Abstract
Costello syndrome (CS) is a rare RASopathy that is typically associated with mild to moderate cognitive impairment. Based on detailed neuropsychological testing, this case series describes variability in the neurobehavioral presentations of three unrelated individuals with different pathogenic HRAS variants that cause CS. Results demonstrate a wide range of functioning among people with CS (extremely low to superior ranges) and describe the first cognitive testing results for an individual with HRAS c.179G>A, p.Gly60Asp. Patient-reported social, emotional, and quality of life outcomes also are discussed. These cases highlight the potential for above average cognitive functioning, the importance of flexible neurobehavioral assessment methods, and key quality of life and mental health domains to evaluate in individuals with CS.
Keywords: case report, cognition, Costello syndrome, emotional, social
1 |. Background
Costello Syndrome (CS) is a rare RASopathy caused by pathogenic germline variation in the HRAS gene. RASopathies are a group of genetic disorders due to germline variants in the Ras/mitogen-activated protein kinase (MAPK) pathway and encompass many conditions (Rauen 2013). Due to underlying activation of RAS/MAPK signaling, these syndromes are associated with common clinical conditions, including craniofacial anomalies, failure to thrive, neurocognitive impairment, and increased cancer risk (Rauen 2013).
While research is limited, neuropsychological studies of people with CS suggest considerable variability in cognitive skills, most likely associated with an individual’s specific genetic variant (Axelrad et al. 2007, 2009). Generally, CS is characterized by neurodevelopmental delay and overall intellectual disability, usually in the mild to moderate range (Axelrad et al. 2007, 2009). Nonverbal reasoning appears to be an area of relative strength (Axelrad et al. 2007, 2009).
Individuals with CS are more likely to experience internalizing problems (e.g., anxiety) than externalizing problems (e.g., hyperactivity) (Axelrad et al. 2004, 2011), and these difficulties may improve with age (Galéra et al. 2006). Overall adaptive functioning is generally commensurate with intellectual ability and can vary widely across domains (Axelrad et al. 2004), with social skills being a relative strength (Axelrad et al. 2009). Considering the potential for cognitive difficulties (Axelrad et al. 2011), differential appearance (Siegel et al. 2012), and increased pain (Leoni et al. 2019), individuals with CS are at heightened risk for poorer quality of life (QoL) (Hopkins et al. 2010). Using a non-validated measure for adolescents and young adults (AYAs) with CS, parents rated their child’s life satisfaction and QoL as significantly lower than the AYA’s self-reports (Hopkins et al. 2010). Specific areas of difficulty included relationships and independence.
As RASopathies are rare, case series can offer insight into the wide range of phenotypic presentations (Gripp et al. 2015; Pierpont et al. 2017). This case series shows the wide range of functioning within individuals with CS as assessed by a neuropsychological evaluation.
2 |. Editorial Policies and Ethical Considerations
Participants provided informed consent to participate in the National Cancer Institute’s IRB-approved protocol “Clinical, Genetic, and Epidemiologic Study of Children and Adults with RASopathies” (NCT04888936). Inclusion as an individual with a RASopathy required a clinical or molecular diagnosis of a RASopathy (excluding NF1), and family members of individuals diagnosed with a RASopathy also were eligible for enrollment. Investigators recruited participants from various sources, including websites, patient advocacy and support groups, and referrals from medical providers. A subset of enrolled individuals was invited to the National Institutes of Health Clinical Center for a week-long visit of multidisciplinary evaluations. As part of this study, a psychology associate or licensed psychologist administered an assessment battery designed for the protocol consisting of age-appropriate standardized cognitive tests and validated patient- and parent-reported outcome measures. This case series describes all participants with CS who received neuropsychological evaluations to date. These participants provided additional written consent to have their results and background information published in a de-identified manner. A summary of each patient’s relevant medical history is available in Supporting Information. All patients who are presented in this manuscript have participated in other RASopathy-related research studies.
3 |. Clinical Reports
3.1 |. Patient 1
Patient 1 is a 13-year-old, White, non-Hispanic adolescent boy with CS (HRAS c.34G>A, p.G12S). The patient had early developmental delays in sitting, walking, crawling, and speaking. He received early intervention; occupational therapy was started at 2 months old for feeding, physical therapy was started at 1 year for torticollis, and speech-language pathology was started at 1.5 years.
At the time of the neuropsychological assessment, the patient was in middle school. He received educational support (i.e., time in a mainstream classroom with an aide and time in a self-contained classroom). The patient had a history of neurodevelopmental disorder with moderate intellectual impairment; delays in reading, writing, and math; absence seizures; and migraines reportedly related to anxiety. The patient’s parents noted that their primary concern was the child’s clinically significant anxiety, which was being treated with daily fluoxetine, mirtazapine, and clonazepam as needed.
The p.G12S HRAS variant is the most common and is generally associated with intellectual disability (Axelrad et al. 2007). Patient 1’s test results revealed intellectual functioning below the performance of same-aged peers (Table 1), consistent with previous reports. Performance was mostly consistent across domains, with impaired performance on measures of processing speed, immediate attention, verbal learning, verbal memory recognition, working memory, and cognitive flexibility. This testing performance aligns with the parent’s report on validated measures of executive functioning and attention (Table 2). A relative strength was Patient 1’s ability to recall newly learned verbal information after a delay (low average range).
TABLE 1 |.
Cognitive testing results for all patients.
| Patient 1 | Patient 2 | Patient 3 | |
|---|---|---|---|
|
| |||
| General intellectual functioning: Wechsler Abbreviated Scale of Intelligence—Version 2 | |||
| Vocabulary (scaled) | Extremely low (1) | Average (10) | High average (13) |
| Matrix Reasoning (scaled) | Extremely low (2) | Not applicable | Average (11) |
| Full Scale IQ (standard) | Extremely low (53) | VCI = Average (95) | High average (111) |
| Attention, working memory, and processing speed: Wechsler Intelligence Scale for Children—Version 5 and Wechsler Adult Intelligence Scale—Version 4 (scaled scores) | |||
| Digit Span Total | Extremely low (1) | Low average (6) | Low average (6) |
| Forwards | Extremely low (1) | Low average (6) | Average (8) |
| Backwards | Extremely low (1) | Average (8) | Average (8) |
| Sequencing | Extremely low (1) | Average (8) | Borderline (5) |
| Symbol Search | Extremely low (1) | Not applicable | High average (13) |
| Cancellation | Extremely low (1) | Not applicable | Low average (7) |
| Verbal fluency: Delis–Kaplan Executive Functioning System (scaled scores) | |||
| Semantic Fluency | Extremely low (2) | Superior (15) | Average (10) |
| Categorical Fluency | Extremely low (1) | Superior (15) | Superior (15) |
| Category Switching Total | Extremely low (1)/ | Average (10)/ | Superior (15)/ |
| Correct/Accuracy | Extremely low (1) | Average (10) | High average (13) |
| Verbal learning and memory: Wide Range Assessment of Memory and Learning—Version 3 (scaled scores) | |||
| Verbal Learning | Extremely low (3) | Average (12) | — |
| Verbal Learning Delayed | Low average (6) | High average (14) | — |
| Verbal Learning Recognition | Extremely low (2) | High average (13) | — |
| Adaptive behavior: Vineland-3 Comprehensive Parent Interview (standard score) | |||
| Adaptive Behavior Composite | Extremely low (64) | Extremely low (61) | Not applicablea |
| Communication | Borderline (70) | Borderline (79) | Not applicable |
| Daily living skills | Extremely low (66) | Extremely low (24) | Not applicable |
| Socialization | Extremely low (56) | Borderline (75) | Not applicable |
Note: Scaled scores: Mean (M) = 10, standard deviation (SD) = 3. Standard scores: M = 100, SD = 15. While tests have different descriptive classifications, the qualitative descriptors were matched to the Wechsler Scale recommendations for ease for the reader.
Abbreviations: —, missing data (the measure was added to the battery following this participant’s testing); VCI, Verbal Comprehension Index.
The Vineland-3 was not administered since the patient is an independent adult.
TABLE 2 |.
Patient and parent-reported outcome measures.
| Patient 1 | Patient 2 | Patient 3 | |
|---|---|---|---|
|
| |||
| Mental health and physical health: Patient-Reported Outcomes Measurement Information System (PROMIS;T scores) | |||
| Anxiety | Self: Mild (52.69) Parent: Severe (66.92) |
WNL (51.36) | Follow-up: Mild (58.32) |
| Fatigue | Self: WNL (30.06) Parent: Moderate (58.38) |
WNL (42.31) | Follow-up: WNL (47.38) |
| Sleep Disturbance | Self: WNL (43.68) Parent: WNL (55.17) |
WNL (46.25) | Follow-up: WNL (45.38) |
| Depression | Self: WNL (41.27) Parent: Mild (55.93) |
WNL (38.19) | Baseline: WNL (37.10) Follow-up: WNL (38.19) |
| Mobility | Self: Moderate (37.42) Parent: Moderate (31.54) |
Mild (41.92) | Follow-up: Mild (56.73) |
| Upper Extremity | Self: Severe (18.81) Parent: Severe (21.04) |
Severe (28.51) | Follow-up: WNL (54.14) |
| Executive Functioning: Behavior Rating Inventory of Executive Functioning (BRIEF-2, BRIEF-A; T scores) | |||
| Global Executive Composite | Parent: Clinically elevated (70) | WNL (55) | Follow-up: WNL (45) |
| Behavior Regulation Index | Parent: Potentially clinically elevated (66) | WNL (52) | Follow-up: WNL (43) |
| Emotion Regulation Index | Parent: Clinically elevated (73) | Meta-cognition Index: WNL (56) | Meta-cognition Index at follow-up: WNL (47) |
| Cognitive Regulation Index | Parent: Potentially clinically elevated (66) | ||
| Individual Measures | |||
| Conners-3 Parent Short Form (T scores) | Inattention: Very elevated (71) Hyperactivity/Impulsivity: Very elevated (84) |
Not applicable | Not applicable |
| Self-reported stress (Rating of Overall Stress Scale) | Not applicable | Mild (3/10) | Baseline: Moderate (6/10) Follow-up: Moderate (7/10) |
| Pain intensity (Numeric Rating Scale-11) | Self: Low (3/10) | High (7/10) | Baseline: No pain (0/10) Follow-up: Low (1/10) |
| Pain Interference Index | Self: None (0/6) Parent: Mild (1/6) |
Moderate (3.67/6) | Follow-up: Mild (0.16/6) |
| Social impairment: Social Responsiveness Scale—Second Edition (SRS-2;T scores) | |||
| Total | Parent: Severe (70) | WNL (59) | Baseline: WNL (41) Follow-up: WNL (42) |
| Social Communication and Interaction | Parent: Moderate (66) | WNL (59) | Baseline: WNL (41) Follow-up: WNL (41) |
| Restricted Interests and Repetitive Behaviors | Parent: Severe (80) | Mild (60) | Baseline: WNL (43) Follow-up: WNL (47) |
| Pediatric Quality of Life (PedsQL)—Generic, Acute Version (raw scores 0–100) | |||
| Total | Self: WNL (77.17) Parent: AR (47.83) |
69.57 | Baseline: 100.00 Follow-up: 94.57 |
| Physical Health | Self: AR (59.38) Parent: AR (37.50) |
46.88 | Baseline: 100.00 Follow-up: 100.00 |
| Emotional Health | Self: WNL (90.00) Parent: AR (60.00) |
85.00 | Baseline: 100.00 Follow-up: 100.00 |
| Social Functioning | Self: WNL (90.00) Parent: AR (40.00) |
65.00 | Baseline: 100.00 Follow-up: 100.00 |
| School/Work Functioning | Self: WNL (80.00) Parent: WNL (60.00) |
95.00 | Baseline: 100.00 Follow-up: 75.00 |
Note: T scores: M = 50, SD = 10. WNL = Within normal limits, AR = At risk. PedsQL: Higher scores represent higher QoL; published pediatric cut-off scores are used to determine AR categories (Varni et al. 2003). PROMIS: Higher scores represent more of the construct; cut-off scores presented on the Health Measures website were used to determine mild, moderate, and severe categories.
On validated patient-reported and parent-reported outcome measures (Table 2), Patient 1’s self-reported QoL was higher than the parent’s report, consistent with research highlighting differences in parent proxy and child self-report generally (Varni et al. 2003) and in those with CS specifically (Hopkins et al. 2010). Patient 1 reported high levels of emotional health and social functioning and moderately high levels of school functioning. The patient identified mild anxiety symptoms and challenges with mobility, upper extremity strength, and physical health QoL. The parent reported substantial challenges in the patient’s physical health and social functioning, moderate challenges in emotional health and school functioning, mild depressive symptoms, and clinically elevated anxiety symptoms.
Patient 1’s parent-reported adaptive behavior was extremely low compared to same-aged peers. However, this impairment represents a strength in context of the patient’s moderate cognitive impairment. The “community” subdomain was adequate, highlighting a relative strength in adaptive skills outside of home (e.g., when traveling, navigating safety issues). The parent also endorsed severely restricted interests and repetitive behaviors and moderate difficulties in social communication and interaction. Such features of autism spectrum disorder are common among children with RASopathies, including CS, but these behaviors may lessen over time (Schwartz et al. 2017). In a qualitative survey completed about Patient 1’s strengths, the parent highlighted the patient’s sense of humor, love for playing, positive relationships, and expression of love for family.
3.2 |. Patient 2
Patient 2 is a 30-year-old, White, non-Hispanic man with CS (HRAS, c.37G>T, p.G13C). The patient has a history of Chiari 1 malformation and visual impairment (optic nerve atrophy, nystagmus, photophobia, and rod-cone dystrophy leading to being categorized as legally blind). A previous neuropsychological evaluation diagnosed the patient with mild intellectual disability, a diagnosis informed by testing that included visual measures without apparent accommodations. Patient 2 reported a history of reading and math learning disabilities. When receiving accommodations in school (enlarged print, sitting in the front row, extended testing time, and a scribe for notes and test-taking), the patient reported average high school and college academic performance. The patient earned an associate degree and a bachelor’s degree. Patient 2 has a history of anxiety, which was treated with escitalopram.
The p.G13C HRAS variant has been associated with a milder phenotype and cognitive performance “well above the Costello mean in multiple areas” (Axelrad et al. 2011, 119). Also, individuals with this variant have demonstrated average performance in nonverbal fluid reasoning (Axelrad et al. 2009, 2011). The examiners in this study chose to remove visual measures to reduce confounding intellectual capabilities with visual impairment. Patient 2’s verbally mediated cognitive functioning was in the average to above average range when compared to the general population. He had a relative weakness in a measure of attention (low average range) and a strength in verbal fluency (superior range).
In contrast to his cognitive test performance, his overall adaptive behavior composite was extremely low compared to the general population. The patient’s adaptive behavior was likely impacted by visual impairment, as scores among people with visual impairment are approximately one standard deviation lower than matched controls across domains and subdomains (Sparrow et al. 2016). Patient 2 demonstrated relative strengths in communication and socialization (borderline) compared to daily living skills (extremely low). This relative strength in socialization skills is consistent with previous research (Axelrad et al. 2011). For the socialization subdomains, coping skills were adequate, whereas interpersonal relationships were moderately low, and leisure skills were low. Receptive and expressive communication were adequate, while written communication was low, reflecting the impact of visual impairment. All subdomains within daily living skills were low, likely related to visual impairment and assistance in daily tasks by others despite the patient’s ability to complete some tasks independently.
Regarding social–emotional health, Patient 2’s report was within normal limits on most measures. Patient 2 reported high pain intensity and moderate pain interference, which he attributed to headaches possibly related to his Chiari 1 malformation. The patient reported mild difficulties with mobility and severe difficulties with upper extremity strength. His QoL was most impacted in the domains of physical health and social functioning related to interpersonal relationships and doing things his peers can do. No maladaptive behaviors were reported.
3.3 |. Patient 3
Patient 3 is a 23-year-old, White, non-Hispanic woman with attenuated CS (HRAS c. 179G>A, p.Gly60Asp). The patient was born prematurely and was hospitalized in the neonatal intensive care unit for approximately 2 months for respiratory distress, cardiac arrhythmia, hypoglycemia, and reflux. There was no reported history of cognitive delay, developmental delay, or academic difficulties. The patient received a bachelor’s degree and was working as a scientific program analyst at a research hospital at the time of testing.
The c.179G>A, p.Gly60Asp HRAS variant is associated with an attenuated phenotype, such as that described in Gripp et al. (2015). Formal cognitive testing for this genotype has not yet been reported. Patient 3’s cognitive test results were in the average to the above average range. The patient’s general intellectual functioning was high average, with better performance in verbal measures than nonverbal measures. Working memory was variable, with one measure being in the borderline range, while another was in the average range. Processing speed also was in the average range. Verbal fluency was a strength, with scores in the high average to superior range on both categorical fluency and category switching.
Patient 3 was given the initial subset of patient-reported outcome measures during neuropsychological testing and all those in the current battery at a 2-year follow-up. Self-reported social–emotional functioning and QoL were within normal limits, although the patient did endorse high stress.
4 |. Discussion
This case series highlights a wide range of functional abilities among individuals with CS with different HRAS variants assessed to date in an ongoing natural history study. The three individuals who completed neurobehavioral assessments demonstrated varying cognitive profiles, with one adolescent in the extremely low range, one adult in the average range for verbal measures, and one adult with attenuated CS in the average to above average range. The participants also reported varying QoL and social–emotional functioning. Participants’ perceived QoL scores ranged from low to high. Two participants had lower physical health QoL than other domains, while one participant reported more difficulties with school and work functioning than other domains. Participants also reported a range of pain intensity and pain interference; future research should continue to investigate experiences of pain in individuals with CS. As participants reported a range of stress and two reported histories of anxiety, further investigation of mental health needs and outcomes among individuals with CS is warranted. Since these participants were selected to be part of a clinical research cohort, the sample is biased; nevertheless, these cases demonstrate the range of cognitive functioning in individuals with CS.
5 |. Relevance to Clinical Practice
Given the diversity of neurobehavioral phenotypic presentations, there is a need for providers to have flexibility in neurobehavioral assessments with this population. For example, Patient 2’s testing highlights the importance of appropriate accommodations in neurobehavioral assessments, as administering measures dependent on vision in the current evaluation would have vastly underestimated his cognitive ability. In clinical practice, providers are encouraged to be aware of physical limitations and use tasks appropriate to patients’ abilities to further explore various domains of cognitive functioning (e.g., processing speed, problem solving, etc.). Furthermore, repeated evaluations are recommended to monitor functioning over time, and targeted interventions should be implemented throughout the lifespan to improve weaknesses and build on strengths to maximize the long-term outcomes of these individuals.
In addition, these neurobehavioral evaluations highlight domains of social–emotional functioning and QoL that are important to assess clinically in patients with CS. In light of participants’ reports of stress and histories of clinically significant anxiety, it is recommended that individuals with CS receive regular assessment of, and individualized treatment for, social–emotional concerns and stress. This treatment may include psychotherapy, social skills training, and medication, which may be overlooked due to other ongoing physical and cognitive needs. Participants also reported a wide range of pain interference and pain intensity. Clinicians and researchers are encouraged to include measures to assess pain in evaluations of these patients so that it can be addressed and treated appropriately.
Finally, although intellectual disability is a common finding in CS, the possibility of average to above average cognitive skills should be included in the description to acknowledge more fully the range of functioning and expand the expectations for individuals with CS. While average cognitive functioning has been reported in research (Axelrad et al. 2011) and in clinical guidelines (Gripp et al. 2019), the possibility of above average cognitive skills when compared to the general population has not been described. In addition, most patient-facing medical websites describe intellectual disability as a feature of CS, without mentioning the potential of average cognitive skills given the variant (e.g., “All people with Costello syndrome have intellectual disabilities. This often ranges from mild to moderate impairment”). There are relationships between specific HRAS pathogenic variants and neurobehavioral outcomes and unique phenotypic presentations among individuals with attenuated CS (Axelrad et al. 2009; Gripp et al. 2015). Thus, providers should consider the specific variant when counseling patients about expected intellectual and adaptive functioning.
Supplementary Material
Supporting Information
Additional supporting information can be found online in the Supporting Information section. Data S1: Supporting Information.
Acknowledgments
The authors thank the participants who contributed to the study. We also thank the Advancing RAS/RASopathies Therapies (ART) team and Brigit Rweikiza, Jada Lawrence, and Jayla Melvin.
Funding
This research is supported by the Intramural Research Program of the National Institutes of Health, Divisions of Cancer Epidemiology and Genetics and the Center for Cancer Research of the National Cancer Institute, Bethesda, MD. The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
Footnotes
Conflicts of Interest
The authors declare no conflicts of interest.
Ethics Statement
This study was reviewed and approved by the National Institutes of Health Institutional Review Board (IRB 20C0107).
Consent
All participants provided informed consent prior to participating in the study.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- Axelrad ME, Glidden R, Nicholson L, and Gripp KW 2004. “Adaptive Skills, Cognitive, and Behavioral Characteristics of Costello Syndrome.” American Journal of Medical Genetics, Part A 128A, no. 4: 396–400. 10.1002/ajmg.a.30140. [DOI] [Google Scholar]
- Axelrad ME, Nicholson L, Stabley DL, Sol-Church K, and Gripp KW 2007. “Longitudinal Assessment of Cognitive Characteristics in Costello Syndrome.” American Journal of Medical Genetics, Part A 143A, no. 24: 3185–3193. 10.1002/ajmg.a.31968. [DOI] [PubMed] [Google Scholar]
- Axelrad ME, Schwartz DD, Fehlis JE, et al. 2009. “Longitudinal Course of Cognitive, Adaptive, and Behavioral Characteristics in Costello Syndrome.” American Journal of Medical Genetics, Part A 149A, no. 12: 2666–2672. 10.1002/ajmg.a.33126. [DOI] [Google Scholar]
- Axelrad ME, Schwartz DD, Katzenstein JM, Hopkins E, and Gripp KW 2011. “Neurocognitive, Adaptive, and Behavioral Functioning of Individuals With Costello Syndrome: A Review.” American Journal of Medical Genetics, Part C 157, no. 2: 115–122. 10.1002/ajmg.c.30299. [DOI] [Google Scholar]
- Galéra C, Delrue MA, Goizet C, et al. 2006. “Behavioral and Temperamental Features of Children With Costello Syndrome.” American Journal of Medical Genetics, Part A 140, no. 9: 968–974. 10.1002/ajmg.a.31169. [DOI] [Google Scholar]
- Gripp KW, Morse LA, Axelrad M, et al. 2019. “Costello Syndrome: Clinical Phenotype, Genotype, and Management Guidelines.” American Journal of Medical Genetics, Part A 179, no. 9: 1725–1744. 10.1002/ajmg.a.61270. [DOI] [Google Scholar]
- Gripp KW, Sol-Church K, Smpokou P, et al. 2015. “An Attenuated Phenotype of Costello Syndrome in Three Unrelated Individuals With a HRAS c.179G>A (p.Gly60Asp) Mutation Correlates With Uncommon Functional Consequences.” American Journal of Medical Genetics, Part A 167, no. 9: 2085–2097. 10.1002/ajmg.a.37128. [DOI] [Google Scholar]
- Hopkins E, Lin AE, Krepkovich KE, et al. 2010. “Living With Costello Syndrome: Quality of Life Issues in Older Individuals.” American Journal of Medical Genetics, Part A 152A, no. 1: 84–90. 10.1002/ajmg.a.33147. [DOI] [Google Scholar]
- Leoni C, Triumbari EKA, Vollono C, et al. 2019. “Pain in Individuals With RASopathies: Prevalence and Clinical Characterization in a Sample of 80 Affected Patients.” American Journal of Medical Genetics, Part A 179, no. 6: 940–947. 10.1002/ajmg.a.61111. [DOI] [Google Scholar]
- Pierpont EI, Semrud-Clikeman M, and Pierpont ME 2017. “Variability in Clinical and Neuropsychological Features of Individuals With MAP2K1 Mutations.” American Journal of Medical Genetics Part A 173, no. 2: 452–459. 10.1002/ajmg.a.38044. [DOI] [Google Scholar]
- Rauen KA 2013. “The RASopathies.” Annual Review of Genomics and Human Genetics 14, no. 1: 355–369. 10.1146/annurev-genom-091212-153523. [DOI] [Google Scholar]
- Schwartz DD, Katzenstein JM, JHighley E, et al. 2017. “Age-Related Differences in Prevalence of Autism Spectrum Disorder Symptoms in Children and Adolescents with Costello Syndrome.” American Journal of Medical Genetics Part A 173, no. 5: 1294–1300. Portico. 10.1002/ajmg.a.38174. [DOI] [Google Scholar]
- Siegel D, Mann J, Krol A, and Rauen K 2012. “Dermatological Phenotype in Costello Syndrome: Consequences of Ras Dysregulation in Development.” British Journal of Dermatology 166, no. 3: 601–607. 10.1111/j.1365-2133.2011.10744.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sparrow SS, Saulnier CA, Cicchetti DV, and Doll EA 2016. Vineland-3: Vineland Adaptive Behavior Scales Manual. 3rd ed. Pearson Assessments. [Google Scholar]
- Varni JW, Burwinkle TM, Seid M, and Skarr D 2003. “The PedsQL* 4.0 as a Pediatric Population Health Measure: Feasibility, Reliability, and Validity.” Ambulatory Pediatrics 3, no. 6: 329–341. 10.1367/1539-4409(2003)003<0329:TPAAPP>2.0.CO;2. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.