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J Clin Invest 2022 Jun;132(12)

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 - the ability to recognize activin A as an agonist with bone morphogenic protein-like signaling that leads to heterotopic ossification (HO). Read More

Quintessence Int 2022 Jun 8;0(0):2-10. Epub 2022 Jun 8.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare autosomal dominant disorder characterized by congenital skeletal malformation and progressive heterotopic ossification. In the oral and maxillofacial region, deformity of the temporomandibular joint is a common feature of FOP, as well as restricted mouth opening derived from heterotopic ossification in the masticatory muscles. Since surgical procedures are generally not recommended because of the risk of flare-ups and increased heterotopic ossification, reports of tooth extractions and their outcomes in patients with FOP are limited. Read More

BMC Musculoskelet Disord 2022 Jun 1;23(1):519. Epub 2022 Jun 1.

Department of Internal Medicine Section Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. Read More

J Bone Miner Res 2022 May 30. Epub 2022 May 30.

Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, USA.

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. Read More

Orthop Res Rev 2022 4;14:147-148. Epub 2022 May 4.

[This corrects the article DOI: 10.2147/ORR.S337491. Read More

Mol Cell Biochem 2022 May 10. Epub 2022 May 10.

College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, 91766, USA.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. Read More

J Clin Invest 2022 Jun;132(12)

Regeneron Pharmaceuticals Inc, Tarrytown, New York, USA.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti-activin A via monoclonal antibody treatment. Read More

J Clin Invest 2022 Jun;132(12)

Department of Molecular & Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, Connecticut, USA.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the gene encoding the bone morphogenetic protein (BMP) type I receptor, ACVR1 (ALK2), the most prevalent of which results in an arginine to histidine substitution at position 206 (ACVR1[R206H]). The fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in fibro-adipogenic progenitors (FAPs), which drives HO. Read More

Ann Plast Surg 2022 Apr 2. Epub 2022 Apr 2.

From the Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Abstract: We report a case of fibrous scalp nodules and bilateral hallux valgus in an infant who one decade later was diagnosed with a rare life-threatening genetic disease. Read More

Hum Gene Ther 2022 05 2. Epub 2022 May 2.

Amsterdam UMC location VUMC, Human Genetics, Amsterdam, Netherlands;

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. Read More

Orthop Res Rev 2022 20;14:113-120. Epub 2022 Apr 20.

Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Internal Medicine Section Endocrinology, Amsterdam, the Netherlands.

Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare disease in which bone is formed in muscular tissue, tendons and ligaments. This is known as heterotopic ossification (HO). FOP is caused by a heterozygous mutation in the highly conserved ACVR1/ALK2 gene which affects about 1 in 1. Read More

Cureus 2022 Mar 22;14(3):e23392. Epub 2022 Mar 22.

Orthopaedics and Traumatology, Omdurman Military Hospital, Khartoum, SDN.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease with less than a thousand confirmed cases. It is a severely disabling genetic condition that affects soft tissues and is characterized by progressive extraskeletal heterotopic ossification and great toe deformities. The mode of FOP inheritance is autosomal dominant with no association to race, gender, or geographic distribution. Read More

Pain 2022 Apr 20. Epub 2022 Apr 20.

Division of Endocrinology and Metabolism, Department of Medicine; the Institute for Human Genetics; and the Program in Craniofacial Biology, University of California, San Francisco, California, USA.

Abstract: Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Read More

Orphanet J Rare Dis 2022 04 18;17(1):168. Epub 2022 Apr 18.

Departments of Orthopaedic Surgery and Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP.

Objective: To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement. Read More

Front Endocrinol (Lausanne) 2022 31;13:892799. Epub 2022 Mar 31.

Department of Internal Medicine, Section Endocrinology, Amsterdam University Medical Center (Amsterdam UMC), Amsterdam Bone Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Adv Ther 2022 06 16;39(6):2796-2805. Epub 2022 Apr 16.

Modus Outcomes, a Division of THREAD, Cambridge, MA, USA.

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling, autosomal dominant, congenital disease characterized by progressive multi-focal heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and fascia. Past FOP studies have focused on the clinical aspects of the disease; therefore, there is a paucity of qualitative research on the patient experience. Our objective was to better understand the experience of children and adolescents living with FOP from their and their parents' perspectives. Read More

Front Med (Lausanne) 2022 22;9:852678. Epub 2022 Mar 22.

Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by heterotopic ossification (HO) of the skeletal muscles, fascia, tendons and ligaments. Patients often experience limitations in jaw function due to HO formation in the maxillofacial region. However, no studies have yet analyzed the age of onset and location of HO and the type of restrictions it may yield in the maxillofacial region. Read More

Drugs 2022 Apr;82(6):711-716

Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.

Palovarotene (Sohonos™) is an orally bioavailable selective retinoic acid receptor (RAR)γ agonist being developed by Ipsen for the reduction of heterotopic ossification (HO) formation in patients with fibrodysplasia ossificans progressiva (FOP). By binding to RARγ, palovarotene inhibits bone morphogenetic protein and SMAD 1/5/8 signalling: interfering with these pathways prevents chondrogenesis and ultimately HO by permitting normal muscle tissue repair or regeneration to occur. Palovarotene received its first approval on 21 January 2022 to reduce the formation of HO in adults and children aged 8 years and above for females and 10 years and above for males with FOP in Canada. Read More

Clin Rheumatol 2022 Jun 28;41(6):1929-1930. Epub 2022 Mar 28.

Department of Genetics and Genomics, National Rehabilitation Institute Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco No. 289, Col. Arenal Guadalupe, C.P. 14389, Ciudad de México, (CDMX), Mexico.

J Bone Metab 2022 Feb 28;29(1):1-15. Epub 2022 Feb 28.

Division of Rheumatology, Department of Medicine, UMass Chan Medical School, Worcester, MA, USA.

Extracellular signal-regulated kinases (ERKs) are evolutionarily ancient signal transducers of the mitogen-activated protein kinase (MAPK) family that have long been linked to the regulation of osteoblast differentiation and bone formation. Here, we review the physiological functions, biochemistry, upstream activators, and downstream substrates of the ERK pathway. ERK is activated in skeletal progenitors and regulates osteoblast differentiation and skeletal mineralization, with ERK serving as a key regulator of Runt-related transcription factor 2, a critical transcription factor for osteoblast differentiation. Read More

Clin Case Rep 2022 Mar 6;10(3):e05556. Epub 2022 Mar 6.

Military Hospital Jalandhar Punjab India.

Temporomandibular joint ankyloses (TMJA) may manifest in patients with several predisposing systemic conditions. A case of extraarticular TMJA is presented in a patient diagnosed with fibrodysplasia ossificans progressive (FOP) is presented. The features, diagnosis, and management of TMJA superimposed on this condition are presented through a qualitative systematic review of literature. Read More

Bioorg Med Chem Lett 2022 05 8;64:128667. Epub 2022 Mar 8.

Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel CH-4002, Switzerland.

Inhibition of mutant activin A type-1 receptor ACVR1 (ALK2) signaling by small-molecule drugs is a promising therapeutic approach to treat fibrodysplasia ossificans progressiva (FOP), an ultra-rare disease leading to progressive soft tissue heterotopic ossification with no curative treatment available to date. Here, we describe the synthesis and in vitro characterization of a novel series of 2-aminopyrazine-3-carboxamides that led to the discovery of Compound 23 showing excellent biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and a favorable in vitro ADME profile. Read More

Bioanalysis 2022 Apr 10;14(7):405-419. Epub 2022 Mar 10.

Drug Metabolism & Pharmacokinetics & Clinical Pharmacology, Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19803, USA.

To develop a bioanalytical method for quantifying INCB000928 in human saliva. Human centrifuged saliva and human whole saliva were compared for matrix selection. Protein precipitation extraction and HPLC-MS/MS was used for analysis. Read More

Bone Rep 2022 Jun 28;16:101177. Epub 2022 Feb 28.

Center for Translational and Clinical Research, Department of Proteomics, School of Medicine, University of Zagreb, Zagreb, Croatia.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease in which bone tissue forms in extraskeletal sites, which is known as heterotopic ossification (HO). Extracellular vesicles (EVs) are small phospholipid-enclosed particles released by various cells which have an emerging, but not completely understood role in various (patho)physiological processes. In order to further study the pathophysiology of FOP we conducted a small observational study comparing the proteomic profiles of EV cargo, derived from pooled plasma of four patient groups: FOP patient ( = 1) during active disease phase (flare-up), FOP patients during remission ( = 2), patients after long bone fracture ( = 20) and healthy controls ( = 10). Read More

Int J Obstet Anesth 2022 05 17;50:103272. Epub 2022 Feb 17.

St George's University Hospitals NHS Foundation Trust, UK.

Orphanet J Rare Dis 2022 03 4;17(1):107. Epub 2022 Mar 4.

Division of Endocrinology and Metabolism, The UCSF Metabolic Bone Clinic, University of California-San Francisco, 513 Parnassus Ave, San Francisco, CA, USA.

Background: COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. Read More

Neuropathol Appl Neurobiol 2022 06 10;48(4):e12805. Epub 2022 Mar 10.

Department of Pathology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.

ACG Case Rep J 2022 Jan 25;9(1):e00737. Epub 2022 Jan 25.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by inflammatory flares of soft tissues, leading to heterotopic ossification and significant cumulative morbidity and early mortality. FOP minor trauma, including intramuscular medication administration, can induce ossification and should be avoided. We present a case of known FOP in a patient who presented with fevers of unknown origin and was found to have biopsy-proven ileal Crohn's disease. Read More

Nucleic Acid Ther 2022 Jun 27;32(3):185-193. Epub 2022 Jan 27.

Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c. Read More

J Clin Rheumatol 2021 Dec;27(8S):S858

From the University Hospital Clínico San Carlos, Madrid, Spain.