Abstract
BackgroundCostello syndrome (CS) and cardio-facio-cutaneous syndrome (CFCS) belong to the RASopathies, a group of neurodevelopmental disorders with skeletal anomalies. Due to their rarity, the characterization of the musculo-skeletal phenotype in both disorders has been poorly characterized.Patients and methodsHerein we reported data on orthopedic findings and functional status of a large sample of CS and CFCS patients. Thirty-four patients (CS = 17 and CFCS = 17) were recruited. Functional and disability evaluations were performed by assessing the 6-min walking test (6MWT) and Pediatric Outcomes Data Collection Instrument (PODCI). Genotype/phenotype correlation was also provided.ResultsOrthopedic manifestations are highly prevalent in CS and CFCS and 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 the MAP2K1/2 variant show different skeletal characteristics compared to BRAF variants, with a higher prevalence of orthopedic abnormalities. Functional assessment showed that patients with CS and CFCS reached lower values compared to the general population, with CFCS patients displaying the lowest scores.ConclusionsOrthopedic manifestations appear universal features of CS and CFCS and they can evolve across patients’ life. Longitudinal assessment of disability status by using 6MWT and PODCI could be useful to evaluate the functional impact of orthopedic manifestations on patients’ outcome and help planning a tailored treatment of these comorbidities.
Highlights
Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFCS) belong to the RASopathies, a group of neurodevelopmental disorders with skeletal anomalies
Functional assessment showed that patients with CS and CFCS reached lower values compared to the general population, with CFCS patients displaying the lowest scores
These conditions are grouped under the term RASopathies together with Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) and other emerging clinically related disorders, due to a common pathogenetic mechanism resulting in dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway [2]
Summary
Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFCS) belong to the RASopathies, a group of neurodevelopmental disorders with skeletal anomalies Due to their rarity, the characterization of the musculo-skeletal phenotype in both disorders has been poorly characterized. RAS/mitogen-activated protein kinase (MAPK) pathway, an intracellular signaling cascade playing a pivotal role in cell cycle regulation, differentiation, growth and senescence [1] These conditions are grouped under the term RASopathies together with Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) and other emerging clinically related disorders, due to a common pathogenetic mechanism resulting in dysregulation of the RAS/MAPK pathway [2]. Available data on skeletal anomalies in CS and CFCS have been collected during the International Costello Syndrome Conferences [8,9,10,11,12,13,14], but poor information is available about the function and disability level [8, 15] or daily living activities in these patients [16]
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