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

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.

Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

“…Ras proteins expressed in the osteoprogenitor cells (Wang et al, 2011;Yu et al, 2005), have a key role controlling bone development and metabolism (Elefteriou et al, 2006;Kossler et al, 2011;Yang et al, 2006). The present study documents an impaired bone metabolism in CFCS, which is caused by upregulated function of the MAPK cascade, a major signaling pathway controlled by Ras proteins, suggesting that BMD alteration may represent a mechanism underlying such distinctive phenotype (Leoni et al, 2021;.…”

“…CFCS is characterized by a distinctive gestalt, a wide range of congenital heart defects, failure to thrive, mild-to-moderate intellectual disability, skin and ectodermal manifestations, and variable signs of musculoskeletal involvement. The musculoskeletal phenotype in CS and CFCS has been widely reported (Leoni et al, 2021;, and authors described a large overlap of clinical findings. Reduced bone mineral density (BMD) has been documented in NF1, NS, and CS (Baldassarre et al, 2017;Choudhry et al, 2012;Leoni et al, 2014;Reinker et al, 2011;Stevenson et al, 2007;Stevenson et al, 2008).…”

The RASopathies: from pathogenetics to therapeutics

“…Patients fail to thrive in the perinatal period due to swallowing difficulties and increased energy expenditure, and the gastrointestinal involvement progresses to include gastrointestinal reflux, oral aversion and constipation ( Leoni et al, 2016 ). CS patients have unique dermatological abnormalities including cutaneous papillomas ( Siegel et al, 2012 ), as well as a variety of musculoskeletal abnormalities, such as hypotonia, elbow contractures and laxity of the small joints ( Leoni et al, 2021 ). Like NS, CS also causes congenital heart defects, including HCM, septal defects and arrhythmias ( Lin et al, 2011 ).…”

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

“… 2 , 3 ). Musculoskeletal abnormalities such as hypotonia have also been reported in CS ( 4 ). Furthermore, HCM was observed in transgenic mutant Hras mouse models and in patients expressing constitutively active forms of HRAS ( 5 – 10 ); however, the molecular mechanisms linking HRAS activation with cardiac dysfunction remain unknown.…”