Layout 1 Reply to: MYH3 mutation and scoliosis Eur J Transl Myol 35 (3) 14034, 2025 doi: 10.4081/ejtm.2025.14034 Dear Editor, We appreciate the valuable comments regarding our recent case report on a 15-year-old girl presenting with scoliosis, growth retardation, facial dysmorphism, and delayed pu- berty, who was found to carry the heterozygous NM_ 002470.4(MYH3):c.326G>A (p.Arg109His) variant.1 We welcome the opportunity to address the concerns raised and to further clarify aspects of our study, as constructive scientific dialogue is important for refining our under- standing of the pathophysiology of scoliosis. We acknowledge that the pathogenicity of the genetic variant has not been definitively established. MYH3 vari- ants have been implicated in a variety of phenotypic pre- sentations, ranging from severe congenital syndromes to milder musculoskeletal abnormalities.2,3 Our patient ex- hibited subtle facial dysmorphism and musculoskeletal abnormalities. She did not present any additional dys- morphic features beyond those described in our report. Given her unusual phenotype, the diagnosis was even more challenging, and this may be one of the reasons why a diagnosis was made at age 15. Our case study contrib- utes to expanding the known clinical spectrum and raises the possibility that this specific variant may have incom- plete penetrance or variable expressivity. Importantly, our work does not suggest a causal relation between the MYH3 variant and rapidly progressing scoliosis, but it raises the possibility that scoliosis may be one of the clin- ical presentations of the disease. Therefore, we suggest that a rapidly developing scoliosis, coupled with other rel- evant clinical signs, should be taken into account as a pos- sible indicator of syndromes that require additional investigation.4,5 No information on first-degree relatives or on the clinical history of the patient are reported in the original work be- cause the primary objective of our case report is to high- light how a musculoskeletal deformity, such as scoliosis, may serve as a clinical marker of underlying pathological conditions warranting further investigation, rather than to provide a complete characterization of this specific case of MYH3 variant. The patient was referred to our rehabili- tation service at the University Hospital of Padua due to rapidly progressing scoliosis. As part of a broader study investigating idiopathic scoliosis, a neurophysiological as- sessment was conducted, allowing for a more comprehen- sive evaluation of the patient’s condition.5 This initial assessment prompted additional investigations, including genetic testing, thereby discovering the genetic variant. No genetic testing was done earlier because (we can only assume since the patient was followed elsewhere) the pa- tient presented with subtle manifestations that had never been further investigated before our evaluation for mus- culoskeletal deformity. Although earlier testing might have been beneficial, the patient’s initial clinical features were not immediately suggestive of a known syndromic condition. Nonethless, we are happy to address the re- viewer’s concerns by reporting that both the mother and grandmother carried the same MYH3 variant but exhib- ited only mild musculoskeletal manifestations, without scoliosis or significant dysmorphism. Other first-degree relatives were unavailable for genetic testing. While it would indeed be interesting to investigate or rule out additional chromosomal defects in conjunction with the MYH3 variant, this is outside of the scope of our in- vestigation, which focuses on reporting the specific mus- culoskeletal manifestations and correlation with EEG activation in the patient. These future assessments fall out- side the scope of our case report. Cardiac and pulmonary assessments, including echocar- diography and pulmonary function tests, were within nor- Key Words: MYH3, scoliosis, genetic testing, Freeman-Sheldon syndrome, Sheldon Hall syndrome. Eur J Transl Myol 35 (3) 14034, 2025 doi: 10.4081/ejtm.2025.14034 Reply to Before scoliosis can be attributed to the variant c.326G>A in MYH3, its pathogenicity must be proven Maria Chiara Maccarone,1,2 Matilde Paramento,1,3 Edoardo Passarotto,1 Paola Contessa,4 Maria Rubega,1 Emanuela Formaggio,1 Stefano Masiero1,4 1Department of Neurosciences, Section of Rehabilitation, University of Padova, Italy; 2Padova Neuroscience Center, University of Padova, Italy; 3Department of Information Engineering, University of Padova, Italy; 4Orthopedic Rehabilitation Unit, Padova University Hospital, Padova, Italy. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 246 - Reply to: MYH3 mutation and scoliosis Eur J Transl Myol 35 (3) 14034, 2025 doi: 10.4081/ejtm.2025.14034 mal limits at the time of evaluation. However, given the potential for scoliosis progression to affect cardiopul- monary function, long-term follow-up remains essential. Additionally, considering the role of MYH3 in muscle function, further studies could explore whether this variant might contribute to neuromuscular dysfunction affecting respiration or cardiovascular health.3 Finally, we acknowledge that the interpretation of EEG spectral analysis in scoliosis remains an emerging area of research.6 While our findings suggest altered sensorimotor processing, further studies are needed to validate EEG as a reliable biomarker in the pathophysiology of scoliosis.5,6 Specifically, prospective studies comparing EEG spectral analysis in scoliosis patients versus controls, along with additional neurophysiological and biomechanical assess- ments, could provide more robust evidence regarding the potential role of altered cortical activity in the pathogen- esis of scoliosis. In conclusion, this case highlights the importance of thor- ough evaluations in patients with atypical musculoskeletal presentations, as scoliosis may be an early marker of un- derlying conditions requiring further investigation. We hope our response provides clarity and contributes to an ongoing discussion on this topic. List of abbreviations AIS, Adolescent Idiopathic Scoliosis EEG, Electroencephalography Funding statement The study was supported by Fondazione Cassa di Rispar- mio di Padova e Rovigo (MP); REACT EU—PON «Ric- erca e Innovazione» 2014–2020, DM 1062/2021 (MR); PRIN2022DM104 under Grant 2022MMNCKC (SM, EP). Conflict of interest The authors declare no conflicts of interest. Ethics approval All methods were carried out in accordance with the guidelines of the 2008 Helsinki Declaration. Ethical ap- proval was obtained in April 2023 (5627/AO/22). Availability of data and materials All data generated or analyzed during this study can be provided upon request. Contributions SM and EF, Development of the study design, supervi- sion, MCM, MP, EP, PC, MR, and EF, data collection, data interpretation, MCM, MR, and EF, writing, MCM, MR, and EF, data analysis. Informed consent All patients participating in this study signed a written in- formed consent form. Corresponding author Maria Chiara Maccarone, Department of Neurosciences, Section of Rehabilitation, University of Padova, via Giustiniani 2, 35128 Padova, Italy. ORCID ID: 0000-0003-2793-1334 E-mail: mariachiara.maccarone@phd.unipd.it Co-authors Matilde Paramento ORCID: 0000-0002-3268-0309 E-mail: matilde.paramento@phd.unipd.it Edoardo Passarotto ORCID ID: 0000-0001-7653-9377 E-mail: edoardo.passarotto@studenti.unipd.it Paola Contessa ORCID ID: 0000-0002-8645-6783 E-mail: paola.contessa@aopd.veneto.it Maria Rubega ORCID ID: 0000-0002-0744-3109 E-mail: maria.rubega@unipd.it Emanuela Formaggio ORCID ID: 0000-0002-3417-0388 E-mail: emanuela.formaggio@unipd.it Stefano Masiero ORCID ID: 0000-0002-0361-4898 E-mail: stef.masiero@unipd.it References 1. Maccarone MC, Paramento M, Passarotto E, et al. A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis. Eur J Transl Myol 2024;35:13249. 2. Yang Y, Zhang W, Wang H. Identification of two novel MYH3 variants causing different phenotypes in pre- natal diagnosis. Prenat Diagn 2023;43:1467-71. 3. Zhao S, Zhang Y, Hallgrimsdottir S, et al. Expanding the mutation and phenotype spectrum of MYH3- associated skeletal disorders. NPJ Genom Med 2022;7:1. 4. Maccarone MC, Barzizza E, Contessa P, et al. Lessons from the pandemic era: do we need new strategies to improve conservative treatment adherence in adoles- cent idiopathic scoliosis? A retrospective analysis. Eur J Transl Myol 2024;34:12859. 5. Paramento M, Rubega M, Di Marco R, et al. Experi- mental protocol to investigate cortical, muscular and body representation alterations in adolescents with id- iopathic scoliosis. PLoS One 2023;18:e0292864. - 247 - mailto:emanuela.formaggio@unipd.it Reply to: MYH3 mutation and scoliosis Eur J Transl Myol 35 (3) 14034, 2025 doi: 10.4081/ejtm.2025.14034 6. Paramento M, Passarotto E, Maccarone MC, et al. Neurophysiological, balance and motion evidence in adolescent idiopathic scoliosis: A systematic review. PLoS One 2024;19:e0303086. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their af- filiated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 27 May 2025. Accepted: 27 May 2025. Early access: 27 June 2025. - 248 -