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Abstract

Background:

Clinical studies have begun to evaluate therapeutic approaches to address the widespread neurodevelopmental and mental health challenges associated with a group of genetic syndromes known as “RASopathies.” However, the perspectives of patients and families regarding the relevance and accessibility of such treatment approaches have not been studied.

Objectives:

To assess the mental healthcare needs and treatment experiences encountered by individuals with RASopathies and caregivers.

Design:

Directed content analysis of focus group and interview transcripts.

Methods:

We qualitatively analyzed data from four virtual focus groups comprised of caregivers (n = 21) of youth with RASopathies and a series of individual interviews with young adults (n = 11) with RASopathies. Perspectives on primary neurodevelopmental and mental health concerns, treatment history, and care accessibility were explored using a directed content analysis framework.

Results:

Consistent with prior research, participants reported that attention/executive functioning, mood, and social concerns were common; anxiety was a particularly frequent comorbidity. Mental health concerns varied across settings and frequently interfaced with physical health symptoms. Barriers to care included poor accessibility of services, adverse medication effects, and a lack of provider experience or knowledge. Addressing neurodevelopmental and mental health symptoms effectively often necessitates family resilience and advocacy on the part of patients and their caregivers. Emergent themes uncovered needs for provider training pertaining to rare diseases, trauma-informed care, and improved community awareness regarding RASopathies.

Conclusion:

This study identified a set of actionable items to inform research, care delivery, and advocacy that reflect the expressed needs and lived experiences of participants representing both caregivers and patients with RASopathies.

Plain language summary

A qualitative study to understand perspectives of caregivers and people with RASopathies on their mental health care needs and treatment experiences

New treatments are being developed and tested to address neurodevelopmental and mental health challenges of people with RASopathies, yet there is a lack of research exploring the patient experience when accessing existing treatments and perceived barriers to care. Our team conducted and analyzed a series of focus groups and interviews with caregivers and young adults with RASopathies. We asked about mental health concerns, treatment history, care accessibility, and ideas for treatment approaches to better meet their needs. Results identified a wide variety of mental health conditions and treatment strategies, with anxiety being a particularly frequent area of concern. Mental health conditions frequently interfaced with physical symptoms. Caregivers and individuals with RASopathies frequently struggled to access care, had adverse medication effects, or encountered providers with a lack of experience or knowledge of RASopathies. Advocacy from patients and their families was often needed to successfully address neurodevelopmental and mental health symptoms. Several themes emerged from these conversations, including needs for provider training in rare diseases, trauma-informed care, and improved community awareness regarding RASopathies. This study identified a set of actionable items to inform research, care delivery and advocacy that was informed by the perspectives of both caregivers and patients with RASopathies.

Keywords

cardiofaciocutaneous syndrome Costello syndrome mental health neurofibromatosis type 1 Noonan syndrome patient-centered psychiatric qualitative treatment

Introduction

While rare diseases are frequently understudied and lacking in adequate treatment options, the neurodevelopmental and mental health conditions that accompany them are a particular area of unmet need.^1–3 The RASopathies are a group of complex rare disorders caused by gene variants that disrupt signaling through the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway.⁴ This dysregulated signaling can impact numerous processes involved in brain development, leading to effects on learning, attention, social skills, emotion regulation, and behavior.^5,6 A range of physical health manifestations is also observed, including craniofacial features, cardiac disease, gastrointestinal issues, dermatologic findings, and increased risk for malignancies. The collective incidence of RASopathies is approximately 1:1000 to 1:2500 births.⁷ Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS) are the most well-known of these conditions.

Neurodevelopmental complications are observed in all RASopathies, but the prevalence and constellation of specific symptoms vary within and across diagnostic groups. Intellectual disability is considerably more common among individuals with gene variants that affect downstream components of the RAS/MAPK pathway (e.g., those causing CS and CFC), than those that affect transducers upstream of RAS (e.g., those causing NF1 or NS).⁸ In NF1 and NS, overall intellectual functioning is often age-appropriate, but effects on specific aspects of learning, attention, or processing are widely observed.^9,10 All RASopathies are associated with an increased risk for social challenges and symptoms of autism spectrum disorder (ASD),^11,12 with the highest rates of autism traits (e.g., repetitive behaviors, differences in social communication) observed in CFC.^13,14 A higher frequency of internalizing (e.g., anxiety, mood disturbance) and externalizing (e.g., impulsivity, aggression) behaviors has also been reported across all RASopathies.^15–18 Anxiety in particular has been noted as a prevalent comorbidity among individuals with CS.^19,20

Despite evidence of widespread neurodevelopmental and mental healthcare needs experienced by individuals with RASopathies, few resources have been dedicated to the development and evaluation of interventions to address these concerns. A small number of studies have investigated pharmacological therapies, primarily in patients with NF1. Stimulant medications have shown efficacy in treating social challenges, aggressive behaviors, and symptoms of attention deficit hyperactivity disorder (ADHD) in NF1.^21,22 Other psychiatric medications, including antidepressants and antipsychotics, have been reported on in observational studies of NF1 and CS; however, their effectiveness remains unclear, with some reports of adverse reactions.^20,23 RAS-targeted therapies such as MEK inhibitors, which aim to address the RAS/MAPK pathway directly, have demonstrated efficacy in reducing physical symptoms (e.g., tumors, cardiomyopathy), but their utility in addressing cognitive and behavioral concerns has not been well-established.^24–26 Similarly, despite basic research showing that antiseizure drugs (e.g., lamotrigine) and statin drugs can improve learning and memory function in animal models of NF and NS, clinical trials with humans have not produced strong evidence of efficacy.^27–33 In terms of psychotherapeutic approaches for RASopathies, trials of a telehealth group social skills intervention, social cognitive training, mind-body therapy, acceptance and commitment therapy, and a working memory training program have all yielded preliminary evidence of feasibility and/or efficacy to improve aspects of cognitive function or behavioral health.^34–39

As established and emerging therapies to address neurodevelopmental and mental health conditions in RASopathies are investigated, it will be critical to focus resources on interventions that have high relevance and accessibility within patient communities. Identifying which care needs are perceived as most pressing for patients and their families, which treatments are routinely utilized by individuals with RASopathies, and the degree to which families consider these treatments accessible is of fundamental importance.⁴⁰ Additionally, research aimed at identifying caregiver challenges remains limited despite evidence of elevated parenting stress and unmet needs across RASopathies.^41–43 Studies reporting higher stress levels among caregivers of children with RASopathies who have greater emotional and behavioral difficulties suggest that intensified focus on interventions to alleviate these difficulties could improve quality of life for family members.^41,44,45 To advance treatment development and delivery, we engaged both patients and caregivers in focus groups and interviews to elicit their perspectives surrounding neurodevelopmental and mental healthcare services. We focused on the period between childhood and early adulthood, a key developmental window during which symptoms are most likely to emerge and caregiving demands are often substantial.⁴⁶ Our study team then qualitatively analyzed the interview transcripts to address the following research questions:

What types of neurodevelopmental or mental health concerns were individuals with RASopathies experiencing?

What treatments and supports were families utilizing to address those concerns?

What were the primary barriers and facilitators to treatment for mental health concerns?

What themes emerged regarding the experience of mental health symptoms and treatment?

Method

Participant recruitment and enrollment

Study participants were recruited through multiple channels, including a database of prior participants in research studies by our team, email listservs, and social media postings by patient advocacy groups (CFC International, Costello Syndrome Family Network, Children’s Tumor Foundation, NF Midwest, NF Network, Noonan Syndrome Foundation, RASopathies Network). Participants were included if they were English-speaking and identified themselves either as a caregiver of a child or young adult (aged 3–25 years) with a RASopathy, or as a young adult (aged 18–28 years) with a RASopathy. (Note. We defined the term caregiver to encompass any adult who supports decision-making and functional participation in educational, health care, daily living, and/or community settings for at least one individual with a RASopathy, such as a parent or guardian.) Exclusionary criteria were: lack of English language fluency; not being within the age ranges noted above; or lacking either a diagnosis of NF1, NS, CFC, or CS or a child with one of these diagnoses. Individuals with RASopathies who were unable to understand and appreciate the study information provided, as per assessment with the University of California, San Diego Brief Assessment of Capacity to Consent,⁴⁷ were also excluded. Participation was limited to one individual per family.

Prior to data collection, an informed consent process was conducted via private videoconferencing meetings using e-consent documentation. Twenty-one caregivers consented to participate in 1 of 4 focus groups, each dedicated to one of the major RASopathy syndromes. Additionally, 11 young adults with a RASopathy consented to participate in private semi-structured interviews. The study duration was from May 2023 to April 2024. Table 1 displays aggregated demographics of individuals with RASopathies reported on in these focus groups and interviews. Participant numbers are provided to accompany illustrative quotes in text and tables, but these quotes are not connected to specific attributes to maintain participant privacy.

Table 1.

Demographics and diagnostic features of individuals with RASopathies reported on in caregiver focus groups and young adult interviews. RASopathy diagnosis is denoted by the presenting clinical syndrome and gene affected.

Characteristics	Caregiver focus groups	Self-report interviews
Total N	22	11
Age (years)
Mean (SD)	12.6 (5.6)	22.7 (3.4)
Range	3-24	18-28
Gender
Male	11	3
Female	10	7
Nonbinary	1	1
RASopathy diagnosis
CFC-BRAF	4	0
CFC-KRAS	1	0
CFC-MAP2K1	1	0
CFC-MAP2K2	1	1
CS-HRAS	4	0
NS-PTPN11	5	2
NS-RAF1	0	1
NS-SOS1	1	0
NS-Not reported	0	1
NF1	5	6

CFC, Cardiofaciocutaneous syndrome; CS, Costello syndrome; NS, Noonan syndrome; NF1, neurofibromatosis type 1.

Data collection

Transcripts for thematic coding were obtained from each of four virtual caregiver focus groups led by a postdoctoral researcher and a post-graduate research assistant (each lasting approximately 75 min) and 11 semi-structured individual interviews led by a post-graduate research assistant (each lasting approximately 25 min). Participants in both groups were asked the same open-ended questions regarding primary neurodevelopmental or mental health concerns (if any), treatment history related to such concerns, experiences obtaining care, and perspectives regarding potential future treatments or support that might be helpful. Focus groups and interviews were recorded and transcribed by the University’s HIPAA-compliant videoconferencing platform. All video recordings were reviewed by a research assistant to ensure accuracy of the transcriptions, and the corresponding transcripts were de-identified prior to analysis.

Data analysis

We conducted a directed content analysis⁴⁸ using a hybrid deductive–inductive coding approach. Initially, raw data from focus group and interview transcripts were coded using a deductive codebook informed by existing literature and clinical experience with RASopathies. During this process, several data segments did not align with the predefined codes. These unmatched statements were grouped inductively based on conceptual similarity and discussed among the research team. From these groupings, new codes were defined and organized into broader categories. While qualitative methods primarily guided the coding and interpretation of participants’ experiences, our content analysis also incorporated visualizations and descriptive summaries of code frequencies to enrich the qualitative findings. To address Research Question 4, inductively derived codes were synthesized to develop overarching themes that captured the most salient patterns in the data. The saturation of themes was determined by the absence of new codes emerging in the iterative coding process, consistent with explanations of data saturation in scholarly literature.⁴⁹ When new data (i.e., additional transcripts) yielded no additional codes/themes and instead repeated what was in previous data, focus group and interview data were considered saturated. The data analysis procedure and code formulation process are visualized in Figure 1.

Figure 1.

Data analysis process reflects a directed content analysis framework for coding focus group and interview transcripts.

Codebook development

The initial deductive codebook was collaboratively developed by a faculty researcher, a postdoctoral researcher, and two graduate student research assistants (herein referred to as researchers). Codes were selected based on empirical research on neurodevelopmental and mental health concerns across RASopathy conditions^{13,16,19,50,51} as well as extensive prior communication and experience with families affected by RASopathies across clinical, research, and community settings. Codes were operationally defined, and the initial codebook was input into NVivo 1.71.

Focus group coding

After initial familiarization with the transcripts and deductive codebook, two researchers independently conducted descriptive coding of each transcript. Next, the researchers met for consensus review to evaluate consistency regarding the number of mentions across all focus group transcripts for each code and the mapping of quotes/content to each code. They discussed iterative changes or additions to the codebook needed to reflect emerging concepts and themes. The same process was followed for each consecutive transcript. The coding categories were then refined and reorganized, and the focus group codebook was reviewed and finalized.

Interview coding

Minor terminology modifications were made to the focus group codebook to enable accurate coding for interview transcripts (e.g., referring to “individuals” rather than “caregivers”). Under the supervision of a graduate student, research assistants independently coded each transcript. Consensus review of transcripts was completed to inform necessary modifications to the codebook.⁴⁸ The researchers concluded that saturation had been reached when no new coding categories were added to the final transcripts.⁴⁹ The finalized interview codebook was reviewed and approved by the research team (see Table 1, Supplemental Materials).

Data validation and triangulation

To increase the rigor of the study, the team collected data via multiple sources (i.e., caregiver focus groups and patient interviews) and across the four major RASopathies. The investigators also engaged in peer debriefing prior to and in critical stages of analysis, such as after the initial focus group coding, after completion of all four focus groups, at multiple points during coding of interviews, and throughout manuscript preparation. To align with recommended standards for qualitative patient-centered research, reflexivity was incorporated into the research process through each researcher’s self-reflections about how their own positionality and characteristics could have influence on the results of this study.^52,53 The author Positionality Statement is available in the Supplementary Materials. The reporting in this study conforms to the COREQ statement.⁵⁴

Results

Research question 1: What types of neurodevelopmental or mental health concerns were individuals with RASopathies experiencing?

Areas of concern described by patients and caregivers were classified across 10 domains (Figure 2). Notably, 4 of 5 domains discussed by the highest proportion of individuals were the same across the caregiver and young adult cohorts: anxiety; attention and executive function; mood (depressed mood or mood dysregulation); and social concerns. Anger and conduct concerns were described as the fifth most-frequently mentioned issue among caregivers, whereas sleep was the fifth most-frequently mentioned among young adults with RASopathies. Supplementary Table 1 provides specific information regarding the number of participants endorsing and the total number of mentions across transcripts for each domain.

Figure 2.

Neurodevelopmental and mental health concerns mentioned by study participants.

We also coded subcategories of concerns. Note that for each fraction, the numerator represents the number of mentions within a subcategory (e.g., a specific type of anxiety) and the denominator represents the number of mentions within a larger category (e.g., anxiety). For most mentions by caregivers (38/59) and young adults (41/65) pertaining to Anxiety, comments were general (e.g., “I’ve experienced anxiety” (YA04)) and were not linked to a specific anxiety subtype. Regarding Attention & Executive Functioning, comments were typically about ADHD or problems paying attention (36/47 for caregivers, 27/30 for young adults). One caregiver explained, “I have been noticing he cannot focus on anything, like playing with a particular toy or swinging or any activity for say, definitely for 10 minutes at a stretch, but the school reports that his attention span is more like 3 minutes” (CG10). In the Mood Concerns category, caregivers most often shared observations related to mood changes or dysregulation (26/41). One parent described, “we’ve had outbursts, where he just will start shutting down and won’t communicate to anybody” (CG01). Mentions by the young adults in the Mood Concerns category typically involved specific mentions of depression (31/33). Regarding Social Concerns, most mentions by caregivers were related to relationships or social skills (30/34). One caregiver expressed concern about the lack of involvement of peers in her child’s life, questioning “where are her friends from school coming over for birthday parties or going to the park or watching a movie?” (CG19). Social Concerns among young adults typically centered around experiences of being the victim of bullying (8/10). One participant shared, “I was diagnosed with a brain tumor, and that same year I was getting bullied to the extreme at school. . .it was a horrible year for me” (YA04).

Research question 2: What treatments and supports were families utilizing to address those concerns?

Figure 3 depicts the primary groupings of interventions that families used to address neurodevelopmental or mental healthcare needs and associated subcategories. Data regarding the frequencies of participant mentions for each of these treatment/support modalities is available in Supplemental Table 2. The Therapy and Medication codes were mentioned by most participants. Therapy subcategories included developmental therapies (e.g., speech/language therapy, occupational therapy), outpatient behavioral or mental health therapies (e.g., applied behavior analysis, cognitive behavioral therapy), inpatient mental health therapies, and undefined therapies. In terms of medications, individuals from both cohorts reported use of medications addressing ADHD (n = 6), sleep (n = 6), mood/anxiety/behavior (n = 6), seizures/pain/migraines (n = 6), as well as dietary supplements (n = 5).

Figure 3.

Treatments or supports for neurodevelopmental and mental health concerns utilized by individuals with RASopathies as reported in caregiver focus groups and young adult interviews.

School supports were more commonly mentioned by caregivers (14 caregivers with 32 total mentions) versus young adults (3 young adults with 8 total mentions). Special education instruction, such as the presence of Individualized Education Programs, was discussed along with classroom accommodations, including structured break times and the use of sensory objects. Further school supports included small class sizes, homeschooling, and staff support (e.g., advocacy of staff members, effective collaboration with staff members, and teachers who were understanding of RASopathies symptoms). Family-based interventions were also mentioned more frequently by caregivers (16 caregivers with 32 total mentions) than by young adults (2 young adults with 2 total mentions). These supports included strategies for communication and for providing the necessary structure to tasks and activities. Regarding community groups/supports, engagement in extracurricular activities and social groups was most frequently endorsed. Individual coping strategies were mentioned by 4 young adults (8 mentions) but not by any caregivers. Examples of coping strategies included physical activity, sleep tracking, having a structured schedule, task reframing, and dietary changes.

Research question 3: What were the primary barriers and facilitators to treatment for mental health concerns?

Study participants discussed barriers (i.e., factors that prevented or made it more difficult to access or continue treatment) and facilitators to care (factors that supported initiating or maintaining access to services) (Figure 4). The top 5 barriers to treatment for caregivers, in order from most mentioned to least, included: scheduling (e.g., waitlist, unavailable providers); insurance coverage; medication barriers; distance to services; and time commitment. In comparison, the top 5 barriers reported by young adults were medication barriers; lack of alliance or alignment with provider; provider lack of expertise; scheduling; and government or community systems. Two barriers common to both data sets were related to scheduling and adverse medication effects. Both young adults and caregivers struggled to find appointments with providers due to waitlists and other delays. While medication was described as helpful for many participants, some individuals reported that medication side effects were a barrier to continuing treatments. One young adult shared, “[The medication] just made all my mental stuff 10 times worse . . . I was too scared to do medication for like 5 years” (YA10).

Figure 4.

Barriers and facilitators to care endorsed by young adults and caregivers. Responses were categorized under four domains. Accessibility factors were defined as those related to a participant’s ability to initiate or continue treatment; individual/family factors referred to the patient or family’s knowledge, resources, attitudes, or experiences that could influence treatment; provider factors were specific to the qualities or experiences of clinicians working with the patient; and systemic barriers and facilitators were those related to institutions of power such as governments or school districts, as well as the impact of larger world events.

Caregivers often cited accessibility as a considerable barrier to care. One caregiver mentioned: “I want to do so many things for him, but I just don’t have the time with my job” (CG06). Family financial resources also prevented access to services, with a caregiver noting “sometimes you have to go outside my insurance, and to get somebody who really can help, a real good fit . . . it can be expensive” (CG01). Young adults focused more on challenges related to alliance with providers. One young adult noted “therapy. . .it really just kind of solidified my distrust in adults . . . it’s definitely made it so I was just kind of struggling alone quietly” (YA09). Another voiced frustration over the lack of knowledge about RASopathies among providers: “Finding providers that understand my conditions is difficult . . . they don’t understand my condition at all. And that makes it very frustrating to get the care that I need. Not just in mental health care, every kind of care.” (YA01). Caregivers also endorsed barriers related to a lack of alliance with providers or encountering inexperienced providers, but to a lesser extent than young adults. Both groups identified diagnostic labels as barriers. More specifically, they described not being able to access services due to rigid diagnostic criteria for a mental health condition. One caregiver stated, “He’s like just in all these little corners, you know, not quite in a category to receive services” (CG06).

In terms of facilitators of care, several differences were apparent between caregivers and young adults. Caregivers highlighted advocacy and family resilience (defined as: how families derive meaning from their experiences to cope with challenges⁵⁵) as important facilitators, whereas young adults placed greater emphasis on provider fit. Family resilience was mentioned by seven caregivers (11 total mentions), but not by any young adults. One caregiver noted, “It’s mostly. . .taking things as they come and finding out the path once I have to walk down [it]” (CG14). Although not mentioned by young adults, caregivers also frequently cited job flexibility and service modality options as facilitators. Both groups, however, underscored the significance of advocacy. Advocacy referred to instances where individuals sought improvements in services by requesting changes in the quality, focus, or availability of services. For example, one participant shared, “I pushed pretty hard to get handwriting support for the dysgraphia” (CG17). Another caregiver experienced relief after finally being approved to start sessions with a behavior therapist to receive parent training, stating, “it’s something I’ve always wanted. I wished it was available. It wasn’t. But so I just kind of had to beg for it.” (CG13)

Research question 4: What themes emerged regarding the experience of mental health treatments?

Research question 4 focused on key themes that arose when study participants shared about their mental healthcare experiences. Four themes were identified across the caregiver and young adult samples: complex constellation of symptoms; shifting neurodevelopmental and behavioral concerns; being different & lack of community knowledge about RASopathies; and suggested treatments or supports to improve care (Table 2).

Table 2.

Key themes identified through content analysis of focus group and interview transcripts.

Theme 1: Complex constellation of symptoms. Study participants described a complicated interface between physical health and mental health symptoms, as well as poor diagnostic fit to conventional diagnostic criteria for mental health conditions.
Caregiver quotes: [CG10]: “I don’t know if it is the seizure that caused it or if it is the medication that he is on is causing it, because that is also known to cause behavioral issues. But the problem is, we cannot onboard on the medication or we cannot add some more medications because of the interaction.” [CG03]: “I think that he has anxiety, but that’s not something that you, I guess, get formally diagnosed with. I found that the ADHD criteria don’t always seem to fit exactly right, so that there’s something else.”	Young adult quotes: [YA02]: “I think there was one therapist. . .who just didn’t recognize that I had an eating disorder. . .just because, like I didn’t look it, or I didn’t have like the textbook stereotypical like habits or signs.” [YA03]: “Yeah, it’s very interlaced with my physical health. So, it’s a little complicated. But when I was 14. . .I developed complex regional pain syndrome, which is like a nerve pain disorder, and that led to the onset of anxiety” [YA01]: “It’s looking like I probably have to come off mirtazapine because my heart has slight arrhythmia in long QT and it’s making it worse.”
Theme 2: Shifting neurodevelopmental and behavioral concerns. Study participant expressed concerns changing over time and across different settings or people.
Caregiver quotes: [CG12]: “We notice [anxiety, attention, and mood concerns] more at school or any new place that he goes to. When he’s at home, he has mood swings, especially when it’s things that is not his preferred task to do” [CG03]: “One thing that we saw as parents was things, things seem better now, and I think it’s because [my child] is maturing a lot. Finally. But it was like, really, just telling him about the same things over and over again, year after year.”	Young adult quotes: [YA10]: “Once I moved out on my own, I really started struggling keeping the house clean, remembering to do certain tasks, remembering to do even things that most adults consider normal things, such as eating, drinking, water, even going to the bathroom, things like that” [YA09]: “I have noticed as I entered my mid-twenties it did kind of get a little bit more severe in the sense that there weren’t any real triggers for [my anxiety]. It was just like very random things would kind of send me spiraling.”
Theme 3: Being different & lack of community knowledge. Study participants described feelings of isolation or being different, as well as being impacted by lack of community knowledge about RASopathies.
Caregiver quotes: [CG02]: “I mean, [Child_Name]’s just different. . . our doctors would say, well, you know [Child_Name] has [Child_Name] syndrome, and she’s just who she is.” [GG14]: “There isn’t a lot of specialists that specialize in just NF. So, it’s just finding our own path, at least here in my area, and that’s been the main struggle, so I don’t really have a lot of information as to what helps.” [CG17]: “So you know, it, it’s a challenge that the parents and the children both carry. . .as a burden, I think. To not know sometimes how to proceed, not know how to explain to people.”	Young adult quotes: [YA10]: “I also looked different and act different than a lot of my peers. I act weird. I get over stimulated. I’m not socially outgoing. I don’t do what quote unquote ‘normal’ kids would do. I have special interests, things like that.”
Theme 4: Suggested treatments or supports to improve care. Study participants elucidated treatments or supports that would directly impact outcomes from their perspective or make it easier for individuals with RASopathies to access care.
Caregiver quotes: [CG17]: “Yeah, to get those resources [for RASopathies] if they’re in place for some of these conditions that have been known for longer like cancer.” [CG07]: “So we haven’t really been able to follow any roadmap. We followed the Noonan’s map, then this map and that map, so having the information-sharing opportunity and getting your alls’ research would be huge for us to understand the pieces and parts.”	Young adult quotes: [YA01]: “You know, trauma-informed [care], especially when it comes to medical trauma.” [YA09]: “I do wish that there were potentially more studies or more medicines available that were not necessarily stimulants that were able to help kind of with ADHD and executive functioning just because I felt there were so many medical reasons that people don’t take stimulants.”

Theme 1: Complex constellation of symptoms

The complicated interface of physical and mental health symptoms surfaced as a theme for both caregivers and young adults. Participants frequently described how physical symptoms (e.g., pain, increased histamine, challenges swallowing, tumors, joint disorders) led to or exacerbated mental health symptoms such as depression, anxiety, or trauma. One caregiver shared about the influence of epilepsy on mental health: “I saw my son was a very happy kid. Then seizure struck him. . .we have been seizure-free for 4 and a half years, but ever since that seizure, we have seen a huge change in his behavior” (CG10). Two young adults mentioned that physical health conditions (e.g., cardiac conditions) increased anxiety; at the same time, some individuals had to stop taking medications for their mental health concerns because of adverse impacts on their medical condition (e.g., tachycardia). Medications for physical health conditions were also described to have unintended mental health effects. One caregiver mentioned that a medication prescribed for plexiform neurofibromas caused adverse effects (e.g., rash, hair loss) that led to worsening anxiety and depression for their child.

The complex constellation of symptoms experienced by individuals with RASopathies also contributed to delayed diagnosis or misdiagnosis. In some cases, diagnostic delays were attributed to the provider(s)’ lack of experience. In other cases, delays or misdiagnoses may have been related to the individual’s symptoms not fitting within conventional diagnostic categories. A particular source of diagnostic uncertainty mentioned by both caregivers and young adults was the considerable overlap in symptoms of ADHD and autism. One young adult emphasized that mental health is “not one-size” (YA02) and that mental health conditions do not present the same way across people.

Theme 2: Shifting neurodevelopmental and behavioral concerns

A second theme expressed by participants was changing symptom presentation across time, setting, or person. Some participants described an evolution of neurodevelopmental and behavioral concerns at different ages. For example, a child’s night terrors at age 4 evolved into broader anxiety later in development. Another child exhibited changes in sensory responsiveness over time, shifting from a pattern of avoiding stimulation toward one of seeking it. Multiple young adults described attention challenges as a dominant theme in the school-age period, whereas depression and anxiety became increasingly apparent in adolescence or later. Some caregivers reported that maturation-related changes, such as puberty, negatively impacted their child’s mental health or behavior, whereas others expressed that maturity brought increased self-management and coping skills for their children. Changes also occurred in terms of symptom severity. For several young adults, mental health symptoms worsened as they reached adulthood, with newly emerging triggers or symptoms (e.g., shaking hands, fast heartbeat).

Symptoms often varied across settings. Several caregivers described anxiety or behavior concerns as particularly apparent in new settings or settings associated with negative experiences (e.g., doctor’s office). Many participants mentioned the school environment as an important reference point. Caregivers often reported observing more concerns in the school than home setting, where “there are not as many expectations” (CG07) or caregivers feel they have more control. Caregivers reported a variety of challenges in the school setting, such as anxiety, attention difficulties, and externalizing behaviors, sometimes in response to sensory needs, culture, differences in learning, or requests from staff to complete non-preferred tasks. They also reported having struggled to communicate with school staff to foster understanding of their child’s needs and to keep “a common language between home and school” (CG19). Young adults expressed similar themes, including difficulties learning in a traditional setting as well as negative experiences in school (e.g., expulsions). Finally, transitioning from high school to college or a career was reported to be difficult, often related to reduced structure compared to the school years.

Behavioral concerns, particularly regarding anxiety and mood, also differed depending on the individual’s preference for or familiarity with the person with whom they were interacting. Caregivers described mood and behavior changes when their child was interacting with a particular person (e.g., other family member, school paraprofessional), with one stating “He has preferred people that he likes to be around, even a para at school where he’s happy with, you get another para next to him and he’s agitated, angry” (CG12). Young adults with RASopathies noted that their own ability to cope decreased based on certain interpersonal interactions (e.g., receiving problematic advice from an acquaintance after disclosing symptoms) or increased in the presence of trusted individuals (e.g., receiving support from a parent).

Theme 3: Being different and lack of community knowledge about RASopathies

A third theme encapsulated feelings of difference and isolation, sometimes compounded by a lack of community understanding of their diagnosis. Caregivers expressed that their children “look different,” are “just different” or are “just who [they are],” but caregivers “don’t know how much [they think they’re] different” (CG01, CG02, CG04). One caregiver wondered how much their child should share with others about their diagnosis, expressing concerns that this could make them stand out. Other caregivers noted that their children visibly struggled to form friendships because they “didn’t quite fit in” (CG02). In contrast, some caregivers questioned the social construct of normalcy, concluding “there’s no such thing as being normal” (CG05) and that differences such as perceived immaturity in comparison to other children “really [don’t] matter” (RA17). In short, caregivers chose to make meaning of the perceived differences of their children with RASopathies in distinct ways that reflected varying thought processes about acceptance.

For young adults with RASopathies, the social impacts of their medical or mental health conditions were often a concern. Several participants mentioned experiencing feelings of isolation during their K-12 school years or perceiving that they didn’t fit in with peers. They reported awkwardness arising from missing school activities due to medical appointments or having a diagnosis that placed them outside of the perceived norm. One young adult shared, “I was experiencing ‘Hey, I’m different from everyone else that’s my age’ and that doesn’t feel great.” (YA11).

Caregivers, but not young adults, reported that the community’s lack of knowledge about RASopathies impacted the way individuals were perceived. They expressed feeling unsure at times how to explain their child’s RASopathy to others, especially when there were few outward manifestations of their condition. Caregivers noted that many in their community did not know about the existence of RASopathies, unlike other conditions, which have campaigns about them. They described difficulties transitioning children from interacting with family members who understood them to others in the broader community or at school. This shift could be particularly challenging in the school setting when staff did not know how to support their child’s neurodevelopmental needs due to a lack of experience with RASopathies. Caregivers shared a perceived need to advocate for their children both in terms of school supports and to raise awareness in the larger community.

Theme 4: Suggested treatments or supports to improve care

Future supports were defined broadly as suggested but not currently utilized treatments or assistance that could impact outcomes or potentially make it easier for individuals with RASopathies to access care. A key suggestion from study participants was to increase the training and professional development of clinicians. Caregivers recommended increased training pertaining to how neurodevelopmental concerns present in children with rare diseases like RASopathies. One caregiver contemplated questions that had arisen as she navigated providers: “Can’t you get us into mental health professionals who understand this condition? Can’t there be someone in the team in that hospital . . . that are specialists in this?” (CG17). Young adults mentioned the need for trauma-informed care, especially to address experiences of medical trauma: “A lot of people, like therapy-wise, don’t understand that just because I’m alive and well, doesn’t mean that all the things that have happened to me in my life weren’t difficult, and I still struggle with processing them now” (YA01). They also voiced the potential benefit of more provider training in working with individuals with complex medical and neurobehavioral needs, including individuals who are minimally verbal.

The need for future research to identify effective treatments was also frequently mentioned. For young adults, comments primarily centered on the need for improved pharmacological or biological treatment strategies for RASopathies (e.g., investigation of the utility of transcranial magnetic stimulation in treating ADHD). Caregivers saw a potential benefit for additional social supports, such as a peer group focused on skills development, but also expressed uncertainty about whether their children would be interested in joining a group. As such, caregivers emphasized the need for increasing the self-confidence and autonomy of children and teens with RASopathies to allow them to make their own choices about what would benefit them as they are developmentally able to do so. Additionally, they suggested that researchers could establish a database of resources about the effectiveness of different neurodevelopmental and mental health treatments for children with RASopathies. An integrated summary of critical needs to advance care and support of RASopathies families is provided in Table 3.

Table 3.

Crucial needs for advancing neurodevelopmental and mental health care in RASopathies.

Domain	Needs
Research and clinical trials	• Systematic evaluation of existing and novel pharmacological or therapy-based treatments within RASopathy cohorts, including directed examination of interactions with physical health complications • Further development and assessment of interventions targeted toward caregivers of individuals with RASopathies • Further examination of patient and caregiver perspectives regarding desirability and acceptability of treatment approaches, including cross-syndrome comparison studies to improve the understanding of treatment priorities across RASopathies • Careful consideration of patient characteristics to enable personalized care approaches • Increased focus on needs related to anxiety, medical trauma, and overall impacts of mental health complications on quality of life
Access and service utilization	• Explore routes of improving access to experienced treatment providers (e.g., telehealth, regional centers of excellence) • Identify methods to reduce disparities in mental health care based on geographic location and other social determinants of health (e.g., racial discrimination, income, access to insurance, transportation, housing, and childcare) • Link families to local, state, federal, or non-profit supports and resources to obtain supported care options • Advocate for state or other governmental systems to change criteria for services to be more inclusive of rare diseases • Connect families with care coordinators and rare disease patient navigators to support their journey through complex care systems, navigate insurance coverage, and access appropriate specialists • Provide roadmaps and resources to support youth and families during the transition to adulthood
Clinician/provider support	• Provide training opportunities such as professional development workshops, online modules, or digital platforms to educate clinicians regarding RASopathies and share approaches to support patients with complex neurobehavioral needs • Development of a research database or other online resources to share evidence-based information regarding the availability and efficacy of neurodevelopmental and mental health treatments for RASopathies • Creation of consultation networks for less experienced providers to consult with specialty providers • Training for clinicians in trauma-informed care, especially regarding the cumulative effects of medical trauma
Community and family resources	• Supports and resources for facilitating communication between patients and their family members regarding mental healthcare needs • Provide funding allocated to support groups, community-led events, and awareness campaigns for individuals with RASopathies and their caregivers • Community education, including development of widely available educational materials for patients, family members, educators, and community members regarding the complexities of rare diseases and the needs and experiences of families

Discussion

Mental health and behavioral challenges are known to contribute to reduced quality of life among individuals with RASopathies, as well as increased stress among their caregivers.^45,56,57 The development of effective treatments to address these concerns has been identified as an urgent priority at recent international RASopathy symposia.^58,59 The goal of the current study was to gain insight into how individuals with RASopathies and their caregivers view their symptoms, utilize available treatments, and perceive experiences related to mental health care. Congruent with other published research, both cohorts expressed that RASopathies are often accompanied by challenges related to attention/executive functioning, mood, and social function.^15,45,58 Notably, anxiety also emerged as a frequently expressed mental health concern among study participants. Coupled with recent research identifying a heightened risk for anxiety among youth with RASopathies who were assessed with diagnostic interviews,^17,60 the finding that anxiety was a topic of considerable discussion among study participants suggests that it could be a more significant comorbidity than previously understood and an area of clinical priority within the RASopathies patient community. Sleep problems and sensory needs were also key concerns mentioned by participants, despite fairly limited focused research on these topics.^60,61

Participants described how their concerns were complex in their expression (shifting across time, setting, and person). This finding underscores the importance of monitoring symptom burden across relevant contexts (e.g., at home, in the classroom) when forming diagnostic impressions and assessing treatment response. Further, mental health concerns often interfere with participants’ physical health. These connections between mental and physical health burdens highlight the value of multidisciplinary perspectives in addressing RASopathy complications like chronic pain, sleep problems, and feeding difficulties.^62–64 Results also suggest that “diagnostic overshadowing” may occur in RASopathies, whereby mental health or behavior problems are overlooked in the face of more apparent physical health symptoms. This conceptualization aligns with multiple studies reporting that neurodevelopmental conditions like ADHD and ASD are diagnosed less frequently among youth with RASopathies than would be expected based on assessments administered for research.^12,13,65 Importantly, several young adults in the current study voiced frustration at not having their mental health concerns recognized or taken seriously, alluding to the importance of including behavioral health experts within multidisciplinary care teams.

Another common concern of study participants involved a lack of understanding and acceptance from those surrounding them (e.g., educators, community members). These results signal a need for support measures focused on increasing education about RASopathies and fostering inclusivity and belonging. Relatedly, participants frequently described providers’ lack of experience or knowledge as a barrier to care, an experience identified in previous research assessing perspectives of families affected by Noonan syndrome.⁵⁷ Unfortunately, these trends are not unique to RASopathies but instead are reflected in the larger rare disease community.^66,67 Our findings underscore the importance of robust advocacy and family support organizations, awareness campaigns, and increased training and education for healthcare professionals (further elaboration of these needs is provided in Table 3). Research demonstrating that attending RASopathies family support conferences is associated with reduced stress among parents⁴² further supports the conclusion that disease-related education and family connections can enhance well-being. The impact of such conferences and gatherings on the experiences of youth with RASopathies should be further explored.

In terms of the current treatment landscape described by study participants, a wide variety of approaches to address neurodevelopmental concerns were shared, including both standard pharmacological and therapy-based treatments as well as family and individual coping strategies. Although assessing the utility of these currently available treatments was beyond the scope of the current study, the significant variability that participants described in their treatment experiences (e.g., perceived efficacy, accessibility, and occurrence of adverse effects) confirms the need for tailored approaches. Relatedly, recognition of how patient selection and differences in symptom burden within and across each RASopathy may impact the results and efficacy of clinical trials is a critical consideration for investigators.^68,69

Our study also highlights the need for removing barriers to treatments and making them accessible across a range of geographical regions and income levels, as well as across a spectrum of disability. Notably, several young adults in our study voiced the experience that mental health concerns emerged or intensified during the time of transition to adulthood. This finding parallels studies reporting high levels of concern among caregivers of individuals with RASopathies when contemplating their child’s future, the long-term impact of their condition, and whether social services will be available to meet their care needs.^44,45,70 To mitigate stress during this vulnerable time, roadmaps and programming to ensure a planned and purposeful healthcare transition when transferring from child- to adult-centered care systems would be of great value.⁷¹

Several differences between young adult and caregiver perspectives were identified. For example, whereas caregivers often describe concerns regarding developmental delays, anger or conduct problems, and autistic symptoms, these concerns were rarely reported by young adults. This discrepancy could be due in part to differences in the age range represented, or to the fact that young adults with RASopathies with more pervasive neurodevelopmental and behavioral challenges may have been less able or willing to participate in our study. As has been described in previous studies, this finding could also indicate a tendency for youth with RASopathies to underreport these symptoms or, conversely, for caregivers to overreport them.^18,72

Another difference in the perspectives expressed was that caregivers often mentioned the importance of family support, whereas young adults tended to emphasize individual coping strategies. Emerging research provides evidence in favor of both family-based and individual skill-building approaches to enhance patient functioning. In terms of family-based approaches, a recent pilot of a psychologist-led acceptance and commitment therapy program for parents of children with RASopathies achieved high feasibility, strong engagement, and positive participant feedback.⁷³ A similar study focusing on parent management training for parents of children with NS found that after engaging in the intervention, mothers reported a decrease in parent-child dysfunctional interactions, along with an overall decrease in parenting stress.⁴⁵ Complementing these interventions designed for caregivers, supports to enhance individual coping among youth with RASopathies are also critically important. Providing tools and strategies around socialization, emotion regulation, chronic pain management, and coping with medical procedures could prove to be especially beneficial.^38,57,74 Further, the varying perspectives of caregivers and young adults suggest that fostering communication among family members about their respective concerns, perceptions, and goals could be valuable in identifying effective support strategies.

Limitations

This study contained several limitations. First, the amount of time each participant spoke varied, leading to a greater representation of the views of some focus group and interview participants. Further, the structure of the focus group and interview questions, which requested information about a range of concerns (such as anxiety, mood, and attention), necessitated follow-up prompts to encourage participants to elaborate on their responses. There was also a tendency for focus group participants to agree, potentially due to conformity and biases regarding social acceptability. While the dependability of data was likely minimally affected by these limitations (which are common in qualitative research), additional structure, balanced speaking time protocols, and opportunities to provide anonymous responses could enhance future studies. Interview data eliciting perspectives of young adults with CS were not available for analysis. Although enrollment was attempted with multiple participants, the videoconferencing format was challenging due to the need for verbal communication and ensuing anxiety. Future studies could design interview structures that better adapt to the needs of individuals with CS and CFC, such as having the interviewer be a familiar person, offering alternative response modalities, and limiting the use of open-ended questions.⁷⁵

Symptom overlap across specific mental health diagnoses occasionally made it difficult to assign the most appropriate code to every utterance (for instance, depressed or unstable mood and anger were coded separately, even though they can intersect). This limitation underscores the need for more focused studies on how mental health conditions manifest in RASopathies. Regarding perspectives on currently available treatments for individuals with RASopathies, conclusions about the potential efficacy of such treatments were not possible within this qualitative study. Both retrospective and prospective controlled studies using patient-reported outcomes could enhance knowledge regarding promising treatment avenues. We did not collect information from the participating caregivers regarding their own health history and whether they were diagnosed with a RASopathy; it is possible that caregivers who have a RASopathy themselves could have distinct perspectives as compared with those with children carrying de novo variants. Finally, interpretations regarding cross-syndrome differences were challenging due to small sample sizes for each individual diagnosis; future studies using survey-based methodologies or multinational recruitment could potentially reach larger cohorts.

Conclusion

This study identified a set of actionable items to inform research and practice that reflect the expressed needs and lived experiences of both patients with RASopathies and their caregivers (Table 3). Our results illuminate the barriers and facilitators that families frequently encounter, offering insights that can drive improvements in care access and elevate care standards. The findings also gesture toward critical future research directions. As the importance of patient-centered outcomes research is increasingly recognized, strong partnerships with patient communities will enhance the relevance and impact of treatment research in RASopathies and other underrepresented conditions.

Supplemental Material

sj-docx-1-trd-10.1177_26330040261427019 – Supplemental material for Patient and caregiver perspectives on neurodevelopmental and mental health care for RASopathies

Supplemental material, sj-docx-1-trd-10.1177_26330040261427019 for Patient and caregiver perspectives on neurodevelopmental and mental health care for RASopathies by Evelyn M. Elizondo, Anne M. Floyd, Allison M. H. Foy, Dante J. Rogers, Betül Çakır-Dilek, Megan Manternach, Jessica Simacek, Rebekah L. Hudock and Elizabeth I. Pierpont in Therapeutic Advances in Rare Disease

Supplemental Material

sj-docx-2-trd-10.1177_26330040261427019 – Supplemental material for Patient and caregiver perspectives on neurodevelopmental and mental health care for RASopathies

Supplemental material, sj-docx-2-trd-10.1177_26330040261427019 for Patient and caregiver perspectives on neurodevelopmental and mental health care for RASopathies by Evelyn M. Elizondo, Anne M. Floyd, Allison M. H. Foy, Dante J. Rogers, Betül Çakır-Dilek, Megan Manternach, Jessica Simacek, Rebekah L. Hudock and Elizabeth I. Pierpont in Therapeutic Advances in Rare Disease

Footnotes

Acknowledgements

We are greatly appreciative of RASopathy patient advocacy groups for their assistance with recruitment and wish to thank the individuals with RASopathies and caregivers who generously contributed to this study.

Declarations

ORCID iDs

Rebekah L. Hudock

Elizabeth I. Pierpont

Supplemental material

Supplemental material for this article is available online.

References

Belzer

Wright

Goodwin

, et al. Psychosocial considerations for the child with rare disease: a review with recommendations and calls to action. Children 2022; 9: 933.

Bogart

Hemmesch

Barnes

, et al. Healthcare access, satisfaction, and health-related quality of life among children and adults with rare diseases. Orphanet J Rare Dis 2022; 17: 196.

Witt

Schuett

Wiegand-Grefe

, et al. Living with a rare disease – experiences and needs in pediatric patients and their parents. Orphanet J Rare Dis 2023; 18: 242.

Tidyman

Rauen

KA.

The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 2009; 19: 230–236.

Kim

Baek

ST.

Neurodevelopmental aspects of RASopathies. Mol Cells 2019; 42: 441–447.

Kang

Lee

YS.

The impact of RASopathy-associated mutations on CNS development in mice and humans. Mol Brain 2019; 12: 96.

Rauen

KA.

The RASopathies. Annu Rev Genomics Hum Genet 2013; 14: 355–69.

Cesarini

Alfieri

Pantaleoni

, et al. Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade. Am J Med Genet A 2009; 149A: 140–6.

Pierpont

EI.

Neuropsychological functioning in individuals with Noonan syndrome: a systematic literature review with educational and treatment recommendations. J Ped Neuropsychol 2016; 2: 14–33.

10.

Hyman

Shores

North

KN.

The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 2005; 65: 1037–44.

11.

Geoffray

M-M

Falissard

Green

, et al. Autism spectrum disorder symptom profile across the RASopathies. Front Psychiatry 2021; 11: 585700.

12.

Foy

AMH

Hudock

Shanley

, et al. Social behavior in RASopathies and idiopathic autism. J Neurodev Disord 2022; 14: 5.

13.

Garg

Brooks

Burns

, et al. Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway. Dev Med Child Neurol 2017; 59: 544–549.

14.

Adviento

Corbin

Widjaja

, et al. Autism traits in the RASopathies. J Med Genet 2014; 51: 10–20.

15.

Naylor

Bruno

Shrestha

, et al. Neuropsychiatric phenotypes in children with Noonan syndrome. Dev Med Child Neurol 2023; 65: 1520–1529.

16.

Alfieri

Piccini

Caciolo

, et al. Behavioral profile in RASopathies. Am J Med Genet A 2014; 164A: 934–42.

17.

Perrino

Licchelli

Serra

, et al. Psychopathological features in Noonan syndrome. Eur J Paediatr Neurol 2018; 22: 170–177.

18.

McNeill

Hudock

Foy

AMH

, et al. Emotional functioning among children with neurofibromatosis type 1 or Noonan syndrome. Am J Med Genet A 2019; 179: 2433–2446.

19.

Axelrad

Schwartz

Katzenstein

, et al. Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review. Am J Med Genet C Semin Med Genet 2011; 157C: 115–22.

20.

Shikany

Baker

Stabley

, et al. Medically actionable comorbidities in adults with Costello syndrome. Am J Med Genet A 2020; 182: 130–136.

21.

Lion-Francois

Gueyffier

Mercier

, et al. The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis 2014; 9: 142.

22.

Mautner

Kluwe

Thakker

, et al. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol 2002; 44: 164–70.

23.

Houpt

Schwartz

Coover

RA.

Assessing psychiatric comorbidity and pharmacologic treatment patterns among patients with neurofibromatosis type 1. Cureus. Epub ahead of print 7 December 2021. DOI: 10.7759/cureus.20244.

24.

Dombi

Baldwin

Marcus

, et al. Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N Engl J Med 2016; 375: 2550–2560.

25.

Andelfinger

Marquis

Raboisson

, et al. Hypertrophic cardiomyopathy in noonan syndrome treated by MEK-inhibition. J Am Coll Cardiol 2019; 73: 2237–2239.

26.

Walsh

Wolters

Widemann

, et al. Impact of MEK Inhibitor therapy on neurocognitive functioning in NF1. Neurol Genet 2021; 7: e616.

27.

Acosta

Kardel

Walsh

, et al. Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study. Pediatr Neurol 2011; 45: 241–245.

28.

Bearden

Hellemann

Rosser

, et al. A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I. Ann Clin Transl Neurol 2016; 3: 266–279.

29.

Krab

LC.

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 2008; 300: 287.

30.

Mainberger

Jung

Zenker

, et al. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1. BMC Neurol 2013; 13: 131.

31.

Payne

Barton

Ullrich

, et al. Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. Neurology 2016; 87: 2575–2584.

32.

Van Der Vaart

Plasschaert

Rietman

, et al. Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol 2013; 12: 1076–1083.

33.

Ottenhoff

Mous

Castricum

, et al. Lamotrigine for cognitive deficits associated with neurofibromatosis type 1: a phase II randomized placebo-controlled trial. Dev Med Child Neurol 2024; dmcn.16094.

34.

Hardy

Berger

Griffin

, et al. Computerized working memory training for children with neurofibromatosis type 1 (NF1): a pilot study. J Child Neurol 2021; 36: 1078–1085.

35.

Vranceanu

Riklin

Merker

, et al. Mind-body therapy via videoconferencing in patients with neurofibromatosis: an RCT. Neurology 2016; 87: 806–14.

36.

Glad

Casnar

Yund

, et al. Adaptive behavior and executive functioning in children with neurofibromatosis type 1 using a mixed design. J Dev Behav Pediatr 2020; 41: 637–643.

37.

Yoncheva

Hardy

Lurie

, et al. Computerized cognitive training for children with neurofibromatosis type 1: a pilot resting-state fMRI study. Psychiatry Res Neuroimaging 2017; 266: 53–58.

38.

Martin

Wolters

Toledo-Tamula

, et al. Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: a pilot study of feasibility and preliminary efficacy. Am J Med Genet A 2016; 170: 1462–70.

39.

Roelofs

Wingbermuhle

Kessels

RPC

, et al. Social cognitive training for adults with Noonan syndrome: a feasibility study. Neuropsychiatr Treat 2019; 15: 611–626.

40.

Tiemens

Kleimeier

Leenders

, et al. The most important problems and needs of rasopathy patients with a noonan syndrome spectrum disorder. Orphanet J Rare Dis 2023; 18: 198.

41.

Perri

Viscogliosi

Trevisan

, et al. Parenting stress index in caregivers of individuals with Noonan syndrome. Am J Med Genet B Neuropsychiatr Genet 2024; e33009.

42.

Ganetsos

Farrelly

Magoulas

, et al. Stress and Coping in caregivers of children with RASopathies: assessment of the impact of caregiver conferences. J Pediatr Genet 2020; 9: 235–242.

43.

Gallai

Esposito

Marotta

, et al. Pediatric neurofibromatosis 1 and parental stress: a multicenter study. Neuropsychiatr Dis Treat 2014; 10: 141–146.

44.

Pierpont

Wolford

Behavioral functioning in cardiofaciocutaneous syndrome: risk factors and impact on parenting experience. Am J Med Genet A 2016; 170: 1974–88.

45.

Montanaro

FAM

Alfieri

Caciolo

, et al. Neuropsychological features in RASopathies: a pilot study on parent training program involving families of children with Noonan syndrome. Am J Med Genet C Semin Med Genet 2022; 190: 510–519.

46.

Solmi

Radua

Olivola

, et al. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Mol Psychiatry 2022; 27: 281–295.

47.

Jeste

Palmer

Appelbaum

, et al. A new brief instrument for assessing decisional capacity for clinical research. Arch Gen Psychiatry 2007; 64: 966.

48.

Hsieh

H-F

Shannon

SE.

Three approaches to qualitative content analysis. Qual Health Res 2005; 15: 1277–1288.

49.

Saunders

Sim

Kingstone

, et al. Saturation in qualitative research: exploring its conceptualization and operationalization. Qual Quant 2018; 52: 1893–1907.

50.

Davico

Borgogno

Campagna

, et al. Psychopathology and adaptive functioning in children, adolescents, and young adults with noonan syndrome. J Dev Behav Pediatr 2022; 43: e87–e93.

51.

Walsh

del Castillo

Kennedy

, et al. A review of psychological, social, and behavioral functions in the RASopathies. J Pediatr Neuropsychol 2020; 6: 131–142.

52.

O’Brien

Harris

Beckman

, et al. Standards for reporting qualitative research: a synthesis of recommendations. Acad Med 2014; 89: 1245–1251.

53.

Weissman

Cohen

Campbell

, et al. Developing recommendations for oversight of patient-centered outcomes research—The PCOROS Study. Patient-Centered Outcomes Research Institute (PCORI). Epub ahead of print 21 August 2020. DOI: 10.25302/08.2020.ME.140921701.

54.

Tong

Sainsbury

Craig

Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int J Qual Health Care 2007; 19: 349–357.

55.

Walsh

Family resilience: a framework for clinical practice. Fam Process 2003; 42: 1–18.

56.

Hamoy-Jimenez

Kim

Suppiah

, et al. Quality of life in patients with neurofibromatosis type 1 and 2 in Canada. Neuro-Oncol Adv 2020; 2: i141–i149.

57.

Coveney

Lambert

Living with Noonan Syndrome: Report of an online survey, https://hdl.handle.net/2134/22361122.v1 (2023, accessed 28 February 2025).

58.

Pierpont

Bennett

Schoyer

, et al. The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy. Am J Med Genet A 2023; ajmg.a.63477.

59.

Kontaridis

Roberts

Schill

, et al. The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery. Am J Med Genet A 2022; 188: 1915–1927.

60.

Serur

Russo

McGhee

, et al. Increased prevalence of psychiatric disorders in children with RASopathies: comparing NF1, Noonan syndrome spectrum disorder, and the general population. Genes 2025; 16: 843.

61.

Pride

Haebich

Walsh

, et al. Sensory processing in children and adolescents with neurofibromatosis Type 1. Cancers 2023; 15: 3612.

62.

Weaver

Gripp

KW.

Comprehensive care for patients with RASopathies. In: Rauen

(ed.) The RASopathies. Cham: Springer Nature Switzerland, pp. 307–317.

63.

Leoni

Viscogliosi

Tartaglia

, et al. Multidisciplinary management of costello syndrome: current perspectives. J Multidiscip Healthc 2022; 15: 1277–1296.

64.

Lalvani

Brown

Neurofibromatosis type 1: Optimizing management with a multidisciplinary approach. J Multidiscip Healthc 2024; 17: 1803–1817.

65.

Pierpont

Tworog-Dube

Roberts

AE.

Attention skills and executive functioning in children with Noonan syndrome and their unaffected siblings. Dev Med Child Neurol 2015; 57: 385–92.

66.

Budych

Helms

Schultz

How do patients with rare diseases experience the medical encounter? Exploring role behavior and its impact on patient–physician interaction. Health Policy 2012; 105: 154–164.

67.

Munro

Cook

Bogart

KR.

An inductive qualitative content analysis of stigma experienced by people with rare diseases. Psychol Health 2022; 37: 948–963.

68.

Payne

JM.

Neurocognitive therapies for monogenic conditions: Time for a new approach?

Dev Med Child Neurol 2024; dmcn.16129.

69.

van der Vaart

Overwater

Oostenbrink

, et al. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol 2015; 72: 1052–1060.

70.

Coveney

Salem

Living with Noonan Syndrome: Parents’ experiences of caring for a child with a rare genetic condition, https://www.noonansyndrome.org.uk/research/living-with-noonan-syndrome/ (2025, accessed 28 February 2025).

71.

Radtke

Berger

Skelton

, et al. Neurofibromatosis Type 1 (NF1): addressing the transition from pediatric to adult care. Pediatr Health Med Ther 2023; Volume 14: 19–32.

72.

Al Ghriwati

Little

Martin

, et al. Parent–child discrepancies in reports of child psychosocial functioning in neurofibromatosis type 1. J Fam Psychol. Epub ahead of print 17 October 2024. DOI: 10.1037/fam0001256.

73.

Little

Al Ghriwati

Siegel

, et al. A pilot acceptance and commitment intervention for parents of children with RASopathies. Clin Pract Pediatr Psychol 2025; 13: 37–48.

74.

Glad

Pardej

Olszewski

, et al. Pilot study of the effectiveness of a telehealth group for improving peer relationships for adolescents with neurofibromatosis type 1. Orphanet J Rare Dis 2024; 19: 115.

75.

Axelrad

Schwartz

Fehlis

, et al. Longitudinal course of cognitive, adaptive, and behavioral characteristics in Costello syndrome. Am J Med Genet A 2009; 149A: 2666–72.

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