{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T09:23:49Z","timestamp":1778750629888,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)\/activin-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Heterotopic ossification is usually progressive leading to severe deformities in the trunk and extremities. Early clinical diagnosis is important to prevent unnecessary iatrogenic harm or trauma. Clinicians should become aware of early detectable skeletal malformations, including great toe deformities, shortened thumb, neck stiffness associated with hypertrophy of the posterior elements of the cervical spine, multiple ossification centers in the calcaneus, and osteochondroma-like lesions of the long bones. Although there is presently no definitive medical treatment to prevent, stop or reverse heterotopic ossification in FOP, exciting advances of novel pharmacological drugs focusing on target inhibition of the activated ACVR1 receptor, including palovarotene, REGN 2477, rapamycin, and saracatinib, have developed and are currently in clinical trials.<\/jats:p>","DOI":"10.3390\/biomedicines8090325","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T09:29:28Z","timestamp":1599038968000},"page":"325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Clinical Aspects and Current Therapeutic Approaches for FOP"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-1586","authenticated-orcid":false,"given":"Hiroshi","family":"Kitoh","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Aichi Children\u2019s Health and Medical Center, Obu, Aichi 474-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e654","DOI":"10.1542\/peds.2005-0469","article-title":"Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva","volume":"116","author":"Kitterman","year":"2005","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3171\/PED-08\/01\/091","article-title":"Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva","volume":"1","author":"Zaghloul","year":"2008","journal-title":"J. Neursurg. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1295","DOI":"10.1542\/peds.2007-1980","article-title":"Early diagnosis of fibrodysplasia ossificans progressive","volume":"151","author":"Kaplan","year":"2008","journal-title":"Pediatrics"},{"key":"ref_4","first-page":"437","article-title":"Fibrodysplasia ossificans progressiva: Diagnosis, management, and therapeutic horizons","volume":"10","author":"Pignolo","year":"2013","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1750-1172-6-80","article-title":"Fibrodysplasia ossificans progressiva: Clinical and genetic aspects","volume":"6","author":"Pignolo","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1385\/BMM:3:3-4:201","article-title":"The genetics of fibrodysplasia ossificans progressiva","volume":"3","author":"Shore","year":"2005","journal-title":"Clin. Rev. Bone Miner. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1385\/BMM:3:3-4:205","article-title":"Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva: The role of environment in the progression of heterotopic ossification","volume":"3","author":"Hebela","year":"2005","journal-title":"Clin. Rev. Bone Miner. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng1783","article-title":"A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva","volume":"38","author":"Shore","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/humu.20868","article-title":"Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1","volume":"30","author":"Kaplan","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.bbrc.2008.10.093","article-title":"A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor","volume":"377","author":"Fukuda","year":"2008","journal-title":"Biochem. Biophys. Res. Commum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1083\/jcb.127.6.1755","article-title":"Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage","volume":"127","author":"Katagiri","year":"1994","journal-title":"J. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"303ra137","DOI":"10.1126\/scitranslmed.aac4358","article-title":"Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A","volume":"7","author":"Hatsell","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bone.2017.11.014","article-title":"Activin A amplifies dysregulated BMP signaling and induced chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Wang","year":"2018","journal-title":"Bone"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1359\/jbmr.071030","article-title":"Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP)","volume":"23","author":"Billings","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_15","first-page":"3462","article-title":"The fibrodysplasia ossificans progressive R20H ACVR1 mutation activates BMP independent chondrogenesis and zebrafish embargo ventralization","volume":"119","author":"Shen","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2106\/00004623-199302000-00008","article-title":"The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients","volume":"75","author":"Cohen","year":"1993","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1080\/09638288.2017.1405083","article-title":"Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva","volume":"41","author":"Nakahara","year":"2019","journal-title":"Disabil. Rehabil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/00003086-199404000-00038","article-title":"Age- and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva","volume":"301","author":"Rocke","year":"1994","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.bone.2017.04.015","article-title":"A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP)","volume":"101","author":"Kaplan","year":"2018","journal-title":"Bone"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"686","DOI":"10.2106\/JBJS.I.00705","article-title":"Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressive","volume":"92","author":"Kaplan","year":"2010","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1385\/BMM:3:3-4:213","article-title":"Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva","volume":"3","author":"Kaplan","year":"2005","journal-title":"Clin. Rev. Bone Miner. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1007\/s00776-010-1542-5","article-title":"Deformity of the great toe in fibrodysplasia ossificans progressive","volume":"15","author":"Nakashima","year":"2010","journal-title":"J. Orthop. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1002\/ajmg.a.37205","article-title":"Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A.; R258G): A report of two patients","volume":"167","author":"Kaplan","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/ajmg.a.32151","article-title":"A unique case of fibrodysplasia ossificans progressiva with an ACVR1mutation, G356D, other than the common mutation (R206H)","volume":"146","author":"Furuya","year":"2008","journal-title":"Am. J. Med. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1242\/jcs.062901","article-title":"Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFbeta signals","volume":"123","author":"Karamboulas","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1097\/01.brs.0000166619.22832.2c","article-title":"Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome","volume":"30","author":"Schaffer","year":"2005","journal-title":"Spine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e52","DOI":"10.2106\/JBJS.J.01443","article-title":"Early clinical and radiographic characteristics in fibrodysplasia ossificans progressiva: A report of two cases","volume":"93","author":"Mishima","year":"2011","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1242\/dev.122.11.3607","article-title":"The role of bone morphogenetic proteins in vertebral development","volume":"122","author":"Duprez","year":"1996","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5582\/irdr.2014.01009","article-title":"Radiographic characteristics of the hand and cervical spine in fibrodysplasia ossificans progressive","volume":"3","author":"Mishima","year":"2014","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1007\/s11999-013-3008-5","article-title":"Review of the molecular development of the thumb: Digit primera","volume":"472","author":"Oberg","year":"2014","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1101\/gad.1641708","article-title":"Tailored Hox gene transcription and the making of the thumb","volume":"22","author":"Deschamps","year":"2008","journal-title":"Genes Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.yexcr.2005.12.002","article-title":"Smads oppose Hox transcriptional activities","volume":"312","author":"Li","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1007\/s00247-016-3662-3","article-title":"Characteristic calcaneal ossification: An additional early radiographic finding in infants with fibrodysplasia ossificans progressiva","volume":"46","author":"Hasegawa","year":"2016","journal-title":"Pediatr. Radiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1083\/jcb.200703113","article-title":"Filamin B represses chondrocyte hypertrophy in a Runx2\/Smad3-dependent manner","volume":"178","author":"Zheng","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/514","article-title":"The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate","volume":"19","author":"McCormick","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/1097-0177(200007)218:3<452::AID-DVDY1000>3.0.CO;2-P","article-title":"EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis","volume":"218","author":"Stickens","year":"2000","journal-title":"Dev. Dyn."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1359\/jbmr.2003.18.9.1593","article-title":"ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development","volume":"18","author":"Zhang","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2106\/00004623-199410000-00002","article-title":"Spinal deformity in patients who have fibrodysplasia ossificans progressive","volume":"76","author":"Shah","year":"1994","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ped.14065","article-title":"Fibrodysplasia ossificans progressive: Review and research activities in Japan","volume":"62","author":"Haga","year":"2020","journal-title":"Pediatr. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1056\/NEJMra050541","article-title":"Anti-inflammatory action of glucocorticoids\u2014New mechanisms for old drugs","volume":"353","author":"Rhen","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jbmr.2728","article-title":"The natural history of flare-ups in fibrodysplasia ossificans progressiva: A comprehensive global assessment","volume":"31","author":"Pignolo","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/00003086-199801000-00017","article-title":"Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva","volume":"346","author":"Brantus","year":"1998","journal-title":"Clin. Orthop."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1053\/hupa.2001.26464","article-title":"Mast cell involvement in fibrodysplasia ossificans progressiva","volume":"32","author":"Gannon","year":"2001","journal-title":"Hum. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.bone.2017.07.019","article-title":"Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases","volume":"109","author":"Kaplan","year":"2018","journal-title":"Bone"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cappato, S., Giacopelli, F., Ravazzolo, R., and Bocciardi, R. (2018). The horizon of a therapy for rare genetic diseases: A \u201cdruggable\u201d future for fibrodysplasia ossificans progressiva. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040989"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3803\/EnM.2018.33.3.331","article-title":"Recent topics in fibrodysplasia ossificans progressiva","volume":"33","author":"Katagiri","year":"2018","journal-title":"Endocrinol. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/bcp.13823","article-title":"Therapeutic advanced for blocking heterotopic ossification in fibrodysplasia ossificans progressiva","volume":"85","author":"Wentworth","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/0014-4827(80)90517-0","article-title":"Vitamin A inhibits chondrogenesis but not myogenesis","volume":"129","author":"Pacifici","year":"1980","journal-title":"Exp. Cell Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nm.2334","article-title":"Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-g agonists","volume":"17","author":"Shimono","year":"2011","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/jbmr.2820","article-title":"Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1R206H fibrodysplasia ossificans progressiva (FOP) Mutation","volume":"31","author":"Chakkalakal","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e40814","DOI":"10.7554\/eLife.40814","article-title":"Palovarotene reduced heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity","volume":"7","author":"Nicholas","year":"2018","journal-title":"eLife"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15438","DOI":"10.1073\/pnas.1510540112","article-title":"Neofunction of ACVR1 in fibrodysplasia ossificans progressiva","volume":"112","author":"Hino","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.stemcr.2018.10.007","article-title":"An mTOR signaling modulator suppressed heterotopic ossification of fibrodysplasia ossificans progressiva","volume":"11","author":"Hino","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1172\/JCI93521","article-title":"Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressive","volume":"127","author":"Hino","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.bbagrm.2013.08.002","article-title":"Serum regulation of Id1 expression by a BMP pathway and BMP responsive element","volume":"1829","author":"Lewis","year":"2013","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/8\/9\/325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:05:52Z","timestamp":1760177152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/8\/9\/325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,2]]},"references-count":55,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["biomedicines8090325"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines8090325","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,2]]}}}