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The RASopathies Network

, by Lisa Schoyer and Beth Stronach

Beth Stronach, Ph.D. and Lisa Schoyer

Beth Stronach, Ph.D. and Lisa Schoyer

Lisa Schoyer trained as an artist at Yale and the California Institute of the Arts. She is founder and president of the RASopathies Network.  Beth Stronach, Ph.D., did postdoctoral work with Norbert Perrimon at Harvard. She is now on the faculty of the University of Pittsburgh, and secretary of the RASopathies Network.

The RASopathies

Germline mutations in RAS genes (HRAS, KRAS, NRAS) or their regulators and effectors give rise to human disorders, some rare, and others more common. These so-called RASopathies are a group of neurodevelopmental genetic syndromes related by phenotypic characteristics and molecular association with the RAS MAPK signaling pathway. The syndromes include Costello syndrome (CS) caused by mutations in HRAS; Cardio-facio-cutaneous (CFC) syndrome caused by mutations in BRAF, MAP2K1 and 2, and KRAS; Neurofibromatosis type 1 (NF1) caused by neurofibromin RAS-GAP mutations; Legius syndrome caused by SPRED1 mutations; and Noonan and Noonan-like syndromes (NS, NSML, NS-LAH), which are currently linked to >18 genes encoding proteins in the RAS signaling pathway, with PTPN11 (Shp2) mutations being the most prevalent. The vast majority of the RASopathy mutations are gain-of-function mutations that lead to activation of RAS signaling. While they may be inherited in autosomal dominant fashion, many RASopathy mutations arise de novo and there is evidence indicating paternal bias from ‘selfish selection’ for such pathogenic mutations in the male germline. Case studies also describe early post-zygotic mosaicism for RASopathy mutations within a wider spectrum of developmental and cancer predisposition syndromes.

Since RAS signaling is required for fundamental cell functions in most if not all tissues, manifestations of the syndromes are systemic. Clinicians typically make a presumptive diagnosis on the basis of cardiac defects, feeding difficulties and failure to thrive, distinct facial features, skin pigmentation, and short stature, although there are numerous other physiological systems affected. Not surprisingly, RASopathies can predispose to cancer. Currently, clinical diagnosis can be made prenatally, postnatally, or throughout the lifespan depending on the severity of manifestations during pregnancy, in the newborn, child, or adult, sometimes when their child is diagnosed. Genetic panels typically confirm the clinical diagnosis by sequencing. But the field is still evolving and new pathogenetic mechanisms are continuing to be discovered.

RASopathies Network

RASopathies Network (RASNet) is a volunteer nonprofit organization whose goal is to provide support and information to families diagnosed with a RASopathy, to raise awareness of the RASopathies, and to connect and foster collaboration among those affected and those researching and treating RASopathies, with the ultimate goal to advance research on RASopathies toward an effective treatment or cure.

RASNet reaches a wide audience on the web through social media campaigns and active engagement with a growing network of professionals. We devote a substantial amount of time and effort to outreach. This includes organizing biennial symposia since 2009, with scientific sessions and family involvement.  Funding for the symposia is through NIH R13 grant support and sponsorships. We also raise funds to support a research project through the Penn Orphan Disease Center annual Million Dollar Bike Ride (MDBR). To date, six projects totaling over $343,000 have been funded through this mechanism.

In addition to biennial symposia and annual fundraising, we are now engaged in a collaboration with the NCI ART project, for “Advancing RAS/RASopathy Therapies”, which started fortuitously when Lisa Schoyer carpooled to the 2nd RAS Initiative Symposium in December, 2017 with Dr. Brigitte Widemann, Chief, Pediatric Oncology Branch of the Center for Cancer Research at NCI. This effort is ramping up to bring families to the NIH clinical center for participation in a RASopathies natural history study slated to begin in 2020.

Dialogue with Lisa Schoyer, founder and president of RASNet

How did you become knowledgeable about the RASopathies? 

My son, Quin, had Costello syndrome (CS), HRAS G12S.  He was medically fragile, with the more involved classic features of CS - short stature, requiring 50% more calories than typical infants/children his age, hypertrophic cardiomyopathy, hypersensitivity to light, and a delightful sense of humor, including understanding irony!  He died of embryonal rhabdomyosarcoma (eRMS) at the age of 6 years 7 months while on his second course of chemo, 17 years ago.

As the parent of a child with CS with a prevalence of 1:380,000, I’ve become a research maven on the subject, having read up on most of the known publications on CS (though I’m falling further behind as they teem!), noticing issues and sharing patterns of concerns on our family listserv with our professional advisors.  Information shared with our clinical research partners include: false-positives from the neuroblastoma screening test – something causes a number of our children to spill above-average levels of catecholamines; Chiari malformations developing post-birth; and also working to apprehend the difference between research, clinical, and molecular diagnoses.

The first time I learned about the term, RASopathies, was when Kate Rauen and I started work on the First International RASopathies Symposium in 2009.  Kate (as Chair) encouraged me as co-chair, to invite CFC International and The Noonan Syndrome Support Group (TNSSG), as well as the Neurofibromatosis type 1 organizations, Children’s Tumor Foundation (CTF) and NF Network, in addition to the Costello Syndrome Family Network (CSFN) Family Forum, expanding what we did in 2007 between the CSFN Family Forum and First International Costello Syndrome Symposium.  Inviting the family support organizations of each of the known RASopathies to hold their family conferences concurrent to the first RASopathies symposium was a great opportunity for families from each of the syndromes, as well as clinicians and researchers who typically went to a specific syndrome family meeting, to see the individuals in the context of the other RASopathies, in a non-clinical, non-research setting.  The syndrome family conferences also provide access for researchers to conduct IRB-approved research, as well as ‘Ask the Experts’ access for families, and bring together the largest worldwide collection of families together at one venue.

When/how was the term RASopathies coined?

Katherine A. (“Kate”) Rauen, MD, PhD, coined the term in 2007.  The first Noonan syndrome gene, PTPN11, was identified by Tartaglia et al. in 2001.  The Costello syndrome gene (HRAS) was identified in 2005 by Aoki et al. when they were looking for a second Noonan gene, using a group of children clinically diagnosed with CS as a control.  They identified HRAS as the cause for the control group’s syndrome instead!  In 2006, a collaboration between Kate Rauen and CFC International with their biobank, resulted in identification of the first genes causing CFC syndrome.  With the third set of data points, Kate saw the molecular relationship that connected them – a matter of function, not genomic location (as learned from past publications).

How did Frank McCormick become involved?

Kate Rauen was working in Frank’s lab when she identified the RASopathies.  It was her relationship with Frank that brought him in from the start, with the First International Costello Syndrome Research Symposium in 2007 – before people understood the relationship between each of the RASopathies and the pathway.

Why did you start RASopathiesNet?

It was a request of the leadership of the Costello Syndrome Family Network (CSFN), CFC International, and the Noonan Syndrome Support Group (no longer extant) after the 2009 concurrent conferences in Berkeley.  They asked me to build a parent-led nonprofit to interface between the family organizations and the researchers, because I was the one among them who was curious about the science that had led to defining the RASopathies, and I was able to understand the researchers just enough to explain the science to the families – it was peer pressure!

It was also a request of the researchers who pointed out that, due to the necessity of chasing funds, staying focused on the RASopathies would be hard to do without a unifying effort.  This latter request came at a meeting I convened during the 2009 ASHG (American Society of Human Genetics) meeting, which I attended as a Genetic Alliance Fellow. It was at this meeting that a discussion on naming the syndromes also arose, the solution of which was to hold a vote among the researchers and family organizations.  Clinical researchers preferred neuro-cardio-facio-cutaneous (NCFC) syndrome, while molecular researchers and family leaders preferred RASopathies.  Key to the win was the family organizations’ leadership.  They represented families who preferred not to have their child’s issues catalogued by a term that could easily cause professionals to look at the problems instead of the person in front of them.  They voted unanimously for “RASopathies.”  The naming gave me the go-ahead to incorporate and apply for non-profit status for RASopathies Network USA.

What need did you see in the community?

I knew from talking with a cardiologist in 1999.  He said that attracting researchers would be very difficult due to its rarity, unless we were so "lucky" as to have a "family of means" give birth to a child with Costello syndrome.  Another possibility would be if CS could be linked to a field already of deep interest to researchers, like cardiology, for example.  With the identification of the RASopathies, it was clear that research for CS would benefit from being part of a larger group of syndromes.

Who collaborated with you early on, and how did you forge relationships with them?

The first clinicians and researchers who collaborated with us were the ones who committed their free time to come to the Costello syndrome family conferences.  Dr. Virginia Proud, from the Children's Hospital of the King's Daughter, was one of the physicians who helped a parent, Tammy Moore, convene the first CS family conference in 1999 in Birmingham, Alabama.  There, 18 families from across the world, including mine, came together.  Other doctors came to that meeting; Dr. Proud continued with us until her death in 2013.  More doctors came to the 2001 conference in Toronto (the only conference I missed, when Quin developed eRMS).  A number of these doctors stayed in touch and became members of the CSFN Medical Advisory Board.  They included Kate Rauen when she was at UC San Francisco; Karen Gripp, MD, duPont Hospital for Children; and also Bronwyn Kerr, MBBS, University Hospital, Manchester, UK, now retired.  They and their teams of researchers have been generous with their time not only at family conferences, but also giving us email access to them when families posed questions and concerns on the listserv.  Also joining the growing RASopathies community were Dr. Bruce Gelb, MD, Mount Sinai Hospital, Icahn School of Medicine, NY; David Stevenson, MD, Stanford, Lucile Packard Children’s Hospital; and Amy Roberts, MD, Boston Children’s Hospital, Harvard Medical School; and particularly in the European RASopathies meetings, Marco Tartaglia, PhD, Bambino Gesu Children’s Hospital, IRCCS, Rome; Giovanni Zampino, MD, Fondazione-Policlinico-Universitario-A. Gemelli-IRCCS, Rome, Italy; and Martin Zenker, MD, Institute of Human Genetics, Otto-von-Guericke-University, Magdeburg, Germany.

How do you envision that research on RAS-driven cancers will inform treatments or cures for RASopathies? And vice versa - do you think research on RASopathies could inform the oncology field?

We know that all the RASopathy mutations directly or indirectly affect the signaling in a gain-of-function manner, similar to malignant tumors.  If we can figure out how to titrate targeted small molecules, we may be able to help not only the syndrome’s mutation that the chemo targets, but also all those with mutations upstream of the target.  We know there are feedback loops, so in addition to finding the right dosage, we need to identify and calibrate the other ingredients of the cocktail, to plug up the loops.
It makes sense to me that our children can help us better understand how the pathway functions in general – and thereby help people understand and treat malignant Ras pathway tumors as well.

How do you describe the role of RASNet? And your role within the organization? What do you hope to accomplish in the short and long term?

The intended role of RASNet is to act as a network node for researchers, affected families, and their clinicians, to stay connected with the latest information.

Short term:

  • RASopathies research funding - we are so fortunate to be one of the chosen organizations that the Penn Million Dollar Bike Ride helps in fundraising and managing the funding process!  We've been able to fundraise for six RASopathies research grants, and have been invited to participate again next year.
  • Working with the NCI CCR to fulfill their ART project
  • Finishing up the 2019 symposium - the R13 grant and getting the proceedings published
  • Preparing for the 2021 symposium - including developing and adding a more robust agenda for families
  • Finding extramural partners for the NCI ART project

Long term:

  • Building a library of resources for families and researchers to better understand each syndrome, as well as best practices on raising their family member with a RASopathy
  • Developing a sustainable registry/natural history for families and researchers alike to be able to learn from
  • Maintaining an up-to-date list of clinics and clinicians who are confident in providing appropriate medical care

Why do you still keep doing what you're doing? How will you know when you're done?

The reality I see is that if we don't do it, who will?  Who will ensure that family leaders are at the table as equals with researchers as we move forward to identify, test, and get therapies to families?  I’m also interested in learning what it is that my son had, and how to make life easier for future families.  For me, the easiest way to do that is by being actively involved in the RASopathies Network.

If you could ask for one thing to make a big difference for individuals with RASopathies, what would it be?

I recognize intellectual property is the root of - or route for - all research.  That said, it would be wonderful if we could find mutual benefit in collaborating, so that all families have access to reasonably-priced effective therapies with minimal side effects.  We’re currently working with the NCI Center for Cancer Research on their ART project, with the goal of setting up a natural history study toward a clinical trial.  It would be REALLY cool if there were a long-term expansion, and a sustainable solution.

Dialogue with Beth Stronach, secretary and board member of RASNet

How did you learn about the RASopathies?

Our son, Sam, was diagnosed in 2007 with Noonan syndrome as a toddler. We credit our pediatricians for suspecting NS based on his manifestations. At that time, my husband and I both worked at a university. Typical of scientists, we scoured the biomedical literature and learned that NS was a genetic disorder of the Ras/MAP Kinase signaling pathway.  This revelation floored me, as research in my lab investigated the role of a closely related signaling pathway, the Jun kinase pathway, in embryonic development of a model genetic organism, the fruit fly Drosophila.  I had always been interested in the genetic and molecular control of animal development and our son’s diagnosis literally brought home the most important reason why I ‘did science’ in the first place, to discover these underlying principles and how they are perturbed in illness and disease.  It was both a humbling and empowering moment.

After a few years, I was looking for a way to reach beyond my academic work and sought to share my experience as a bioscientist and mother of a child with NS. I found RASopathies Network on the internet, and what solidified my eventual involvement with the organization is a ‘small world’ story. I came across an article by Matt Might about his child’s undiagnosed condition and his unceasing efforts to find the cause and eventually a treatment. Matt was at the University of Utah, where I had done my doctoral work. This was enough for me to email him and ask how he thought I might be able to productively use my experience to do something useful for my son and others with disorders of the RAS pathway, the RASopathies. I got a response almost immediately urging me to contact Lisa Schill, Vice President of RASNet, an amazing mom of a child with NS, and a tireless advocate for the RASopathies.  That was the connection that first got me involved in the RASopathies community.

What do the RASopathies mean to you?

To me, the RASopathies are a prime example of the complexity of human genetics. The syndromes arise from mutations that activate a signaling pathway which controls virtually every physiological system in the human body.  Mutations in different proteins in the pathway manifest overlapping, yet distinct perturbations that serve to classify the syndromes clinically. Different alleles of the same protein can result in a spectrum of phenotypic manifestations and predisposition to cancers. Even the same mutation can manifest differently in individuals of the same family. This heterogeneity is fascinating. With a scientist’s mind, I marvel at the complexity at every level from the molecular regulation of RAS signaling to the diversity of human phenotypic expression and emotional resiliency of individuals with a RASopathy. As a mom, I often struggle with issues surrounding having a child with a genetic disorder, I feel relief that the genetic lottery gave us a mildly affected child, but that gives way to guilt that I cannot relate better to those families who weren’t as fortunate in the lottery. The RASopathies are ‘case studies’ at many levels of science and society. For me, RASopathies Network provides a way to educate, connect, and support the community of RASopathy families, doctors, and researchers.

What are your short- and long-term goals for RASopathies Network?

My short term goals for RASNet include improvement of our website with the latest and most useful content, to find additional people willing to volunteer for activities that we need to sustain our efforts in the longer term, and to foster meaningful bridges with the individual syndrome groups.

In the long term, it is my hope that RASNet will be a primary resource for newly diagnosed families to find information, to link with specialist providers, researchers, and other families, and to facilitate recruitment into registries and clinical trials.  

What’s your big ask from the biomed research community, the advocacy community, clinicians and others?

Two things: First, pay attention to your children, your patients, and your research participants, and communicate regularly amongst yourselves to spread knowledge and awareness of issues arising, and to be creative and fearless in proposing and implementing interventions for RASopathies.

Second, consider that a fraction of the resources dedicated to solving and curing RAS-driven cancers (money, talent, time, and reagents), if applied to RASopathies, could make a huge difference for those suffering from the debilitating genetic disorders involving the same molecules and pathways.

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