Antonio Valassina1,2, Giuseppe Zampino3,1, Chiara Leoni4, Domenico Marco Romeo5, Michele Pelliccioni3, Mariangela Di Già3, Roberta Onesimo3, Valentina Giorgio3, Elisabetta Flex6, Marta Tedesco3, Marco Tartaglia7, Donato Rigante3,1. 1. Università Cattolica Sacro Cuore, Rome, Italy. 2. Unit of Neurophysiopathology and Sleep Medicine, Neurosciences and Orthopedics, Department of Geriatrics, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 3. Center for Rare Diseases and Birth Defects, Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Gemelli 8, 00168, Rome, Italy. 4. Center for Rare Diseases and Birth Defects, Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Gemelli 8, 00168, Rome, Italy. chiara.leoni@policlinicogemelli.it. 5. Pediatric Neurology Unit, Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 6. Department of Oncology and Molecular Medicine, Istituto Superiore Di Sanità, Rome, Italy. 7. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Abstract
BACKGROUND: 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. PATIENTS AND METHODS: Herein 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. RESULTS: Orthopedic 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. CONCLUSIONS: Orthopedic 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.
BACKGROUND: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. PATIENTS AND METHODS: Herein 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. RESULTS: Orthopedic manifestations are highly prevalent in CS and CFCS and overlap in the two disorders. Overall, patients with CS harboring the recurrent HRASGly12Ser 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. CONCLUSIONS: Orthopedic 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.
Authors: Karen W Gripp; Lindsey A Morse; Marni Axelrad; Kathryn C Chatfield; Aaron Chidekel; William Dobyns; Daniel Doyle; Bronwyn Kerr; Angela E Lin; David D Schwartz; Barbara J Sibbles; Dawn Siegel; Suma P Shankar; David A Stevenson; Mihir M Thacker; K Nicole Weaver; Sue M White; Katherine A Rauen Journal: Am J Med Genet A Date: 2019-06-20 Impact factor: 2.802
Authors: Marni E Axelrad; David D Schwartz; Jennifer M Katzenstein; Elizabeth Hopkins; Karen W Gripp Journal: Am J Med Genet C Semin Med Genet Date: 2011-04-14 Impact factor: 3.908
Authors: Mary Ella M Pierpont; Pilar L Magoulas; Saleh Adi; Maria Ines Kavamura; Giovanni Neri; Jacqueline Noonan; Elizabeth I Pierpont; Kent Reinker; Amy E Roberts; Suma Shankar; Joseph Sullivan; Melinda Wolford; Brenda Conger; Molly Santa Cruz; Katherine A Rauen Journal: Pediatrics Date: 2014-09-01 Impact factor: 7.124