Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome

Johnson, Barbara; Goldberg-Strassler, Dina; Gripp, Karen W.; Thacker, Mihir M.; Leoni, Chiara; Stevenson, David A.

doi:10.1002/ajmg.a.36828

Cited by 24 publications

(36 citation statements)

References 13 publications

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“…The lower PODCI scale scores collected in CS and CFCS compared to normative data suggest how cognitive impairment, complex clinical history, neurological condition and musculoskeletal deformities have a great impact on the disability in RASopathies. Data on functional and disability status published by Johnson et al detected lower scores in CS compared to CFCS [14]. Interestingly, both Johnson's and our study did not detect a signi cant difference in the comfort and pain domains between syndromic patients and normative values.…”

Section: Discussioncontrasting

confidence: 54%

“…Coxa valga subluxans (CVS) was radiologically diagnosed when femoral neck-shaft angle was >140°. Functional and disability evaluations were performed by assessing the 6-minute walking test (6MWT) [16] in all patients with independent walking and by using the Pediatric Outcomes Data Collection Instrument (PODCI) [14,[17][18]. The 6MWT was used to measure the distance covered on a at and hard surface in a total of six minutes, to monitor overtime worsening of general status and deambulation [16].…”

Section: Methodsmentioning

confidence: 99%

“…The musculo-skeletal pro ling of NS and NF1 syndrome has previously been outlined in the medical literature [5][6][7], while incidence similar characterization is lacking for both CS and CFCS, possibly because their overall lower prevalence. Indeed, available data on skeletal anomalies in CS and CFCS have been collected during the International Costello Syndrome Conferences [8][9][10][11][12][13] and poor information is available about the function and disability level [8,14] or daily living activities in these patients [15].…”

Section: Introductionmentioning

confidence: 99%

“…Dr Romeo analysed and interpreted data, reviewed results and drafted the article. Drs Pelliccioni, Di Già, Onesimo and Giorgio Hip contractu res 2 (12) 2 (14) 0 (0) 0 (0) 6 (35)…”

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confidence: 99%

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Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: insights on the functional assessment status

Leoni

Romeo

Michele

et al. 2020

Preprint

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BackgroundCostello syndrome (CS) and cardio-facio-cutaneous syndrome (CFCS) belong to the RASopathies, a group of neurodevelopmental disorders with skeletal anomalies as associated features. Due to their rarity, the characterization of the musculo-skeletal phenotype in both CS and CFCS has been poorly characterized compared to other RASopathies. Patients and methodsHerein we assessed a thorough evaluation of orthopedic findings in CS and CFCS in a monocentric cohort of patients, including information about their functional status. A total of 34 patients with molecularly confirmed diagnosis of CS (N=17) and CFCS (N=17) were recruited. Data on orthopedic findings were collected by filling in a comprehensive checklist of 100 items assessment. Functional and disability evaluations were performed by assessing the 6-minute walking test (6MWT) in patients with independent walking and Pediatric Outcomes Data Collection Instrument (PODCI). Genotype/phenotype correlations were assessed taking into account available data in the literature. ResultsOrthopedic manifestations are highly prevalent in CS and CFCS, and do overlap in the two disorders. Overall, patients with CS harboring the recurrent HRAS Gly12Ser substitution show a more severe skeletal phenotype compared to patients carrying the Gly12Ala and Gly13Cys variants. Among CFCS patients, those with MAP2K1/2 mutations show different skeletal characteristics compared to BRAF variants, with a higher prevalence of orthopedic abnormalities. Generalized muscular hypotrophy is detected in most recruited patients. Functional assessment demonstrates that patients with CS and CFCS reach lower values compared to the general population with CFCS patients showing the lowest scores.ConclusionsOrthopedic manifestations appear universal features of CS and CFCS and they can evolve along patients’ life. Longitudinal assessment of disability status by using 6MWT and PODCI could be useful to evaluate the functional impact of orthopedic and neurological manifestations on patients’ outcome, and help monitoring planning a tailored treatment of these comorbidities.

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Section: Discussioncontrasting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Dr Romeo analysed and interpreted data, reviewed results and drafted the article. Drs Pelliccioni, Di Già, Onesimo and Giorgio Hip contractu res 2 (12) 2 (14) 0 (0) 0 (0) 6 (35)…”

mentioning

confidence: 99%

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Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: insights on the functional assessment status

Leoni

Romeo

Michele

et al. 2020

Preprint

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“…The only lysine acetylation site we identified in Ras WT and Ras G12V , that is located in a loop region, is K147 R (Figure 5A). Mutation of K147 in K-Ras has been found in human with Cardiofaciocutaneous syndrome 2 (CFC2), a multiple congenital anomaly disorder (Johnson et al, 2015;Myers et al, 2014;Stark et al, 2012). Importantly, this K147 R is part of the important G5/SAK motif needed for high affinity nucleotide binding.…”

Section: Although Arg and Lys Have Similar Physicochemical Propertiementioning

confidence: 99%

Insights into K-Ras 4B regulation by post-translational lysine acetylation

Knyphausen

Lang

Baldus

et al. 2016

Biological Chemistry

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Ras is a molecular switch cycling between an active, GTP-bound and an inactive, GDP-bound state. Mutations in Ras, mostly affecting the off-switch, are found in many human tumours. Recently, it has been shown that K-Ras 4B is targeted by lysine acetylation at K104. Based on results obtained for an acetylation mimetic Ras mutant (K104Q), it was hypothesised that K104-acetylation might interfere with its oncogenicity by impairing SOS-catalysed guanine-nucleotide exchange. We prepared site-specifically K104-acetylated K-Ras 4B and the corresponding oncogenic mutant protein G12V using the genetic-code expansion concept. We found that SOS-catalysed nucleotide exchange, also of allosterically activated SOS, was neither affected by acetylation of K104 in wildtype K-Ras 4B nor in the G12V mutant, suggesting that glutamine is a poor mimetic for acetylation at this site. In vitro, the lysine-acetyltransferases CBP and p300 were able to acetylate both, wildtype and G12V K-Ras 4B. In addition to K104 we identified further acetylation sites in K-Ras 4B, including K147, within the important G5/SAK-motif. However, the intrinsic and the SOS-catalysed nucleotide exchange was not affected by K147-acetylation of K-Ras 4B. Finally, we show that Sirt2 and HDAC6 do neither deacetylate K-Ras 4B if acetylated at K104 nor if acetylated at K147 in vitro.

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Behavioral functioning in cardiofaciocutaneous syndrome: Risk factors and impact on parenting experience

Pierpont

Wolford

2016

American J of Med Genetics Pt A

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The present study is an investigation of behavioral functioning in children with cardiofaciocutaneous syndrome (CFC). CFC is a rare single-gene disorder associated with cardiac disease, characteristic skin and facial features, intellectual disability, and neurological complications such as seizures and structural brain anomalies. Emotional and behavioral features of CFC have not been systematically investigated. We aimed to identify key variables that contribute to psychopathology during childhood and adolescence, and to examine the impact of challenging behaviors on the caregiving experience. Parents of 34 children and adolescents with CFC completed standardized broadband measures of child emotional and behavioral functioning, as well as measures of sensory modulation, functional communication, and caregiver stress. Results indicate that children with CFC syndrome are at heightened risk for psychopathology, with attention problems, social difficulties, and unusual behaviors (e.g., obsessive thoughts, strange behaviors, repetitive acts) found to be especially prevalent. Behavioral challenges in children with CFC syndrome were significantly associated with a history of obstetric complications and with problems modulating sensory information. With regard to the impact of child neurocognitive and behavioral issues on the caregiving experience, parent self-reported stress was significantly higher among parents of children who engaged in more problem behaviors, and lower among parents whose children could communicate effectively with others. Results of this study suggest avenues to help families cope with CFC-related stressors and enhance overall functioning. In particular, this study highlights the need for educational and treatment interventions aimed at addressing sensory needs, increasing functional communication, and identifying and managing challenging behaviors. © 2016 Wiley Periodicals, Inc.

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Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome

Cited by 24 publications

References 13 publications

Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: insights on the functional assessment status

Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: insights on the functional assessment status

Insights into K-Ras 4B regulation by post-translational lysine acetylation

Behavioral functioning in cardiofaciocutaneous syndrome: Risk factors and impact on parenting experience

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