Layout 1 Thematic Section: Advances in Musculoskeletal and Neuromuscular Rehabilitation | Maccarone & Masiero Eur J Transl Myol 35 (1) 13249, 2025 doi: 10.4081/ejtm.2024.13249 Scoliosis is a three-dimensional spinal deformity that deviates from its vertical alignment. Diagnosis typically involves identifying a lateral deviation of at least 10° on a posterior-anterior radiograph, coupled with vertebral rotation.1 On the one hand, Adolescent Idiopathic Scoliosis (AIS) accounts for up to 80% of cases, typically affecting adolescents and having an unclear pathogenesis. On the other hand, non-idiopathic scoliosis refers to spinal curvature resulting from identifiable causes rather than occurring without a known cause. These causes could include congenital vertebral abnormalities, neuromuscular conditions like cerebral palsy or Duchenne muscular dystrophy, and genetic syndromes such as Marfan syndrome and neurofibromatosis. Additionally, scoliosis can arise due to secondary reasons like spinal cord abnormalities, tumors (both intraspinal and extraspinal), and infections. Non- idiopathic scoliosis should be early recognized as it represents a challenge to the physician due to the possibility of curve progression, with the risk of complications such as pain and pulmonary insufficiency.2 Generally, recognizing a case of non-idiopathic scoliosis is straightforward due to its association with identifiable underlying conditions. Nevertheless, sometimes the diagnosis can be more complex. We report the case of a 15-year-old female patient who was previously being monitored for growth delay and Growth Hormone (GH) deficiency. She exhibited a no- table and unanticipated advancement of her scoliosis. The patient was born at 39 weeks with a birth weight of 2350 g (2nd percentile) and a length of 45 cm (1st percent- ile). Despite steady growth, she remained below the 3rd percentile. At age 9, she underwent her first endocrino- logical evaluation, revealing normal IGF1 levels, a healthy pituitary-thyroid axis, negative celiac disease screening, and normal biochemical profiles. Based on clinical sus- picion, genetic testing for Silver-Russell syndrome was performed, but the results were negative. The administra- tion of GH therapy began in late June 2020, resulting in an improvement in growth velocity and a slight increase in stature. Despite regular monitoring, minimal trunk asymmetries were observed, with no evidence of a hump, even with a family history of severe AIS in the patient’s mother and grandmother. Unexpectedly, at the July 2023 evaluation, significant trunk asymmetries were noted, including a Abstract Scoliosis is a three-dimensional spinal deformity characterized by a lateral deviation of at least 10° Cobb, categorized into idiopathic and non-idiopathic forms, caused by identifiable factors like congenital abnormalities, neuromuscular conditions, or genetic syndromes. This case report discusses a 15-year-old girl with growth delay and Growth Hormone (GH) deficiency who experienced rapid scoliosis progression. Initial evaluations were normal, and Electroencephalography (EEG) showed nonspecific alterations, but further assessment revealed a MYH3 gene variant associated with scoliosis, short stature, and distinct facial features. Treatment with a Lyon ARTbrace and tailored exercises stopped curve progression. This case highlights the need for thorough evaluations in atypical AIS cases to uncover potential causes. Key Words: rehabilitation; adolescent idiopathic scoliosis; electroencephalography; GH deficiency; MYH3 gene. Eur J Transl Myol 35 (1) 13249, 2025 doi: 10.4081/ejtm.2024.13249 A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis 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. - 29 - A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis Eur J Transl Myol 35 (1) 13249, 2025 doi: 10.4081/ejtm.2024.13249 prominent 30 mm right rib hump. X-rays revealed a right thoracic scoliosis with a Cobb angle of 45° and a left lum- bar countercurve of 45° (Figure 1A), with a Risser sign of 1, indicating incomplete skeletal maturity. At the time of the examination, the patient had not yet reached menarche. Given the rapid progression of the curve, additional eval- uations were warranted to investigate a potential underly- ing cause for its accelerated worsening. Electroencephalographic (EEG) data were acquired from 64 channels at a sampling frequency of 500 Hz and refer- enced to Cpz (ANT Neuro, Enschede, The Netherlands). A 1-min EEG resting state recording of quiet upright standing was acquired first with eyes closed and then with eyes closed on the floor and on a foam support. The data were processed in Matlab (MathWorks, Natick, MA, Usa) using personalized scripts based on EEGLAB toolbox. The EEG recordings were band-pass filtered from 1 to 40 Hz (the optimal Chebyshev finite impulse re- sponse filters were designed using Parks–McClellan al- gorithm, the order was customized to minimize the error in the pass and stop bands). Noisy channels were identi- fied by visual inspection and interpolated using the nea- rest-neighbor spline method. Eyes movements and cardiac activity were removed using independent component anal- ysis and data were re-referenced to the average reference. The fast Fourier transform was applied to non–overlap- ping epochs of 2 s and then averaged across epochs. The recordings were Hanning windowed to control for spectral leakage. Power spectra were estimated for all frequencies between 1 and 40 Hz, then the relative power (%) was cal- culated by dividing the power of each frequency bands (delta [1–4] Hz, theta [4.5–7.5] Hz, alpha [8–12] Hz, and beta [13–30] Hz) with the total power of [1–30] Hz. An increase of theta power in fronto-central electrodes was observed when the subject was standing with eyes closed on the foam. The alpha power was localized not only in the occipital electrodes but also in the central elec- trodes over the sensorimotor areas (Figure 1D). In addition to the neurophysiological assessment, the pa- tient and her parents underwent whole-exome sequencing to further investigate a potential genetic component, de- spite initial analysis suggesting its exclusion. This further analysis revealed rare variants, including a heterozygous p.Arg109His variant in the MYH3 gene (OMIM 160720). All methods were conducted in accordance with the guidelines of the 2008 Helsinki Declaration. Ethical ap- proval was obtained in April 2023 (n. 5627/AO/22). Written informed consent was provided by both the sub- jects and their legal guardians. Given the severity of the AIS, the medical team presented the possibility of a surgical solution to the patient and her parents. However, they declined. The patient was prescribed a Lyon ARTbrace (an asym- metrical, rigid, torsion brace) to be worn full-time and was strongly encouraged to participate in a tailored rehabilita- tion program.3 After 8 months of conservative treatment with brace wea- ring and tailored exercises, the scoliosis showed a cessa- tion of progression, with a right thoracic rib hump measuring 16 mm on clinical evaluation. On the in-brace X-ray, a notable correction by the orthosis was observed (Fig. 1C); on the out-of-brace X-ray, the thoracic curve was measured at 40°, while the lumbar curve was 34° (Figure 1B). In the case we presented, an underlying cause for the sco- liosis was found after extensive genetic investigations. What initially appeared to be idiopathic scoliosis was eventually revealed, due to a sudden progression, to be linked to a rare genetic variant. The patient had been undergoing GH treatment for three years prior to the progression of the curve. Although GH treatment in children with short stature has been shown to increase growth velocity, there is currently no evidence to suggest an association between GH treatment and the de- velopment or exacerbation of AIS.4 However, a study in- volving patients with idiopathic short stature who underwent GH treatment found that 3.7% developed new- onset scoliosis during treatment, while scoliosis pro- gressed in 16.4% of cases.5 The results of the EEG evaluations indicated that the theta relative power was elevated over the fronto-central elec- trodes during the performance of the standing task on the foam with eyes closed. This observation is consistent with the hypothesis that the demands on postural control and sensory processing are increased in patients with scoliosis.6 Furthermore, alpha power was observed in both occipital and central electrodes over the sensorimotor re- gions, suggesting likely increased motor control to com- pensate for altered body perception. In the past, EEG evaluations have primarily been conducted on patients with idiopathic scoliosis,7 making our case the first to in- vestigate this rare genetic variant from an EEG perspec- tive during balance maintenance tasks. Genetic investigation identified a rare variant, which is of maternal origin. The MYH3 gene encodes an embryonic heavy chain myosin that is essential for sarcomere as- sembly in skeletal and cardiac muscle cells.8 A recent study found 17 individuals with previously unreported MYH3 variants who had scoliosis, short stature, and dis- tinct facial features.9 These characteristics were sub- sequently observed not only in our patient but also in her mother and grandmother. This case report illustrates that when patients exhibit trunk asymmetries or AIS with rapid progression, and there is clinical suspicion of a non-idiopathic etiology, further evaluations are warranted. Identifying the precise cause of scoliosis in such cases is important, as it can signifi- cantly influence treatment decisions and outcomes. The patient history collection should guide in selecting which investigations should be performed to explore possible causes of non-idiopathic scoliosis.10 Advanced diagnostic tools, such as genetic testing and neurophysiological as- sessments, can uncover underlying conditions that might not be apparent through initial evaluations. Our approach identified a rare genetic variant as a potential cause, and highlighted increased motor and sensory processing, even in simple tasks, as possible effects of scoliosis. These find- ings may have implications for longitudinal patient mon- itoring and early intervention strategies in assessing familial predisposition to develop scoliosis. - 30 - A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis Eur J Transl Myol 35 (1) 13249, 2025 doi: 10.4081/ejtm.2024.13249 List of abbreviations AIS, Adolescent Idiopathic Scoliosis GH, growth hormone EEG, electroencephalography Contributions SM and EF, development of the study design, supervision; MCM, MP, EP, PC, MR and EF, data collection, data in- terpretation; MCM, MR and EF writing; MCM, MR and EF data analysis. - 31 - Figure 1. A) This X-ray image shows the spine of the patient before the commencement of treatment for scoliosis; B) This X-ray image shows the spine of the patient after 8 months of conservative treatment; C) This X-ray, taken while wearing the brace 8 months after the initial X-ray assessment, shows the good correction performed by the orthosis; D) Relative EEG power (%) in theta [4.5-7.5] Hz and alpha [8-12] Hz bands while standing on the floor with eyes closed and standing on a foam with eyes closed. A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis Eur J Transl Myol 35 (1) 13249, 2025 doi: 10.4081/ejtm.2024.13249 Ethics approval All methods were carried out in accordance with the guidelines of the 2008 Helsinki Declaration. Ethical ap- proval has been obtained on April 2023 (5627/AO/22). Informed consent All patients participating in this study signed a written in- formed consent form for participating in this study. 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 interests. Availability of data and materials All data generated or analyzed during this study can be provided upon request. 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 ID: 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. Negrini S, Donzelli S, Aulisa AG, et al. 2016 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis Spinal Disord 2018;13:3. 2. Burnei G, Gavriliu S, Vlad C, et al. Congenital scolio- sis: an up-to-date. J Med Life 2015;8:388-97. 3. de Mauroy JC, Journe A, Gagaliano F, et al. The new Lyon ARTbrace versus the historical Lyon brace: a prospective case series of 148 consecutive scoliosis with short time results after 1 year compared with a historical retrospective case series of 100 consecutive scoliosis; SOSORT award 2015 winner. Scoliosis 2015;10:26. 4. DiMeglio A, Canavese F, Charles YP. Growth and ad- olescent idiopathic scoliosis: when and how much? J Pediatr Orthop 2011;31:S28-36. Erratum in: J Pediatr Orthop 2011;31:221. 5. Park M, Kim YJ, Oh KE, et al. The association be- tween idiopathic scoliosis and growth hormone treat- ment in short children. Ann Pediatr Endocrinol Metab 2022;27:207-13. 6. Formaggio E, Bertuccelli M, Rubega M, et al. Brain oscillatory activity in adolescent idiopathic scoliosis. Sci Rep 2022;12:17266. 7. 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. 8. 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. 9. Zhao S, Zhang Y, Hallgrimsdottir S, et al. Expanding the mutation and phenotype spectrum of MYH3-asso- ciated skeletal disorders. NPJ Genom Med 2022;7:11. 10. 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. 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: 12 October 2024. Accepted: 16 October 2024. Early access: 19 December 2024. - 32 - mailto:mariachiara.maccarone@phd.unipd.it mailto:paola.contessa@aopd.veneto.it