Bone 2017 Jun 16. Epub 2017 Jun 16.

Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA; Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to normal tissue repair. FOP is caused by gain-of-function mutations in ACVR1, which encodes a type I BMP receptor. Read More

Bone 2017 Jun 13. Epub 2017 Jun 13.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) causes progressive disability due to heterotopic ossification from episodic flare-ups. Using data from 500 FOP patients (representing 63% of all known patients world-wide), age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods.

Results: Compared to data from a 1994 survey of 44 individuals with FOP, our current estimates of age- and joint-specific risks of new joint involvement are more accurate (narrower confidence limits), based on a wider range of ages, and have less bias due to its greater comprehensiveness (captures over three-fifths of the known FOP patients worldwide). Read More

Orphanet J Rare Dis 2017 Jun 12;12(1):110. Epub 2017 Jun 12.

Department of Orthopaedic Surgery, Center for Research in FOP & Related Disorders, The Perelman School of Medicine, The University of Pennsylvania, 3737 Market Street, Philadelphia, PA, 19104, USA.

Fibrodysplasia ossificans progressiva (FOP), a disabling disorder of progressive heterotopic ossification (HEO), is caused by heterozygous gain-of- function mutations in Activin receptor A, type I (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Presently, symptomatic management is possible, but no definitive treatments are available. Although extensive guidelines for symptomatic management are widely used, regional preferences exist. Read More

Bone 2017 Jun 6. Epub 2017 Jun 6.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic disorder characterized by episodic soft tissue swelling (flare-ups) that leads to progressive heterotopic ossification and restricted joint mobility.

Methods: Here we present the first longitudinal patient-reported mobility assessment (PRMA) in FOP based on a simple evaluation tool. At initial presentation and follow-up (1-11year span; median: 6 year span), 64 patients (36 females; 28 males) with classic FOP completed a questionnaire designed to rapidly assess mobility at 15 sites (three axial; six upper limb, and six lower limb). Read More

Ghana Med J 2016 Dec;50(4):248-250

Department of Surgery, Cape Coast Teaching Hospital, Cape Coast, Ghana.

Fibrodysplasia Ossificans Progressiva is a rare debilitating disorder of the musculoskeletal system affecting one in two million individuals. It is characterized by progressive extraskeletal ossification of soft tissues resulting in the original skeleton being encased in unyielding new bone leading to disability and ultimately death from cardiorespiratory failure. The present case brings to light the delays and potential pitfalls in diagnosis as a result of the rarity of the condition. Read More

Bone 2017 May 23. Epub 2017 May 23.

The following essays are the personal statements of two remarkable young individuals, Ian Cali and Laura Rossano, who candidly share their perspectives on living life with fibrodysplasia ossificans progressiva (FOP). These essays are excerpts from the opening comments that Ian and Laura delivered at The First and The Second International FOP Association Drug Development Forums in 2014 and 2016, respectively. We present these unedited essays in this special issue of BONE so that physicians, scientists, and researchers everywhere can glimpse the valiant challenges that envelop the lives of all individuals with FOP and can appreciate that diseases are not just biological processes but indelible human experiences. Read More

Front Endocrinol (Lausanne) 2017 24;8:74. Epub 2017 Apr 24.

Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Purpose: Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Read More

Eur J Med Genet 2017 Jul 1;60(7):399-402. Epub 2017 May 1.

Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Background: Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease. Read More

Bone 2017 Aug 29;101:123-128. Epub 2017 Apr 29.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) is a catastrophic genetic disorder of progressive heterotopic ossification (HO). Assessment of functional mobility in FOP will be essential to support clinical trials of investigational agents.

Results: Of necessity, we developed a simple, rapidly-administered, cumulative analogue joint involvement scale (CAJIS) for FOP based on assessments in 144 individuals worldwide with classic FOP. Read More

Bone 2017 Apr 25. Epub 2017 Apr 25.

School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Department of Medical Laboratory Science, Bengbu Medical College, Bengbu 233030, China; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address:

Heterotopic ossification (HO), a serious disorder of extra-skeletal bone formation, occurs as a common complication of trauma or in rare genetic disorders. Many conserved signaling pathways have been implicated in HO; however, the exact underlying molecular mechanisms for many forms of HO are still unclear. The emerging picture is that dysregulation of bone morphogenetic protein (BMP) signaling plays a central role in the process, but that other conserved signaling pathways, such as Hedgehog (HH), Wnt/β-catenin and Fibroblast growth factors (FGF), are also involved, either through cross-talk with BMP signaling or through other independent mechanisms. Read More

Arch Pediatr 2017 Jun 14;24(6):547-551. Epub 2017 Apr 14.

Service de pédiatrie générale multidisciplinaire, hôpital Estaing, CHU Clermont-Ferrand, 1, place Lucie-Aubrac, 63003 Clermont-Ferrand, France.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by the association of congenital bone abnormalities and extraskeletal ossification flare-ups occurring in muscles and fasciae. Early diagnosis is important to prevent ossification flare-ups, but some atypical presentations can lead to errors in diagnosis and therefore delay. Here, we report on a case of an atypical presentation of FOP in a girl, in whom prominent transverse reductional abnormalities delayed diagnosis. Read More

Indian J Anaesth 2017 Mar;61(3):266-268

Department of Onco.Anaesthesia and Palliative Medicine, Dr. BRAIRCH, AIIMS, New Delhi, India.

Stone Man syndrome or fibrodysplasia ossificans progressiva (FOP) is an extremely rare (1 in 2 million) genetic disorder characterised by ectopic ossification of the skeletal and connective tissues leading to progressive fusion of axial and appendicular skeleton. Surgery and anaesthesia-induced trauma can lead to disease flare-up if due precautions are not taken and disable the patient further. However, rarity of the disease may lead to its common misdiagnosis and anaesthesiologist may be caught unaware. Read More

Zebrafish 2017 Apr 10. Epub 2017 Apr 10.

1 Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine , Boston, Massachusetts.

Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant genetic disorder in humans characterized by explosive inflammatory response to injury leading to gradual ossification within fibrous tissues, including skeletal muscle, tendons, and ligaments. A variety of animal models are needed to study and understand the etiology of human FOP. To address this need, here we present characterizations of the first adult zebrafish model for FOP. Read More

J Oral Maxillofac Surg 2017 Mar 16. Epub 2017 Mar 16.

Professor, Dental and Oral Medical Center, Kurume University School of Medicine, Kurume, Japan.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic condition characterized by congenital malformation and progressive heterotopic ossification (HO) caused by a recurrent single nucleotide substitution at position 617 in the ACVR1 gene. As the condition progresses, HO leads to joint ankylosis, breathing difficulties, and mouth-opening restriction, and it can shorten the patient's lifespan. This report describes 3 cases of FOP confirmed by genetic testing in patients with restricted mouth opening. Read More

Eur J Orthop Surg Traumatol 2017 May 9;27(4):491-502. Epub 2017 Mar 9.

Emeritus Professor of Pediatric Surgery, Aristotle University of Thessaloniki, "G. Gennimatas" Hospital, Thessaloniki, Greece.

The formation of lamellar bone in the soft tissues, where bone normally does not exist, is called myositis ossificans. However, it would be more accurate to describe as myositis ossificans the involvement of skeletal muscles and as ectopic or heterotopic ossification the involvement of soft tissues in general. The lesion is subdivided in genetic and non-genetic or acquired types. Read More

Bone 2017 Jan 20. Epub 2017 Jan 20.

Division of Endocrinology and Metabolism and the Institute for Human Genetics, Department of Medicine, University of California, San Francisco, CA, United States.

A working group on rare bone diseases was held in Atlanta, Georgia as part of the 2016 annual meeting of the American Society for Bone and Mineral Research. The meeting was organized by Matthew Drake. Given recent advances in our understanding of fibrodysplasia ossificans progressiva (FOP), the initial portion of the program was devoted to basic, translational, and clinical aspects of FOP. Read More

Stem Cells Int 2016 15;2016:2725670. Epub 2016 Dec 15.

Medical Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea.

The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. Read More

Acad Radiol 2017 Mar 15;24(3):321-327. Epub 2016 Dec 15.

Division of Geriatric Medicine & Gerontology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Rationale And Objectives: Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in patients with FOP.

Materials And Methods: Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. Read More

JCI Insight 2016 Dec 8;1(20):e89805. Epub 2016 Dec 8.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. Read More

JNMA J Nepal Med Assoc 2016 Apr-Jun;54(202):91-93

Maulana Azad Medical College, New Delhi, India.

Fibrodysplasia ossificans progressiva is a rare disorder of heterotopic ossification. Procedures like biopsy and surgery are known to be aggravating factors in promoting heterotopic ossification Clues to clinical diagnosis may therefore be a great advantage to treating orthopedician. Valgus deformity of great toe is an important diagnostic clue for treating physicians and thus aids in preventing the clinicians from subjecting the patients to unnecessary invasive and traumatic procedures. Read More

J Trace Elem Med Biol 2017 Jan 4;39:186-192. Epub 2016 Oct 4.

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Germany. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is a rare inherited disease characterized by progressive heterotopic ossification. Disease onset, severity and symptoms vary between FOP patients, as does the frequency and activity of so-called flare-ups, during which tendons, ligaments, muscle and soft tissue are replaced by bone. Traumata, infections or other stressors are known inducers of flare-ups, and the hormone Activin A may be involved in disease activity; however, reliable biomarkers for FOP activity are missing, and the basal trace element and inflammatory state of patients are unknown. Read More

Sci Transl Med 2016 Nov;8(366):366ra163

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1(R206H) knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. Read More

Ann Transl Med 2016 Oct;4(Suppl 1):S28

Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Centre, Leiden, The Netherlands.

Stem Cells 2017 Mar 8;35(3):705-710. Epub 2016 Nov 8.

Department of Surgery, Section of Plastic Surgery, Burn/Wound and Regenerative Medicine Laboratory, University of Michigan, Michigan, USA.

The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomato(fl/fl) ). Read More

Cell Signal 2017 Jan 4;29:23-30. Epub 2016 Oct 4.

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany. Electronic address:

Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. Read More

Proc Natl Acad Sci U S A 2016 Nov 28;113(46):13057-13062. Epub 2016 Oct 28.

Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158;

Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). Read More

Morphologie 2016 Dec 23;100(331):250-255. Epub 2016 May 23.

Service de rhumatologie, CHU d'Angers, 49933 Angers cedex, France; GEROM groupe d'études remodelage osseux et biomatériaux, IRIS-IBS institut de biologie en santé, CHU d'Angers, université d'Angers, 49933 Angers cedex, France. Electronic address:

Fibrodysplasia ossificans progressiva is a very rare heritable disease characterized by a progressive heterotopic endochondal ossification, occurring in the first decade of life, and leading thereafter to a severe ankylosis of the spine, limbs and jaw, with a progressive and severe functional disability. To date the cause of the disease remains unknown and no medical treatment has been proved efficient. It has recently been shown that a recurrent mutation in activation domain of the activin-receptor IA (ACVR1), a BMP receptor, could lead to an abnormal signalling pathway of BMP-4 and contribute to the occurrence of the devastating lesions characteristic of the disease. Read More

Dis Model Mech 2016 Sep;9(9):1067

Shoulder Elbow 2016 Jan 10;8(1):37-40. Epub 2015 Aug 10.

The Shoulder Unit, Princess Elizabeth Orthopaedic Centre, Royal Devon and Exeter Hospital, Exeter, UK.

Fibrodysplasia progressiva ossificans (FPO) is an extremely rare condition characterized by abnormal heterotopic bone formation. The condition is eponymously known as 'stoneman' disease because patients can become effectively entombed within abnormal heterotopic bone. We present the first known case of a diaphyseal humeral fracture managed conservatively in an adult patient with this condition. Read More

J Med Genet 2016 Dec 26;53(12):859-864. Epub 2016 Aug 26.

Rare Disease Unit, Istituto Giannina Gaslini, Genoa, Italy.

Background: Fibrodysplasia ossificans progressiva is an autosomal dominant disorder due to germline mutations of ACVR1/ALK2 causing progressive heterotopic endochondral ossifications. Evidence of central nervous system involvement has emerged only recently.

Methods: We performed an observational cross-sectional brain MRI study in 13 patients (8 females, mean age 20 years), examining the relationship of clinical and neuroradiological findings. Read More

Stem Cell Res Ther 2016 Aug 17;7(1):115. Epub 2016 Aug 17.

Institute for Human Genetics and the Division of Endocrinology and Metabolism, University of California, 513 Parnassus Avenue, HSE901G, San Francisco, CA, 94143-0794, USA.

Background: The Activin A and bone morphogenetic protein (BMP) pathways are critical regulators of the immune system and of bone formation. Inappropriate activation of these pathways, as in conditions of congenital heterotopic ossification, are thought to activate an osteogenic program in endothelial cells. However, if and how this occurs in human endothelial cells remains unclear. Read More

Arch Bone Jt Surg 2016 Jun;4(3):285-8

Orthopedic Research Center, Shahid Kamyab Hospital, Nakhrisi Junc, Fadaeian Islam St, Mashhad, Iran.

Progressive osseous heteroplasia is a rare inherited disease that begins with skin ossification and proceeds into the deeper connective tissues. The disease should be distinguished from other genetic disorders of heterotopic ossification including fibrodysplasia ossificans progressiva (FOP) and Albright hereditary osteodystrophy (AHO). We report a case of progressive osseous heteroplasia in a twenty four years old male with a complaint of ankylosis of the entire upper left limb and digital cutaneous lesions and sparing of the other limbs and the axial skeleton. Read More

Bone 2016 Nov 2;92:29-36. Epub 2016 Aug 2.

Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China. Electronic address:

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Read More

Pediatr Radiol 2016 Oct 4;46(11):1568-72. Epub 2016 Aug 4.

Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi, 466-8550, Japan.

Background: We have clinically encountered children with fibrodysplasia ossificans progressiva who had abnormal calcaneal ossification.

Objective: To evaluate whether calcaneal ossification variants are significant radiographic findings in children with fibrodysplasia ossificans progressiva.

Materials And Methods: Lateral feet radiographs in nine children who fulfilled the diagnostic criteria of fibrodysplasia ossificans progressiva were reviewed. Read More

Expert Opin Ther Pat 2016 Aug 4:1-14. Epub 2016 Aug 4.

a Department of Pharmaceutical Sciences, College of Pharmacy , University of Nebraska Medical Center , Omaha , NE , USA.

Introduction: The bone morphogenetic protein (BMP) is a critical signaling pathway and plays a diverse role in embryonic pattern formation and is implicated in a variety of disease processes, including anemia, bone formation, atherosclerosis, skin diseases, and cancers, among others.

Areas Covered: This review covers small molecule inhibitors/antagonists of BMP in patent applications between 2008 - 2015, along with brief synopses of the disclosed inhibitors in the primary literature.

Expert Opinion: The development of potent and selective BMP inhibitors is ongoing with most of the work centered around improving the selectivity and pharmacokinetic profile. Read More

Radiographics 2016 Jul-Aug;36(4):1195-214

From the Mallinckrodt Institute of Radiology (K.M.S., E.F.S., G.K.) and Department of Pathology (A.S., J.A.C.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8131-MIR, St Louis, MO 63110.

Pediatric fibroblastic and myofibroblastic tumors are a relatively common group of soft-tissue proliferations that are associated with a wide spectrum of clinical behavior. These tumors have been divided into the following categories on the basis of their biologic behavior: benign (eg, myositis ossificans, myofibroma, fibromatosis colli), intermediate-locally aggressive (eg, lipofibromatosis, desmoid fibroma), intermediate-rarely metastasizing (eg, inflammatory myofibroblastic tumors, infantile fibrosarcoma, low-grade myofibroblastic sarcoma), and malignant (eg, fibromyxoid sarcoma, adult fibrosarcoma). Imaging has a key role in the evaluation of lesion origin, extent, and involvement with adjacent structures, and in the treatment management and postresection surveillance of these tumors. Read More

Stem Cell Res 2016 Jan 1;16(1):54-8. Epub 2015 Dec 1.

Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Föhrer Strasse 15, 13353 Berlin, Germany; Berlin Institute of Health-Stem Cell Core Facility, Berlin, Germany.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, autosomal dominant transmitted genetic disease. Patients experience progressive bone formation replacing tendons, ligaments, muscle and soft tissue. Cause of FOP are gain-of-function mutations in the Bone Morphogenetic Protein (BMP) receptor Activin A receptor type 1 (ACVR1) (Kaplan et al. Read More

J Orthop Case Rep 2015 Oct-Dec;5(4):10-3

Department Of Orthopaedics, Sri Ramachandra Medical College, Porur, Chennai - 600116. India.

Introduction: Myositis ossificans progressiva is very rare with a worldwide prevalence of approximately 1 case in 2 million individuals. No ethnic, racial, or geographic predisposition has been described. Although familial forms inherited on a dominant autosomal basis have been described, most cases are sporadic. Read More

Reumatol Clin 2016 Jun 6. Epub 2016 Jun 6.

Departamento de Reumatología, Hospital Universitario San Cecilio, Granada, España.

Exp Mol Med 2016 Jun 3;48(6):e237. Epub 2016 Jun 3.

Medical Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, South Korea.

Fibrodysplasia ossificans progressiva (FOP) syndrome is caused by mutation of the gene ACVR1, encoding a constitutive active bone morphogenetic protein type I receptor (also called ALK2) to induce heterotopic ossification in the patient. To genetically correct it, we attempted to generate the mutant ALK2-iPSCs (mALK2-iPSCs) from FOP-human dermal fibroblasts. However, the mALK2 leads to inhibitory pluripotency maintenance, or impaired clonogenic potential after single-cell dissociation as an inevitable step, which applies gene-correction tools to induced pluripotent stem cells (iPSCs). Read More

Am J Med Genet A 2016 Aug 27;170(8):2191-5. Epub 2016 May 27.

Department of Pediatric, Pediatric Genetic Unit, MBBM Foundation A.O.S. Gerardo, Monza, Italy.

The Carey-Finema-Ziter syndrome (CFZS, MIM 254940) is an apparently autosomal recessively inherited disorder consisting of the combination of non-progressive congenital myopathy with Moebius and Pierre Robin sequence, facial anomalies and growth delay. Mental development has been described as normal or delayed. Temporomandibular joint (TMJ) ankylosis is the immobility of the joint caused by ankylotic fusion of the mandible to the cranial base or zygoma. Read More

Eur J Med Genet 2016 Jun 13;59(6-7):330-6. Epub 2016 May 13.

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran; Comprehensive Genetic Center, Hope Generation Foundation, Tehran, Iran; Gene Clinic, Tehran, Iran. Electronic address:

"Disorganized Development of Skeletal Component" (DDSC) is a group of genetic skeletal dysplasia, caused by mutations in 9 genes including ACVR1. The most known ACVR1-related disorder is fibrodysplasia ossificans progressiva (FOP). FOP variants are frequently encountered with diagnostic challenges due to overlapping clinical manifestations and variable severity. Read More

Dis Model Mech 2016 Jun 28;9(6):685-96. Epub 2016 Apr 28.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy

The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. Read More

Clin Calcium 2016 May;26(5):691-8

Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Japan.

Fibrodysplasia ossificans progressive (FOP) is a genetic disorder characterized by progressive heterotopic ossification (HO) in skeletal muscle, tendons and ligaments. FOP is caused by gain-of-function mutations of ALK2, a receptor of bone morphogenetic proteins. Immune responses have been suggested to be involved in HO in FOP, because muscle trauma induces acute HO in patients with FOP. Read More

J Bone Miner Res 2016 Sep 20;31(9):1652-65. Epub 2016 Apr 20.

Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.

Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIF-1α integrates the cellular response to both hypoxia and inflammation and is a prime candidate for regulating HEO. We investigated the role of hypoxia and HIF-1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. Read More

J Bone Miner Res 2016 Mar 14;31(3):650-6. Epub 2015 Nov 14.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Fibrodysplasia ossificans progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare-ups. However, the natural history of FOP flare-ups is poorly understood. A 78-question survey on FOP flare-ups, translated into 15 languages, was sent to 685 classically-affected patients in 45 countries (six continents). Read More

Skeletal Radiol 2016 Jul 22;45(7):991-6. Epub 2016 Mar 22.

Department of Medical Imaging, Chi Mei Medical Center, Tainan, Taiwan.

This case subject is a 1-year-old girl presenting with recurrent diffuse soft-tissue swelling of the scalp and periorbital region. Her family denied any known history of trauma. There was no obvious discoloration or local heat at the lesion. Read More

ACS Biomater Sci Eng 2015 Nov 25;1(11):1139-1150. Epub 2015 Sep 25.

Department of Biomedical Engineering, Carnegie Mellon University, 700 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.

Trauma-induced heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP) are acquired and genetic variants of pathological bone formation occurring in soft tissues. Conventional treatment modalities target the inflammatory processes preceding bone formation. We investigated the development of a prophylaxis for heterotopic bone formation by addressing the biological basis for HO - dysregulation in the bone morphogenetic protein (BMP) signaling pathway. Read More

Neurol India 2016 Mar-Apr;64(2):354-6

Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India.

J Bone Miner Res 2016 Sep 12;31(9):1666-75. Epub 2016 Mar 12.

Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.

Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment, and premature death. Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1(R206H) , that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Read More