routine (wait list period), participants will begin receiving the 8-week intervention.

8 weeks of maintaining usual routine followed by 8-week intervention that emphasizes mindfulness, acceptance, perspective taking, and values-based actions.

Waitlist

8-week intervention that emphasizes mindfulness, acceptance, perspective taking, and values-based actions.

ACT Intervention

Staci M Peron, Ph.D.

Staci Peron, Ph.D.

Background:

RASopathies are a group of genetic diseases that affect a child s development. They cause physical, cognitive, and behavioral symptoms. Caring for a child with a RASopathy can be stressful. Acceptance and Commitment Therapy (ACT) is a therapy that helps people become more aware and accepting of difficult thoughts and feelings. ACT has been found to be helpful for parents with high parenting stress.

Objective:

To find out if Acceptance and Commitment Therapy (ACT) can help caregivers of children with a RASopathy better cope with parenting stress.

Eligibility:

People aged 18 years or older who care for a child (younger than 18 years) with a RASopathy. The child must live with the caregiver at least 50% of the time.

Design:

The study is fully remote. Participants need a mobile device that can play audio and video and connect to the internet. They can borrow an iPod if needed.

Participants will download a free app called MetricWire. They will use this app to watch videos and answer questions.

The first 8 participants will be in a pilot study. They will receive the ACT intervention starting the first week after they begin the study.

After the pilot study, we will start a new phase called the randomized trial. In this phase, participants will have a 50-50 chance of being in the group that will start the intervention right away or the group that will start the intervention after about 2 months.

Participants will fill out surveys on 5 random days each week. These surveys have 7 questions and take about 2 minutes. They will also fill out 3 longer questionnaires: once before ACT begins, once just after the 8-week study period, and once about 3 months later. Questions will cover topics including:

Parenting stress

Life satisfaction

Self-compassion

Uncomfortable feelings and thoughts

Mindfulness

Participants will take part in an 8-week ACT intervention. They will have one 75-minute session with an ACT coach in the first week.

Participants will watch 9- to 17-minute videos each week. The videos talk about how to practice ACT techniques to cope with parenting stress.

Participants will have 20- to 30-minute coaching sessions in weeks 3 and 6. The coach will help them practice exercises and work through any problems.

Background:

* RASopathies are a group of neurodevelopmental genetic conditions caused by mutations affecting components within the RAS-map kinase (RAS-MAPK) cellular signaling pathway.
* Caregivers of children with a RASopathy are faced with numerous challenges related to the physical, cognitive, and behavioral symptoms associated with their child s condition.
* The use of virtual interventions has been increasing over the past decade, which increase accessibility and are especially critical during times of physical distancing, such as due to COVID-19.
* Similarly, Ecological Momentary Assessments (EMA) are being utilized more frequently in order to maximize ecological validity of results and minimize recall bias.
* To our knowledge, no psychological interventions have been investigated targeting parenting stress among caregivers of a child with a RASopathy.

Primary Objectives:

* Internal Pilot Study: To assess the feasibility (e.g., enrollment and attrition) and acceptability (e.g., satisfaction) of an Acceptance and Commitment Therapy (ACT) coping intervention on parenting stress for caregivers of a child with a RASopathy
* Randomized Controlled Trial (RCT): To compare Parental Stress Scale (PSS) changes from baseline to 8 weeks between the Immediate Intervention Arm and the Waitlist Control Arm

Eligibility:

* Caregiver (parent or legal guardian) of a child (\< 18 years) residing with them at least 50% of the time who has a diagnosis of RASopathy syndrome including NF1, Noonan Syndrome, Legius Syndrome, Cardiofaciocutaneous (CFC) syndrome, and Costello Syndrome, or another RASopathy
* Access to necessary resources for participating in a technology-based intervention (i.e., computer, smartphone, internet access) or be willing to use an iPod provided by the study team
* Must score a 15 or higher total score on modified questions from the PSS to indicate at least a moderate level of parenting stress
* Ability to read and speak English

Design:

* This is an 8-week psychological intervention study that has two phases: the first, an internal pilot study, will enroll an initial, small cohort of caregivers (n = 8), all of whom will participate in the ACT intervention. (COMPLETE)
* Due to the success of the internal pilot study (with specific benchmarks met), the second phase of this study will be an RCT comparing participants who receive the intervention immediately (Immediate Intervention Arm) with those in a control group (Waitlist Control Arm). Participants randomized to the Waitlist Control Arm will cross over to receive the intervention after the waitlist period.
* The intervention for the RCT phase involves a baseline 90-minute coaching session and two follow-up coaching sessions with a therapist over video chat, followed by weekly prerecorded video modules that the participants can view at their convenience over the following 8 weeks.
* Participants will complete measures of parenting stress, mindfulness, psychological flexibility, self-compassion, and perceptions of child well-being at baseline, the 8-week post-intervention assessment, and a 3-month follow-up assessment. Additionally, the study will use EMA whereby questions will be sent electronically at random times and days (once a day at varying times on 5 days a week) during weeks 0-8 (the first week will serve as baseline data for comparison) for the Immediate Intervention Arm and weeks 0-18 for the Waitlist Control Arm using the Catalyst mobile applicatioon by MetricWire software.
* We plan to enroll 8 participants in the internal pilot phase and 56 participants in the RCT phase to account for the potential attrition of two caregivers from the intervention, for a total accrual target of 64 evaluable participants.

Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial

Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Phase III Randomized Controlled Trial

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

Feasibility defined by compliance with viewing \>50% of the weekly videos (proposed target rate of 5 out of 8 videos watched; must watch at least 80% of each video), and 70% of participants attending both coaching sessions 2 and 3. Acceptability defined by descriptive data per caregiver reports of satisfaction on the Study Satisfaction survey (mean of questions 1-7 and 9).

RCT: Mean scores on the Parental Stress Scale (PSS) will be compared from pre- to post-intervention (baseline to 8 weeks between the immediate intervention arm and the wait list control arm.

Feasibility defined by compliance with daily surveys (target rate of 30 out of 40 surveys (75%) completed on average by each participant). Acceptability defined by post-intervention participant reports of satisfaction with completing daily EMA ratings on the Study Satisfaction survey.

We will examine pre- to post-intervention changes in scores on measures of psychological flexibility (MPFI-SF), self-compassion (SCS-SF), experiential avoidance (BEAQ), depression (PROMIS Depression 8a) and child affect (PROMIS Positive Affect Scale).

We will look for a significant indirect association between treatment arm assignment and pre- to post-intervention PSS changes via psychological flexibility as measured by the BEAQ.

National Cancer Institute (NCI)

Affected participants, must have a correct clinical diagnosis of NF1.

Unaffected individuals greater than 2 years of age who are relatives of participants.

Douglas R Stewart, M.D.

This study may identify genes that predict the seriousness of neurofibromatosis type 1 (NF1). Finding these genes may explain why some people with NF1 have more medical problems than others. The study will also examine medical problems in NF1 that are rarely seen and are not well understood.

Male and female patients with NF1 who have gone through puberty may be eligible for this study, as well as patients of any age who have unique or under-recognized disease features. Affected and unaffected family members, including parents, siblings, and more distant relatives, may also be enrolled. Candidates are screened with a discussion of medical history or review of medical records, or both. Participants undergo the following procedures:

Patients with NF1

* Physical examination and family history
* Photographs of the iris of each eye
* Photographs of the back, abdomen and thigh to count skin tumors
* Photographs of the face and body (with underwear on) to help track growth and appearance
* Magnetic resonance imaging (MRI) of the spine (This test uses a magnetic field and radio waves to look for tumors and curvature of the spine. The patient lies still in the scanner, a narrow cylindrical device, wearing earplugs to muffle loud knocking sounds that occur during the scan. A contrast material called gadolinium is injected into a vein through a catheter to enhance the images.)
* Blood draw for genetic studies
* Possibly a skin biopsy (with the use of numbing medicine, removal of a small sample of skin tissue) to grow cells in the laboratory

Patients with NF1 who have unique or under-recognized disease features

* Physical examination and family history
* Blood draw for genetic studies
* Possibly a skin biopsy
* Possibly additional tests, such as blood work, x-rays, photographs, MRIs, ultrasounds, or other tests

Unaffected family members

* Blood draw for genetic studies
* Brief skin and eye examinations
* Possibly a skin biopsy for cell culture

Families are asked to give permission for researchers to recontact them for follow-up information, additional blood samples, or follow-up visit.

We hypothesize that normal germline variation in gene expression accounts, in part, for variation in the clinical severity and phenotype of the monogenic disorder neurofibromatosis type 1 (NF1). The phenotype of NF1 is constituted by a variety of quantifiable features; we term these features sub-phenotypes . Our main focus is on sub-phenotypes with published evidence of variation in expression from an inherited component. These include our primary sub-phenotype of spinal neurofibroma burden (quantified by MRI of spinal neurofibromas) and the secondary sub-phenotypes of dermal neurofibroma burden, head circumference, number of Lisch nodules, scoliosis, history of plexiform neurofibromas, and height. Other sub-phenotypes, as collected by a routine history and physical, will also be evaluated.

According to our hypothesis, the severity of a sub-phenotype will correlate with heritable differences in the germline expression of certain genes. As an example, consider a spectrum of individuals affected with the primary sub-phenotype of spinal neurofibroma burden. For most genes, there will be no relationship of expression level to the number of spinal neurofibromas. However, some genes will have a direct (or inverse, or other) correlation of their level of expression and the number of neurofibromas. Such genes would be considered as candidate modifier genes. The secondary sub-phenotypes will also be analyzed in a similar way. To limit false positives, candidate genes will then be tested for association (using the transmission/disequilibrium test, TDT) with the appropriate sub-phenotype.

Recruitment will be focused on identifying individuals with a range of severity of the primary sub-phenotype, spinal neurofibroma burden. We will primarily recruit post-pubertal individuals who meet the 1988 NIH criteria for neurofibromatosis type 1 (NIH Consensus Development Conference 1988). We will exclude those with recognized segmental or mosaic NF1. The rate of cutaneous neurofibroma growth and number is known to vary widely; these tumors typically appear in adolescence. For this reason we will ascertain patients after puberty. We expect most individuals to be 18 years or older, but will also accept post-pubertal pediatric patients (and use a hand film to demonstrate bone age). Parents (whether affected or not) are critical when using family-based tests of association (like the TDT) and tests of linkage and will also be recruited.

Tests of association with the TDT require trios (mother, father, proband). Multiple trios can be derived from a single family, if there are multiple affected individuals within the family. We set a recruitment goal of 100 trios and a ceiling of 1500 individuals (500 affected individuals, plus 1000 parents or additional sibs in about 400 families).

In the interest of improving care for people living with NF1, this protocol also seeks to characterize, at the PI s discretion, individuals with unique or under-recognized features of NF1 as well as individuals with NF1-like phenotypes, including those patients with a known or suspected RAS pathway disorder.

Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)

Variation in Gene Expression in Neurofibromatosis Type 1

.De-identified clinical data will be shared with collaborators under appropriate agreements.

Phenotype severityPhenotype individuals and family members affected with NF1 by routine history and physical. The primary (spinal neurofibroma burden) and secondary (dermal neurofibroma burden, head circumference, number of Lisch nodules, scoliosis, history of plexiform neurofibromas, height) sub- phenotypes will be quantified with as appropriate technology (MRI, iris exam and photography, physical exam, medical history).

Identify candidate modifier genes by determining the correlation coefficient of the level of gene expression and the severity of each sub- phenotype (as phenotyped in Aim 1).

Characterize individuals with 1) unique or under-recognized features of NFl, and 2) individuals with NFl-like phenotypes, including those patients with a known or suspected RAS pathway disorder.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
RASopathy Biorepository	NCT04395495	RAS Mutation Neurofibromatos... Noonan Syndrome Noonan Syndrome... Noonan Neurofib... Cardiofaciocuta... Costello Syndro... Legius Syndrome Smith-Kingsmore... MTOR Gene Mutat... GATOR-1 Gene Mu... SYNGAP1-Related... DLG4 MAPK1 Gene Muta...		-	Children's Hospital Medical Center, Cincinnati
Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial	NCT05361811	Neurofibromatos... Noonan Syndrome Legius Syndrome Cardiofaciocuta... Costello Syndro...	Waitlist ACT Interventio...	18 Years -	National Institutes of Health Clinical Center (CC)
Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)	NCT00111384	Neurofibromatos... Legius Syndrome		2 Years - 100 Years	National Institutes of Health Clinical Center (CC)
RASopathy Biorepository	NCT04395495	RAS Mutation Neurofibromatos... Noonan Syndrome Noonan Syndrome... Noonan Neurofib... Cardiofaciocuta... Costello Syndro... Legius Syndrome Smith-Kingsmore... MTOR Gene Mutat... GATOR-1 Gene Mu... SYNGAP1-Related... DLG4 MAPK1 Gene Muta...		-	Children's Hospital Medical Center, Cincinnati
Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial	NCT05361811	Neurofibromatos... Noonan Syndrome Legius Syndrome Cardiofaciocuta... Costello Syndro...	Waitlist ACT Interventio...	18 Years -	National Institutes of Health Clinical Center (CC)

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