{"paper_id":"3231b206-a117-4dbb-a68d-3487c50c096e","body_text":"Congenital Malformation of The Great Toe in Children. Did You Exclude Fibrodysplasia Ossificans Progressiva – FOP. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case report Congenital Malformation of The Great Toe in Children. Did You Exclude Fibrodysplasia Ossificans Progressiva – FOP. Maria Kirstine Møller - Madsen, Darko Antičević This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-963656/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and severely disabling genetic disorder. The worldwide prevalence is approximately 1 per 2 million. Heterozygous mutations in ACVR1/ALK2 gene exist in all sporadic and familial cases of FOP. The primary aim of this study is to describe the clinical course of three children suffering from FOP and followed for fifteen, twenty-two and forty years, respectively Secondary aim is to provide clinical advice on how to diagnose the condition with special reference to the great toes malformation and give current best therapeutic approaches. Results: All three cases characterized with malformed great toes initially followed by progressive loss of mobility for a period from fifteen to forty years. Conventional radiology indicates the diagnosis and RNA/DNA test confirm it. Conclusion: Congenital malformation of the great toes in early childhood may be the first clinical sign of FOP. A devastating disease due to its progressive formation of heterotopic ossifications in soft tissue even after minor injuries. Leading to progressive immobility, skeletal deformities, chronic pain, growth defects and disabling joint stiffness. No curative treatment exists today. Management is symptomatic combined with a prophylactic lifestyle avoiding blunt and pointed trauma including surgery. Internal Medicine Fibrodysplasia ossificans progressive FOP great toe case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Background Fibrodysplasia ossificans progressiva (FOP) is a rare disease. The worldwide prevalence of FOP is approximately 1 per 2 million. There is no known ethnic, racial, gender, or geographic predisposition (1). Classical FOP is an autosomal dominant genetic condition caused by a recurrent activating mutation in the gene ACVR1/ALK2 encoding Activin A receptor type 1. It is a bone morphogenetic protein (BMP) type 1 receptor (2). The mutation in the BMP exists in all sporadic and familial cases of FOP (4). Overactive BMP signalling pathway is the underlying cause of the heterotopic ossification (HO). FOP is characterized by congenital malformation of the medial ray of the feet, especially of the big toe. HOs involve muscles of the head, neck and back in the early childhood followed by shoulders and extremities. FOP affects the quality of life significantly (3-6). Most patients suffering from FOP become dependent on a wheelchair cause cumulative immobility. Further, lifelong personal assistance in daily activities must be foreseen. Although, the great toe malformation is a hallmark of FOP, information about natural history of the great toe malformation is scarce. In addition, delay in diagnosis of FOP is a result of frequent temporal failure to associate malformations of the great toes, present at birth, with onset of HOs in the first decade of life (7-9). We present three young female patients with follow-up from fifteen to twenty-five years. We focus on the great toe and its influence on over-all mobility status for the patients. Case 1 A girl, nine years of age, born 1996 referred to our hospital because of pain and swelling at the right humeral bone combined with restricted range of motion in the elbow flection after a fall on the ground. The primary x-ray examination showed extra-skeletal bone masses in the distal anterior part of humerus (figure 1 ). Excision of the exostosis was performed. Recurrence was found after a few weeks. A second excision was done, and the child was referred to a rheumatologist for further examination. The diagnosis, FOP was obtained, and further surgery was avoided. X-rays of the forefoot was obtained and showed great toes deformities (figure 2 ). Biological immunosuppressive medication was initiated to control the hyperactive BMP signalling pathway and thus limiting the bone regeneration. The medical treatment continued for three years with limited effects on the clinical symptoms. Eighteen years old, she suffered from a left pertrochanteric fracture after a fall. Standard osteosynthesis was performed despite the diagnosis obtained. Conventional x-rays three years later showed fracture healing but also significant HO in the adjacent soft tissue and physical examination showed progressive restricted range of motion in the left hip to full stiffness. One year later, she had a dislocated left patellar fracture. Non-operative treatment was advised. The patella showed healing with progressive HO. Excessive bone formation in the adjacent soft tissue (figures 3 a, b, c). Dual energy X-ray absorption- scanning (DXA-scanning) revealed osteoporosis and zoledronic acid injections acid was initiated, subcutaneously. In addition to the progressive immobility co-morbidities as urinary tract infections, unilateral hydronephrosis and nephrolithiasis was observed. Later the patient reported classic episodes of painful inflammatory soft tissue swellings, flare-ups in the region of the sterno-cleido-mastoid muscle. Diffuse multifocal tissue swelling of the neck was detected using magnetic resonance imaging (MRI). The diffuse soft tissue swelling responded to subcutaneous corticosteroid injection. Genetic testing for FOP was not available at the time of diagnosis. Today she is twenty-four years old and full-time wheel-chair user and dependent of a personal caregiver. Educated and working as social worker. She is still followed in the outpatient clinic. Case 2 A girl, two year and ten months of age, the first child of healthy non-consanguineous parents, was admitted to hospital due to painful and hard swelling in the left cubital fossa after a fall on the ground. One month earlier, she had received intramuscular injections unrelated to the fall at a regional hospital three weeks after the fall. As a consequence of the injections, she developed additional swelling in the left axilla and anteromedial left arm. Her laboratory tests were within normal range. Radiographic images showed four small rice grain like extra-articular calcifications in the region of the cubital fossa (figure 4 ). Range of motion of the left elbow was restricted. Forty-five degrees lack of extension and flexion up to one hundred twenty degrees. Movement of left shoulder and elbow caused pain. Due to great toe deformity, she was referred to a paediatric orthopaedic surgeon for further examination. Great toe shortness and valgus deformity with painful swelling and muscular calcifications was noted and FOP diagnosis was made (figure 5 a, b). Genetic testing was performed at age of six and FOP was confirmed. No surgical procedures were ever made from her six years of age and up to the last follow-up at twenty-five years. She reported almost normal life activities, with some precautions, until she was nine years of age. At that time, she developed HOs in the muscle of right thigh with limitation of motion in the right hip and knee joint. At age eleven, she was using under-arm crutches. At age thirteen and half she was using wheelchair out-door. During the growth period treatment was symptomatic and supportive only. At the last follow-up, at twenty-five years of age she suffered from additional HOs at left sterno-cleido-mastoid muscle, and at muscle latissimus dorsi to muscle illio-costalis lumborum, as well as in the muscles of nuchae, submandibular and rectus abdominis. The phalangeal bones of the great toes developed fusion (figure 6 a, b). Today she is wearing special shoes to avoid pain on weight-bearing. Case 3 A girl, the first child of healthy non-consanguineous parents was born in her family home 1975. She has three healthy siblings. Family history FOP negative. The patient has short great toes, noted by parents, but with no attention from healthcare providers. Muscle swelling after a fall gave indication for biopsy twice in two different countries. First biopsy at age four years due to painful mass in a muscle of left scapula region. Second biopsy obtained in different country at age eleven and half year of the paravertebral muscles. Based on malformations of great toes and histology of the biopsies the diagnosis of FOP was made. Genetic testing was not available at that time. In the following years, she had multiple flare-ups. Muscles from proximal to distal part and from dorsal to ventral regions according to topical FOP pattern was affected (figure 7 a, b). At age twenty-five, the first flare-up at the right great toe was observed. Co-morbidities as urological, allergic, dental, and upper respiratory tract pathologies was stated. A special medical team with relevant competences followed her frequently. She was given a “FOP passport” to be shown to any medical professionals, in case of emergency. At age thirty-three years recurrent flare-ups at both great toes took place. Joint fusions of both great toes became more severe. At age of thirty-four years, she was not able to walk or stand more than approximately five minutes. Despite her limited mobility, she was free from flare-ups for four years approximately. Right great toe and second toe were completely fused and impacted to each other at the age of forty-two. This condition gave basis for skin sores, local infection, and pain. After months of failed conservative management amputation of the second toe took place (figure 8 a, b). Today at age forty-five, she is free of pain in her feet. In-door was mobility preserved in custom made shoes (figure 9 a, b). Discussion The great toe malformation The great toe malformation is a red flag of FOP in early childhood. Before other clinical signs are present, FOP should be confirmed or excluded through DNA sequencing analysis (10-11). Natural history of FOP has been extensively studied (12-13). Rogers and Geho identified forty patients out of forty-two having great toe abnormalities (14). Connor and Evans studied thirty-four patients with FOP. All of them had characteristic skeletal malformations including abnormal great toes. Great toe malformations can be divided into four subtypes based on clinical and radiological findings. The most frequent is type I representing a short great toe without valgus deviation and without lateral deviation at the metatarsophalangeal joint. Type II, III and IV are less frequent (15-17). Nakashima and co-authors (3) performed a cross-sectional study of thirty-one feet in sixteen FOP patients and concluded that twenty-nine feet (93,5%) showed several degrees of great toe deformity. An analysis of radiographic characteristics of all feet without any follow-up, confirmed that proximal phalanx of the great toe was consistently shortened but morphologically dissimilar from case to case. Additional findings were occurrence of the fusion between the distal and proximal phalanx. In patients presented in this study with longitudinal follow-up of more than twenty years of age, temporal pattern of the great toe interphalangeal bony fusion was observed in all (figure 6 b and 7 b). In case three the focus was on the natural history of HO manifestation. All patients presented had characteristic congenital malformations of the great toes. The mean age of clinical onset of HO was approximately five years. Cohen et al. mention that the HO progression are seen in patterns proximal to distal, axial to appendicular and dorsal to ventral. Jaw involvement was late in almost all patients (13). It is of interest that in presented case one and two FOP started in the elbow region. The oldest patient, case three, was subject for two biopsy despites of correct diagnosis. In the 1970 to 1990 biopsy was often performed in FOP patients Kitterman et al. in 2005 (7). Unfortunately, the diagnosis of FOP is often delayed because of the rareness and challenging clinical picture. In the cases presented an early confirmatory specific genetic test may have changed the treatment strategy, especially the surgical interventions. Genetic tests Few case reports describe the applicability of the rapid genetic testing to prepare a specific personalized treatment plan prior to development of clinical symptoms (3, 8). In 2006 it became possible to detect the ACVR1 single gene mutation for FOP, which resulted in an accelerated research on how to apply the optimal management of FOP (22-23). The discovery of the FOP gene provided a highly specific target for future drug development that holds promise for altering not just the symptoms of the disease but also the disease itself (24). Still the diagnosis of FOP is primarily made by the clinical assessment of the patient. Confirmation of diagnosis by genetic testing is possible, thus avoiding misdiagnosis and devastating surgical interventions. Management At present, no specific management of FOP exists. It is evident that the innate immune system, the macrophages, neutrophils, and natural killer cells play an important role in the inflammatory soft tissue swelling, flare-ups. Hence, it has been of interest to use biological immunosuppressive therapeutics. The literature describes targeting the BMP signalling pathways at different levels or targeting cellular components important in the extra-skeletal bone regeneration may be useful (18-19, 24). In our case one, three different biological therapeutics had been prescribed. The efficacy and safety of these drugs have not yet been documented. Infliximab, which is a TNF-alpha inhibitor, may reduce the macrophages activity at the inflammatory response and thereby be helpful to reduce the sporadic soft tissue swelling. The formation of HO in FOP is described in the literature as an episodic rather than a continuous process related to soft tissue swelling following infections, trauma, immunizations, and iatrogenic harms (24). These episodes are usually preserved with corticosteroids and prevention of trauma. However, a frequent use of corticosteroids for swellings in the trunk and neck opposite to swelling in the extremities, is not recommended due to the difficulty in assessing the onset of the swelling. Due to the complexity of FOP pathogenesis, the use of a combination of drugs with different targets, which can act in synergy, might be helpful (23). Conclusion Isolated congenital malformation of the great toes combined with progressive heterotopic ossifications in the soft tissue may be the first clinical manifestation of FOP calling for a thorough examination of the patient. Conventional x-ray and RNA/DNA diagnostic test of the ACVR1 gene assure the diagnosis. Prevention of any trauma, soft tissue infection or surgical intervention including intramuscular injections are recommended. No curative treatment exists today. Declarations Ethics approval are obtained from hospitals as well as consent for retrospective investigation and long-term follow-up of three patients. Ethics board of “St Catherine” Speciality Hospital (IRB) approved study with reference number: 21/9-1 of Aug 2021. Document is available upon request. Informed consent for using medical data , as well as, radiographs, photos and other imaging tool are obtained by means of signature from all three patients. Note: at present time our patients are of adult age. Consent for publication of our patients’ medical data and imaging are obtained from all three patients with signature, providing that in no way their identity could be revealed in the manuscript. Documents are available upon request from corresponding author Author´s contributions : Maria Kirstine Møller – Madsen (MKMM) has designed patient 1 with supervision from Darko Anticevic (DA). DA has designed patients 2 and 3. The discussion and conclusions are performed of both authors. Both authors read and approved the final version of the manuscript. Availability of data and materials : The data of three patients presented in this manuscript are available from the corresponding author (DA) on reasonable request. Competing interests : The authors declare that they have no competing interests. Funding: There is no funding. Acknowledgment Thank you to Michel Bach-Hellfritzsch, MD for figure description. References She D, Zhang K. Fibrodysplasia ossificans progressiva in China. Bone. 2018 Apr; 109:101–3. doi: 10.1016/j.bone.2017.11.016 . Epub 2017 Nov 22. Review. PubMed PMID: 29175272. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011 Dec 1; 6:80. doi: 10.1186/1750-1172-6-80 . PMID: 22133093; PMCID: PMC3253727. Nakashima Y, Haga N, Kitoh H, Kamizono J, Tozawa K, Katagiri T, et al. Deformity of the great toe in fibrodysplasia ossificans progressiva. J Orthop Sci. 2010;15:804–9. Fonseca JE, Branco JC, Reis J, Evangelista T, Tavares V, Gomes AR, Queiroz MV. Fibrodysplasia ossificans progressiva: report of two cases. Clin Exp Rheumatol. 2000 Nov-Dec; 18(6):749–52. PMID: 11138342. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May; 38(5):525–7. doi: 10.1038/ng1783 . Epub 2006 Apr. Ortiz-Agapito F, Colmenares-Bonilla D. Quality of life of patients with. fibrodysplasia ossificans progressiva. J Child Orthop. 2015 Dec;9(6):489–93. doi: 10.1007/s11832-015-0704-6. Epub 2015 Nov 13. PMID: 26564023; PMCID:. PMC4661157. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in Fibrodysplasia Ossificans Progresiva. Pediatrics. 2005;116(5):e654–61. DOI: 10.1542/peds.2005-0469 . Janati J, Aghighi Y, Tofighi A, Akhavan A, Behrouzan O. Radiologic findings in seven patients with fibrodysplasia ossificans progressiva. Arch Iran Med. 2007 Jan; 10(1):88–90. PMID: 17198460. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 2013 Jun;10 Suppl 2(0 2):437–48. PMID: 23858627; PMCID: PMC3995352. Towler OW, Shore EM, Xu M, Bamford A, Anderson I, Pignolo RJ, Kaplan FS. The congenital great toe malformation of fibrodysplasia ossificans progressiva? – A close call. Eur J Med Genet. 2017 Jul;60(7):399–402. doi: 10.1016/j.ejmg.2017.04.013 . Epub 2017 May 1. PMID: 28473268. Bauer AH, Bonham J, Gutierrez L, Hsiao EC, Motamedi D. Fibrodysplasia ossificans progressiva: a current review of imaging findings. Skeletal Radiol. 2018 Aug;47(8):1043–50. doi: 10.1007/s00256-018-2889-5 . Epub 2018 Feb 14. PMID: 29445932. Connor JM, Evans DAP. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg (Br) 1982; 64(1):76–83. Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of hetereotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg (Am) 1993; 75(2):215–9. Rogers JG, Geho WB. Fibrodysplasia ossificans progressive. J Bone Joint Surg (Am) 1979; 61(6):909–14. Harrison RJ, Pitcher JD, Mizel MS, Temple HT, Scully SP. The radiographic morphology of foot deformities in patients with fibrodysplasia ossificans progressiva. Foot Ankle Int. 2005 Nov; 26(11):937-41. doi: 10.1177/107110070502601107 . PMID: 16309607. Brennan TA, Lindborg CM, Bergbauer CR, Wang H, Kaplan FS, Pignolo RJ. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone. 2018 Apr; 109:259–66. doi: 10.1016/j.bone.2017.08.023 . Epub 2017 Aug 26. PMID: 28851540. Bouvard B, Masson C, Legrand E, Audran M. Fibrodysplasia ossificans progressiva. A case report and focus on the BMP signaling pathway. Morphologie 2016 Dec;100(331):250–5. doi: 10.1016/j.morpho.2016.01.004 . Epub 2016 May 23. PMID: 26948676. Gencer-Atalay K, Ozturk EC, Yagci I, Ata P, Delil K, Ozgen Z, Akyuz G. Challenges in the treatment of fibrodysplasia ossificans progressiva. Rheumatol Int 2019 Mar;39(3):569–76. doi: 10.1007/s00296-018-4179-x . Epub 2018 Oct 20. PMID: 30343406. Luo, Alsamarah Y, Zhang A, Hao K J. Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva. Curr Mol Med. 2016;16(1):4-11. doi: 10.2174/1566524016666151222142446 . PMID: 26695699. Kaplan, Xu FS, Glaser M, Collins DL, Connor F, Kitterman M, Sillence J, Zackai D, Ravitsky E, Zasloff V, Ganguly M, Shore A. EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008 May; 121(5):e1295-300. doi: 10.1542/peds.2007-1980 . PMID: 18450872; PMCID: PMC3502043. Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The Horizon of a Therapy for Rare Genetic Diseases: A \"Druggable\" Future for Fibrodysplasia Ossificans Progressiva. Int J Mol Sci. 2018 Mar 26;19(4):989. doi: 10.3390/ijms19040989 . PMID: 29587443; PMCID: PMC5979309. Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol 2019 Jun;85(6):1199–207. doi: 10.1111/bcp.13777 . Epub 2018 Nov 6. PMID: 30281842; PMCID: PMC6533500. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):191–205. doi: 10.1016/j.berh.2007.11.007. PMID: 18328989; PMCID: PMC2424023. Kartal M, Shore EM, Xu M, Schwering L, Uhl M, Korinthenberg R, Niemeyer C, Kaplan FS, Lauten M. Fibrodysplasia ossificans progressiva (FOP): watch the great toes! Eur J Pediatr. 2010 Nov;169(11):1417–21. doi: 10.1007/s00431-010-1232-5 . Epub 2010 Jun 26. PMID: 20577760; PMCID: PMC4964587. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-963656\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Case report\",\"associatedPublications\":[],\"authors\":[{\"id\":56581460,\"identity\":\"f19923e5-ed14-431d-85b0-bac52bca35dd\",\"order_by\":0,\"name\":\"Maria Kirstine Møller - Madsen\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0003-0636-8538\",\"institution\":\"Langenæs Alle 51 2.mf\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Maria\",\"middleName\":\"Kirstine Møller -\",\"lastName\":\"Madsen\",\"suffix\":\"\"},{\"id\":56581461,\"identity\":\"2d2df8d1-3f48-4bad-a1ff-2acce71923db\",\"order_by\":1,\"name\":\"Darko Antičević\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYDCCAwzMEAaYMmCQAws+IEYLD1SLMVgwgSgtUH5iA4jEp4Xv+NnHBh8Y7PLs2ZkfPuYpsEufH3b4IdAWOzndBuxaJM+kGyfOYEgu5mFmMzbmMUjO3Xg7zQCoJdnY7AB2LQYH0pgP8zAwJ/Yw87BJzjA4kLtxdgJIy4HEbbi0nH8G0lIP0sL+E6gl3XB2+gf8Wm6kMSfzMBwG28LwAWi+vHQOflskbzxjNpxhcDyx5zCbscQHg2TDDdI5BQcSDHD7he98GrPEh4rqxPb+ww8/JPyxk5efnb75w4cKOzlcWqDOQwkQdBGCQL6BFNWjYBSMglEwEgAAkhpbfSLCbUIAAAAASUVORK5CYII=\",\"orcid\":\"https://orcid.org/0000-0001-6713-1273\",\"institution\":\"University of Osijek\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Darko\",\"middleName\":\"\",\"lastName\":\"Antičević\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2021-10-11 10:20:35\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-963656/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-963656/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":14623595,\"identity\":\"e63686c8-741a-4146-910d-a0b705a83d82\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":335205,\"visible\":true,\"origin\":\"\",\"legend\":\"Lateral radiograph of the right elbow (patient 1).\\nOn the anterior side of the elbow joint an osseous bridge is connecting the supracondylar part of the humerus with the ulnar tuberosity. Otherwise, normal joint.\\n\",\"description\":\"\",\"filename\":\"Figure1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/a7673274a9731641ad9349b2.png\"},{\"id\":14623594,\"identity\":\"c372723c-fece-4f0b-9ce0-828527fcae39\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":243156,\"visible\":true,\"origin\":\"\",\"legend\":\"Standing dorsal-plantar (DP) radiograph of both feet (patient 1).\\nSymmetrical findings, with medial angulation of the head of the first metatarsal bone. The proximal phalanx is articulating with the lateral side of the head, worsening the clinical appearance of the hallux valgus. In the first toe there is only one bone, and the toe appears shorter than normal. Otherwise, normal findings.\\n\",\"description\":\"\",\"filename\":\"Figure2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/1f9fef08f2a73c09126481ea.png\"},{\"id\":14623597,\"identity\":\"812ed443-fcf1-43e4-a625-6b98c414b386\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":324444,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b, c. Left knee, lateral radiograph with fracture of the patella (patient 1). \\nOn the initial radiograph (3 a), huge amounts of heterotrophic ossification are seen in the quadriceps muscle. After six weeks (3 b) heterotrophic ossification is seen in the gastrocnemius muscles, with increasing density at the twelve week follow up (3 c). Soft tissue ossification just proximal of the muscle is also noticed (3 c). \\n\",\"description\":\"\",\"filename\":\"Figure3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/12c9a0cd6b5452b1f2f9194f.png\"},{\"id\":14623596,\"identity\":\"c60861eb-2512-4a18-855b-d44d9078312f\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":255463,\"visible\":true,\"origin\":\"\",\"legend\":\"Radiograph of left elbow (patient 2, three years old) with heterotropic ossification in the cubital fossa.\",\"description\":\"\",\"filename\":\"Figure4..png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/6e71fdc6b1765a339658efdb.png\"},{\"id\":14623867,\"identity\":\"28913fd8-a84d-4ef3-928b-306dfe0bf0a0\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:58:50\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":6844960,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b. Photo and radiograph (patient 2, five and a half years old). Clinically the patient seems to have hallux valgus, however the radiograph shows what looks like a large accessory epiphysis in the distal part of the first metatarsal bone, articulating on the lateral side with the phalanx. The proximal part of the phalanx is cone shaped, and the middle of the bone there seems to be a physis.\",\"description\":\"\",\"filename\":\"Figure5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/b9f3cf54c59de6e15b2d13d8.png\"},{\"id\":14623599,\"identity\":\"a0593797-91ee-4902-88be-912e04981a4f\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":3588678,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b. Photo and radiograph (patient 2, 25-years). With maturation of the bones the large distal accessory physis of the metatarsal bone has fused with the proximal part of the bone. The physis in the phalanx has also fused, with only one bone in the great toe, articulating on the lateral side of the metatarsal head.\",\"description\":\"\",\"filename\":\"Figure6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/564ca3da090e915f60341447.png\"},{\"id\":14623600,\"identity\":\"30418078-a31c-4fd8-bf1a-53fb1e939b6c\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":8233026,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b. 7 a: Patient 3 eleven (or twelve) years old. Multiple heterotopic ossification in the back. 7 b: Patient 3 fourteen years old. The same pattern as in patient 2.\",\"description\":\"\",\"filename\":\"Figure7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/8f71c058d5ab4fc44ff596de.png\"},{\"id\":14623602,\"identity\":\"0cfaebe1-6ef6-441d-9548-28aa947b44ef\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:51\",\"extension\":\"png\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":8473512,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b. Radiograph of the right foot (patient 3, forty-three years old). Multiple synostosis. \",\"description\":\"\",\"filename\":\"Figure8.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/b1b8cd223cea6f17865b6c22.png\"},{\"id\":14623601,\"identity\":\"5ea23659-5fac-4392-bbe5-cbf9042299ba\",\"added_by\":\"auto\",\"created_at\":\"2021-10-18 14:55:50\",\"extension\":\"png\",\"order_by\":9,\"title\":\"Figure 9\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":20039377,\"visible\":true,\"origin\":\"\",\"legend\":\"a, b. Clinical photo of right foot after amputation of the second toe (a). Two years after amputation of the second toe in patient 3, shoe fitting is possible and in-door mobility is possible, again (b).\",\"description\":\"\",\"filename\":\"Figure9.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/282c87c3f9e8ee011eeab411.png\"},{\"id\":14703207,\"identity\":\"7319a4c7-2d51-4da5-939b-4d229c49e396\",\"added_by\":\"auto\",\"created_at\":\"2021-10-20 09:53:39\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":6594784,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-963656/v1/6374af77-32f6-493d-bdf9-ee99aee34c80.pdf\"}],\"financialInterests\":\"\",\"formattedTitle\":\"\\u003cp\\u003eCongenital Malformation of The Great Toe in Children. Did You Exclude Fibrodysplasia Ossificans Progressiva – FOP.\\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eFibrodysplasia ossificans progressiva (FOP) is a rare disease. The worldwide prevalence of FOP is approximately 1 per 2 million. There is no known ethnic, racial, gender, or geographic predisposition (1). Classical FOP is an autosomal dominant genetic condition caused by a recurrent activating mutation in the gene ACVR1/ALK2 encoding Activin A receptor type 1. It is a bone morphogenetic protein (BMP) type 1 receptor (2). The mutation in the BMP exists in all sporadic and familial cases of FOP (4). Overactive BMP signalling pathway is the underlying cause of the heterotopic ossification (HO). FOP is characterized by congenital malformation of the medial ray of the feet, especially of the big toe. HOs involve muscles of the head, neck and back in the early childhood followed by shoulders and extremities. FOP affects the quality of life significantly (3-6). Most patients suffering from FOP become dependent on a wheelchair cause cumulative immobility. Further, lifelong personal assistance in daily activities must be foreseen. Although, the great toe malformation is a hallmark of FOP, information about natural history of the great toe malformation is scarce. In addition, delay in diagnosis of FOP is a result of frequent temporal failure to associate malformations of the great toes, present at birth, with onset of HOs in the first decade of life (7-9). We present three young female patients with follow-up from fifteen to twenty-five years. We focus on the great toe and its influence on over-all mobility status for the patients.\\u003c/p\\u003e\"},{\"header\":\"Case 1\",\"content\":\"\\u003cp\\u003eA girl, nine years of age, born 1996 referred to our hospital because of pain and swelling at the right humeral bone combined with restricted range of motion in the elbow flection after a fall on the ground. The primary x-ray examination showed extra-skeletal bone masses in the distal anterior part of humerus (figure \\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Excision of the exostosis was performed. Recurrence was found after a few weeks. A second excision was done, and the child was referred to a rheumatologist for further examination. The diagnosis, FOP was obtained, and further surgery was avoided. X-rays of the forefoot was obtained and showed great toes deformities (figure \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Biological immunosuppressive medication was initiated to control the hyperactive BMP signalling pathway and thus limiting the bone regeneration. The medical treatment continued for three years with limited effects on the clinical symptoms. Eighteen years old, she suffered from a left pertrochanteric fracture after a fall. Standard osteosynthesis was performed despite the diagnosis obtained. Conventional x-rays three years later showed fracture healing but also significant HO in the adjacent soft tissue and physical examination showed progressive restricted range of motion in the left hip to full stiffness. One year later, she had a dislocated left patellar fracture. Non-operative treatment was advised. The patella showed healing with progressive HO. Excessive bone formation in the adjacent soft tissue (figures \\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ea, b, c). Dual energy X-ray absorption- scanning (DXA-scanning) revealed osteoporosis and zoledronic acid injections acid was initiated, subcutaneously. In addition to the progressive immobility co-morbidities as urinary tract infections, unilateral hydronephrosis and nephrolithiasis was observed. Later the patient reported classic episodes of painful inflammatory soft tissue swellings, flare-ups in the region of the sterno-cleido-mastoid muscle. Diffuse multifocal tissue swelling of the neck was detected using magnetic resonance imaging (MRI). The diffuse soft tissue swelling responded to subcutaneous corticosteroid injection. Genetic testing for FOP was not available at the time of diagnosis. Today she is twenty-four years old and full-time wheel-chair user and dependent of a personal caregiver. Educated and working as social worker. She is still followed in the outpatient clinic.\\u003c/p\\u003e\"},{\"header\":\"Case 2\",\"content\":\"\\u003cp\\u003eA girl, two year and ten months of age, the first child of healthy non-consanguineous parents, was admitted to hospital due to painful and hard swelling in the left cubital fossa after a fall on the ground. One month earlier, she had received intramuscular injections unrelated to the fall at a regional hospital three weeks after the fall. As a consequence of the injections, she developed additional swelling in the left axilla and anteromedial left arm. Her laboratory tests were within normal range. Radiographic images showed four small rice grain like extra-articular calcifications in the region of the cubital fossa (figure \\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e). Range of motion of the left elbow was restricted. Forty-five degrees lack of extension and flexion up to one hundred twenty degrees. Movement of left shoulder and elbow caused pain. Due to great toe deformity, she was referred to a paediatric orthopaedic surgeon for further examination. Great toe shortness and valgus deformity with painful swelling and muscular calcifications was noted and FOP diagnosis was made (figure \\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ea, b). Genetic testing was performed at age of six and FOP was confirmed. No surgical procedures were ever made from her six years of age and up to the last follow-up at twenty-five years. She reported almost normal life activities, with some precautions, until she was nine years of age. At that time, she developed HOs in the muscle of right thigh with limitation of motion in the right hip and knee joint. At age eleven, she was using under-arm crutches. At age thirteen and half she was using wheelchair out-door. During the growth period treatment was symptomatic and supportive only. At the last follow-up, at twenty-five years of age she suffered from additional HOs at left sterno-cleido-mastoid muscle, and at muscle latissimus dorsi to muscle illio-costalis lumborum, as well as in the muscles of nuchae, submandibular and rectus abdominis. The phalangeal bones of the great toes developed fusion (figure \\u003cspan refid=\\\"Fig6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ea, b). Today she is wearing special shoes to avoid pain on weight-bearing.\\u003c/p\\u003e\"},{\"header\":\"Case 3\",\"content\":\"\\u003cp\\u003eA girl, the first child of healthy non-consanguineous parents was born in her family home 1975. She has three healthy siblings. Family history FOP negative. The patient has short great toes, noted by parents, but with no attention from healthcare providers. Muscle swelling after a fall gave indication for biopsy twice in two different countries. First biopsy at age four years due to painful mass in a muscle of left scapula region. Second biopsy obtained in different country at age eleven and half year of the paravertebral muscles. Based on malformations of great toes and histology of the biopsies the diagnosis of FOP was made. Genetic testing was not available at that time. In the following years, she had multiple flare-ups. Muscles from proximal to distal part and from dorsal to ventral regions according to topical FOP pattern was affected (figure \\u003cspan refid=\\\"Fig7\\\" class=\\\"InternalRef\\\"\\u003e7\\u003c/span\\u003ea, b). At age twenty-five, the first flare-up at the right great toe was observed. Co-morbidities as urological, allergic, dental, and upper respiratory tract pathologies was stated. A special medical team with relevant competences followed her frequently. She was given a \\u0026ldquo;FOP passport\\u0026rdquo; to be shown to any medical professionals, in case of emergency. At age thirty-three years recurrent flare-ups at both great toes took place. Joint fusions of both great toes became more severe. At age of thirty-four years, she was not able to walk or stand more than approximately five minutes. Despite her limited mobility, she was free from flare-ups for four years approximately. Right great toe and second toe were completely fused and impacted to each other at the age of forty-two. This condition gave basis for skin sores, local infection, and pain. After months of failed conservative management amputation of the second toe took place (figure \\u003cspan refid=\\\"Fig8\\\" class=\\\"InternalRef\\\"\\u003e8\\u003c/span\\u003ea, b). Today at age forty-five, she is free of pain in her feet. In-door was mobility preserved in custom made shoes (figure \\u003cspan refid=\\\"Fig9\\\" class=\\\"InternalRef\\\"\\u003e9\\u003c/span\\u003ea, b).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eThe great toe malformation\\u003c/h2\\u003e \\u003cp\\u003eThe great toe malformation is a red flag of FOP in early childhood. Before other clinical signs are present, FOP should be confirmed or excluded through DNA sequencing analysis (10-11). Natural history of FOP has been extensively studied (12-13). Rogers and Geho identified forty patients out of forty-two having great toe abnormalities (14). Connor and Evans studied thirty-four patients with FOP. All of them had characteristic skeletal malformations including abnormal great toes. Great toe malformations can be divided into four subtypes based on clinical and radiological findings. The most frequent is type I representing a short great toe without valgus deviation and without lateral deviation at the metatarsophalangeal joint. Type II, III and IV are less frequent (15-17). Nakashima and co-authors (3) performed a cross-sectional study of thirty-one feet in sixteen FOP patients and concluded that twenty-nine feet (93,5%) showed several degrees of great toe deformity. An analysis of radiographic characteristics of all feet without any follow-up, confirmed that proximal phalanx of the great toe was consistently shortened but morphologically dissimilar from case to case. Additional findings were occurrence of the fusion between the distal and proximal phalanx. In patients presented in this study with longitudinal follow-up of more than twenty years of age, temporal pattern of the great toe interphalangeal bony fusion was observed in all (figure \\u003cspan refid=\\\"Fig6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003eb and \\u003cspan refid=\\\"Fig7\\\" class=\\\"InternalRef\\\"\\u003e7\\u003c/span\\u003eb). In case three the focus was on the natural history of HO manifestation. All patients presented had characteristic congenital malformations of the great toes. The mean age of clinical onset of HO was approximately five years. Cohen et al. mention that the HO progression are seen in patterns proximal to distal, axial to appendicular and dorsal to ventral. Jaw involvement was late in almost all patients (13). It is of interest that in presented case one and two FOP started in the elbow region. The oldest patient, case three, was subject for two biopsy despites of correct diagnosis. In the 1970 to 1990 biopsy was often performed in FOP patients Kitterman et al. in 2005 (7). Unfortunately, the diagnosis of FOP is often delayed because of the rareness and challenging clinical picture. In the cases presented an early confirmatory specific genetic test may have changed the treatment strategy, especially the surgical interventions.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eGenetic tests\\u003c/h2\\u003e \\u003cp\\u003eFew case reports describe the applicability of the rapid genetic testing to prepare a specific personalized treatment plan prior to development of clinical symptoms (3, 8). In 2006 it became possible to detect the ACVR1 single gene mutation for FOP, which resulted in an accelerated research on how to apply the optimal management of FOP (22-23). The discovery of the FOP gene provided a highly specific target for future drug development that holds promise for altering not just the symptoms of the disease but also the disease itself (24). Still the diagnosis of FOP is primarily made by the clinical assessment of the patient. Confirmation of diagnosis by genetic testing is possible, thus avoiding misdiagnosis and devastating surgical interventions.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eManagement\\u003c/h2\\u003e \\u003cp\\u003eAt present, no specific management of FOP exists. It is evident that the innate immune system, the macrophages, neutrophils, and natural killer cells play an important role in the inflammatory soft tissue swelling, flare-ups. Hence, it has been of interest to use biological immunosuppressive therapeutics. The literature describes targeting the BMP signalling pathways at different levels or targeting cellular components important in the extra-skeletal bone regeneration may be useful (18-19, 24). In our case one, three different biological therapeutics had been prescribed. The efficacy and safety of these drugs have not yet been documented. Infliximab, which is a TNF-alpha inhibitor, may reduce the macrophages activity at the inflammatory response and thereby be helpful to reduce the sporadic soft tissue swelling. The formation of HO in FOP is described in the literature as an episodic rather than a continuous process related to soft tissue swelling following infections, trauma, immunizations, and iatrogenic harms (24). These episodes are usually preserved with corticosteroids and prevention of trauma. However, a frequent use of corticosteroids for swellings in the trunk and neck opposite to swelling in the extremities, is not recommended due to the difficulty in assessing the onset of the swelling. Due to the complexity of FOP pathogenesis, the use of a combination of drugs with different targets, which can act in synergy, might be helpful (23).\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cul\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003eIsolated congenital malformation of the great toes combined with progressive heterotopic ossifications in the soft tissue may be the first clinical manifestation of FOP calling for a thorough examination of the patient.\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003eConventional x-ray and RNA/DNA diagnostic test of the ACVR1 gene assure the diagnosis.\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003ePrevention of any trauma, soft tissue infection or surgical intervention including intramuscular injections are recommended.\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003eNo curative treatment exists today.\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n\\u003c/ul\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u003c/strong\\u003e are obtained from hospitals as well as consent for retrospective investigation and long-term follow-up of three patients. Ethics board of \\u0026ldquo;St Catherine\\u0026rdquo; Speciality Hospital (IRB) approved study with reference number: 21/9-1 of Aug 2021. Document is available upon request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInformed consent for using medical data\\u003c/strong\\u003e, as well as, radiographs, photos and other imaging tool are obtained by means of signature from all three patients. Note: at present time our patients are of adult age.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e of our patients\\u0026rsquo; medical data and imaging are obtained from all three patients with signature, providing that in no way their identity could be revealed in the manuscript. Documents are available upon request from corresponding author\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor\\u0026acute;s contributions\\u003c/strong\\u003e: Maria Kirstine M\\u0026oslash;ller \\u0026ndash; Madsen (MKMM) has designed patient 1 with supervision from Darko Anticevic (DA). DA has designed patients 2 and 3. The discussion and conclusions are performed of both authors. Both authors read and approved the final version of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e:\\u0026nbsp;The data of three patients presented in this manuscript are available from the corresponding author (DA) on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e: The authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u003c/strong\\u003e There is no funding.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgment\\u003c/strong\\u003e Thank you to Michel Bach-Hellfritzsch, MD for figure description.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eShe D, Zhang K. Fibrodysplasia ossificans progressiva in China. Bone. 2018 Apr; 109:101\\u0026ndash;3. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.bone.2017.11.016\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2017 Nov 22. Review. PubMed PMID: 29175272.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003ePignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011 Dec 1; 6:80. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1186/1750-1172-6-80\\u003c/span\\u003e\\u003c/span\\u003e. PMID: 22133093; PMCID: PMC3253727.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eNakashima Y, Haga N, Kitoh H, Kamizono J, Tozawa K, Katagiri T, et al. Deformity of the great toe in fibrodysplasia ossificans progressiva. J Orthop Sci. 2010;15:804\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eFonseca JE, Branco JC, Reis J, Evangelista T, Tavares V, Gomes AR, Queiroz MV. Fibrodysplasia ossificans progressiva: report of two cases. Clin Exp Rheumatol. 2000 Nov-Dec; 18(6):749\\u0026ndash;52. PMID: 11138342.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eShore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May; 38(5):525\\u0026ndash;7. doi: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1038/ng1783\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2006 Apr.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eOrtiz-Agapito F, Colmenares-Bonilla D. Quality of life of patients with.\\u0026nbsp;\\u003c/span\\u003e\\u003cspan\\u003efibrodysplasia ossificans progressiva. J Child Orthop. 2015 Dec;9(6):489\\u0026ndash;93.\\u0026nbsp;\\u003c/span\\u003e\\u003cspan\\u003edoi: 10.1007/s11832-015-0704-6. Epub 2015 Nov 13. PMID: 26564023; PMCID:.\\u0026nbsp;\\u003c/span\\u003e\\u003cspan\\u003ePMC4661157.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eKitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in Fibrodysplasia Ossificans Progresiva. Pediatrics. 2005;116(5):e654\\u0026ndash;61. DOI:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1542/peds.2005-0469\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eJanati J, Aghighi Y, Tofighi A, Akhavan A, Behrouzan O. Radiologic findings in seven patients with fibrodysplasia ossificans progressiva. Arch Iran Med. 2007 Jan; 10(1):88\\u0026ndash;90. PMID: 17198460.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003ePignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 2013 Jun;10 Suppl 2(0 2):437\\u0026ndash;48. PMID: 23858627; PMCID: PMC3995352.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eTowler OW, Shore EM, Xu M, Bamford A, Anderson I, Pignolo RJ, Kaplan FS. The congenital great toe malformation of fibrodysplasia ossificans progressiva? \\u0026ndash; A close call. Eur J Med Genet. 2017 Jul;60(7):399\\u0026ndash;402. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.ejmg.2017.04.013\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2017 May 1. PMID: 28473268.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eBauer AH, Bonham J, Gutierrez L, Hsiao EC, Motamedi D. Fibrodysplasia ossificans progressiva: a current review of imaging findings. Skeletal Radiol. 2018 Aug;47(8):1043\\u0026ndash;50. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1007/s00256-018-2889-5\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2018 Feb 14. PMID: 29445932.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eConnor JM, Evans DAP. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg (Br) 1982; 64(1):76\\u0026ndash;83.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eCohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of hetereotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg (Am) 1993; 75(2):215\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eRogers JG, Geho WB. Fibrodysplasia ossificans progressive. J Bone Joint Surg (Am) 1979; 61(6):909\\u0026ndash;14.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eHarrison RJ, Pitcher JD, Mizel MS, Temple HT, Scully SP. The radiographic morphology of foot deformities in patients with fibrodysplasia ossificans progressiva. Foot Ankle Int. 2005 Nov; 26(11):937-41. doi: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1177/107110070502601107\\u003c/span\\u003e\\u003c/span\\u003e. PMID: 16309607.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eBrennan TA, Lindborg CM, Bergbauer CR, Wang H, Kaplan FS, Pignolo RJ. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone. 2018 Apr; 109:259\\u0026ndash;66. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.bone.2017.08.023\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2017 Aug 26. PMID: 28851540.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eBouvard B, Masson C, Legrand E, Audran M. Fibrodysplasia ossificans progressiva. A case report and focus on the BMP signaling pathway. Morphologie 2016 Dec;100(331):250\\u0026ndash;5. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.morpho.2016.01.004\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2016 May 23. PMID: 26948676.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eGencer-Atalay K, Ozturk EC, Yagci I, Ata P, Delil K, Ozgen Z, Akyuz G. Challenges in the treatment of fibrodysplasia ossificans progressiva. Rheumatol Int 2019 Mar;39(3):569\\u0026ndash;76. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1007/s00296-018-4179-x\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2018 Oct 20. PMID: 30343406.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eLuo, Alsamarah Y, Zhang A, Hao K J. Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva. Curr Mol Med. 2016;16(1):4-11. doi: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.2174/1566524016666151222142446\\u003c/span\\u003e\\u003c/span\\u003e. PMID: 26695699.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eKaplan, Xu FS, Glaser M, Collins DL, Connor F, Kitterman M, Sillence J, Zackai D, Ravitsky E, Zasloff V, Ganguly M, Shore A. EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008 May; 121(5):e1295-300. doi: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1542/peds.2007-1980\\u003c/span\\u003e\\u003c/span\\u003e. PMID: 18450872; PMCID: PMC3502043.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eCappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The Horizon of a Therapy for Rare Genetic Diseases: A \\u0026quot;Druggable\\u0026quot; Future for Fibrodysplasia Ossificans Progressiva. Int J Mol Sci. 2018 Mar 26;19(4):989. doi: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.3390/ijms19040989\\u003c/span\\u003e\\u003c/span\\u003e. PMID: 29587443; PMCID: PMC5979309.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eHsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol 2019 Jun;85(6):1199\\u0026ndash;207. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1111/bcp.13777\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2018 Nov 6. PMID: 30281842; PMCID: PMC6533500.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eKaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):191\\u0026ndash;205. doi: 10.1016/j.berh.2007.11.007. PMID: 18328989; PMCID: PMC2424023.\\u003c/span\\u003e\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cspan\\u003eKartal M, Shore EM, Xu M, Schwering L, Uhl M, Korinthenberg R, Niemeyer C, Kaplan FS, Lauten M. Fibrodysplasia ossificans progressiva (FOP): watch the great toes! Eur J Pediatr. 2010 Nov;169(11):1417\\u0026ndash;21. doi:\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1007/s00431-010-1232-5\\u003c/span\\u003e\\u003c/span\\u003e. Epub 2010 Jun 26. PMID: 20577760; PMCID: PMC4964587.\\u003c/span\\u003e\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Fibrodysplasia ossificans progressive, FOP, great toe, case report\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-963656/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-963656/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground: \\u003c/strong\\u003eFibrodysplasia ossificans progressiva (FOP) is an ultra-rare and severely disabling genetic disorder. The worldwide prevalence is approximately 1 per 2 million. Heterozygous mutations in ACVR1/ALK2 gene exist in all sporadic and familial cases of FOP. The primary aim of this study is to describe the clinical course of three children suffering from FOP and followed for fifteen, twenty-two and forty years, respectively Secondary aim is to provide clinical advice on how to diagnose the condition with special reference to the great toes malformation and give current best therapeutic approaches.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eResults: \\u003c/strong\\u003eAll three cases characterized with malformed great toes initially followed by progressive loss of mobility for a period from fifteen to forty years. Conventional radiology indicates the diagnosis and RNA/DNA test confirm it.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eConclusion: \\u003c/strong\\u003eCongenital malformation of the great toes in early childhood may be the first clinical sign of FOP. A devastating disease due to its progressive formation of heterotopic ossifications in soft tissue even after minor injuries. Leading to progressive immobility, skeletal deformities, chronic pain, growth defects and disabling joint stiffness. No curative treatment exists today. Management is symptomatic combined with a prophylactic lifestyle avoiding blunt and pointed trauma including surgery.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Congenital Malformation of The Great Toe in Children. Did You Exclude Fibrodysplasia Ossificans Progressiva – FOP.\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2021-10-18 14:55:48\",\"doi\":\"10.21203/rs.3.rs-963656/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"599a19a0-c6d3-4f43-ae69-d1ea3c79be36\",\"owner\":[],\"postedDate\":\"October 18th, 2021\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":7917340,\"name\":\"Internal Medicine\"}],\"tags\":[],\"updatedAt\":\"2021-10-20T09:53:34+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2021-10-18 14:55:48\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-963656\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-963656\",\"identity\":\"rs-963656\",\"version\":[\"v1\"]},\"buildId\":\"_2-kVJe1T_tPrBINL-cwx\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}