See the published version of this preprint at Orphanet Journal of Rare Diseases.
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Research
Chiara Leoni
Fondazione Policlinico Universitario A. Gemelli, IRCCS
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4089-637X
License:
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Background
Costello 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 methods
Herein 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.
Results
Orthopedic 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.
Conclusions
Orthopedic 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.
Keywords
Costello syndrome, cardiofaciocutaneous syndrome, RASopathies, musculo-skeletal profiling, functional and disability assessment, genotype-phenotype correlation, patient-centered care, innovative biotechnologies, clinical biomarker, personalized medicine, tailored treatments
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Peer Review Timeline
CURRENT STATUS: Published
View the published article at Orphanet Journal of Rare Diseases.
No community comments so far
Editorial decision: Accept
On 03 Jan, 2021
Editor assigned
On 29 Dec, 2020
Submission checks complete
On 29 Dec, 2020
Editor invited
On 29 Dec, 2020
No comments provided
Editorial decision: Minor revision
On 12 Dec, 2020
Review #3 received
Received 06 Dec, 2020
Review #2 received
Received 05 Dec, 2020
Reviewer #5 agreed
On 01 Dec, 2020
Reviewer #4 agreed
On 01 Dec, 2020
Reviewer #3 agreed
On 29 Nov, 2020
Reviewer #2 agreed
On 28 Nov, 2020
Review #1 received
Received 15 Nov, 2020
Reviewers invited
Invitations sent on 09 Nov, 2020
Reviewer #1 agreed
On 09 Nov, 2020
Editor assigned
On 05 Nov, 2020
Submission checks complete
On 05 Nov, 2020
Editor invited
On 05 Nov, 2020
Version 1
Posted 29 Jun, 2020
No comments provided
Editorial decision: Major revision
On 15 Oct, 2020
Review #2 received
Received 14 Oct, 2020
Reviewer #2 agreed
On 29 Sep, 2020
Review #1 received
Received 20 Jul, 2020
Reviewer #1 agreed
On 28 Jun, 2020
Editor assigned
On 26 Jun, 2020
Reviewers invited
Invitations sent on 26 Jun, 2020
First submitted
On 25 Jun, 2020
Submission checks complete
On 25 Jun, 2020
Editor invited
On 25 Jun, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Internal Medicine
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at Orphanet Journal of Rare Diseases.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Chiara Leoni
Fondazione Policlinico Universitario A. Gemelli, IRCCS
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4089-637X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Orphanet Journal of Rare Diseases.
No community comments so far
Editorial decision: Accept
On 03 Jan, 2021
Editor assigned
On 29 Dec, 2020
Submission checks complete
On 29 Dec, 2020
Editor invited
On 29 Dec, 2020
No comments provided
Editorial decision: Minor revision
On 12 Dec, 2020
Review #3 received
Received 06 Dec, 2020
Review #2 received
Received 05 Dec, 2020
Reviewer #5 agreed
On 01 Dec, 2020
Reviewer #4 agreed
On 01 Dec, 2020
Reviewer #3 agreed
On 29 Nov, 2020
Reviewer #2 agreed
On 28 Nov, 2020
Review #1 received
Received 15 Nov, 2020
Reviewers invited
Invitations sent on 09 Nov, 2020
Reviewer #1 agreed
On 09 Nov, 2020
Editor assigned
On 05 Nov, 2020
Submission checks complete
On 05 Nov, 2020
Editor invited
On 05 Nov, 2020
Version 1
Posted 29 Jun, 2020
No comments provided
Editorial decision: Major revision
On 15 Oct, 2020
Review #2 received
Received 14 Oct, 2020
Reviewer #2 agreed
On 29 Sep, 2020
Review #1 received
Received 20 Jul, 2020
Reviewer #1 agreed
On 28 Jun, 2020
Editor assigned
On 26 Jun, 2020
Reviewers invited
Invitations sent on 26 Jun, 2020
First submitted
On 25 Jun, 2020
Submission checks complete
On 25 Jun, 2020
Editor invited
On 25 Jun, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Internal Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Orphanet Journal of Rare Diseases.
Background
Costello 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 methods
Herein 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.
Results
Orthopedic 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.
Conclusions
Orthopedic 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.
Figure 1
Figure 2
Figure 3
This is a list of supplementary files associated with this preprint. Click to download.
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