Article
Genetics & Heredity
Daniele De Brasi, Francesca Orlando, Valeria Gaeta, Maria De Liso, Fabio Acquaviva, Luigi Martemucci, Augusto Mastrominico, Maja Di Rocco
Summary: FOP is an ultra-rare genetic condition characterized by extraskeletal bone formation, with activating mutations of the ACVR1 gene being responsible for the skeletal and nonskeletal features. The clinical phenotype includes congenital bilateral hallux valgus malformation and early-onset heterotopic ossification, with essential care interventions focusing on avoiding unnecessary surgeries and administering medications to control inflammation.
Article
Endocrinology & Metabolism
Haitao Wang, Carmen L. De Cunto, Robert J. Pignolo, Frederick S. Kaplan
Summary: Progressive heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP) exhibits distinctive spatial and temporal patterns, correlating with infrared thermographs of the human body. Dysregulated temperature response of connective tissue progenitor cells in FOP patients influences the anatomical distribution of HO initiation and sustainment at various sites. This provides insights into potential therapeutic targets for this disabling condition.
Article
Medicine, Research & Experimental
John B. Lees-Shepard, Sean J. Stoessel, Julian T. Chandler, Keith Bouchard, Patricia Bento, Lorraine N. Apuzzo, Parvathi M. Devarakonda, Jeffrey W. Hunter, David J. Goldhamer
Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO). This study found that a monoclonal blocking antibody, JAB0505, exacerbated injury-induced HO in FOP mouse models, raising concerns about its safety and efficacy for treating FOP patients.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Cell Biology
Xinmiao Meng, Haotian Wang, Jijun Hao
Summary: FOP is a rare genetic disease caused by mutations in the ALK2 gene, leading to heterotopic ossification. Effective therapies are currently unavailable, but significant advances have been made in drug development.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Francesc Ventura, Eleanor Williams, Makoto Ikeya, Alex N. Bullock, Peter ten Dijke, Marie-Jose Goumans, Gonzalo Sanchez-Duffhues
Summary: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare congenital disease caused by heterozygous gene point mutations in the ACVR1 gene, leading to ectopic bone formation. Although there is no approved cure for FOP yet, multiple clinical trials are underway to find safe and effective treatments for this condition.
Review
Biochemistry & Molecular Biology
Roberto Ravazzolo, Renata Bocciardi
Summary: This article summarizes the basic research on the genetic mutation responsible for FOP, including advancements in related fields and potential therapeutic approaches. It also explores the reasons why the single mutation R206H in the ACVR1 gene is highly prevalent in FOP patients, as well as factors that may modulate FOP expression.
Article
Multidisciplinary Sciences
Yeon-Suk Yang, Jung-Min Kim, Jun Xie, Sachin Chaugule, Chujiao Lin, Hong Ma, Edward Hsiao, Jaehyoung Hong, Hyonho Chun, Eileen M. Shore, Frederick S. Kaplan, Guangping Gao, Jae-Hyuck Shim
Summary: The study developed gene therapy approaches that demonstrated efficacy in mouse models and human induced pluripotent stem cells, showing potential for preventing disabling heterotopic ossification in fibrodysplasia ossificans progressiva. These promising treatments could offer significant clinical benefits for patients with this rare genetic disorder.
NATURE COMMUNICATIONS
(2022)
Article
Pediatrics
Joshua Chun Ki Chan, Evelyn Eugenie Kuong, Joyce Pui Kwan Chan, Ho Ming Luk, Jasmine Lee Fong Fung, Joanna Yuet-ling Tung, Brian Hon Yin Chung
Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare condition with challenging diagnosis due to its rarity and non-specific symptoms. Early diagnosis and suitable management are crucial for preserving patients' function and quality of life. This report shares the diagnostic journeys and clinical courses of 8 FOP patients in Hong Kong, highlighting the associated challenges.
FRONTIERS IN PEDIATRICS
(2023)
Article
Pediatrics
Ambika Gupta, Puneeta Mishra, Madhumita Roy Chowdhury, Shah Alam Khan, Manisha Jana, Madhulika Kabra, Neerja Gupta
Summary: This study evaluates the natural history of Fibrodysplasia Ossificans Progressiva (FOP) and highlights possible masqueraders causing diagnostic delay and iatrogenic interventions. The findings indicate that clinical suspicion followed by molecular testing is a straightforward and effective method for confirming FOP. Diagnostic delay may result in disease progression and unnecessary invasive interventions.
INDIAN JOURNAL OF PEDIATRICS
(2023)
Review
Biotechnology & Applied Microbiology
Elisabeth M. W. Eekhoff, Ruben D. de Ruiter, Bernard J. Smilde, Ton Schoenmaker, Teun J. de Vries, Coen Netelenbos, Edward C. Hsiao, Christiaan Scott, Nobuhiko Haga, Zvi Grunwald, Carmen L. De Cunto, Maja di Rocco, Patricia L. R. Delai, Robert J. Diecidue, Vrisha Madhuri, Tae-Joon Cho, Rolf Morhart, Clive S. Friedman, Michael Zasloff, Gerard Pals, Jae-Hyuck Shim, Guangping Gao, Frederick Kaplan, Robert J. Pignolo, Dimitra Micha
Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease where soft connective tissue turns into heterotopic bone. Although the genetic defect is known, effective treatments have been hindered by the complexity of the disease. Gene therapy shows promise as a therapeutic option for FOP, but the role of the immune system and the primary causative cell remain unknown.
HUMAN GENE THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Ruben D. D. de Ruiter, Lisanne E. E. Wisse, Ton Schoenmaker, Maqsood Yaqub, Gonzalo Sanchez-Duffhues, E. Marelise W. Eekhoff, Dimitra Micha
Summary: FOP is an ultra-rare disease caused by genetic defects in the ACVR1 gene. We found that FOP patients have elevated Activin A production in their fibroblasts, and TGF beta 1 is a specific stimulant of Activin A in FOP. This study is the first to identify TGF beta 1 as a triggering factor of Activin A production in FOP, suggesting it as a possible therapeutic target.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Endocrinology & Metabolism
Masakazu Yamamoto, Sean J. Stoessel, Shoko Yamamoto, David J. Goldhamer
Summary: Fibrodysplasia ossificans progressiva (FOP) is a devastating disease characterized by abnormal bone formation. Researchers found that overexpressing the wild-type receptor ACVR1 can suppress injury-induced heterotopic ossification and protect against spontaneous abnormal skeletogenesis. This provides potential therapeutic strategies for FOP.
JOURNAL OF BONE AND MINERAL RESEARCH
(2022)
Article
Genetics & Heredity
Serena Cappato, Rasa Traberg, Jolita Gintautiene, Federico Zara, Renata Bocciardi
Summary: Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues. A novel variant in the ACVR1 gene was identified in a 3-year-old child with early and highly suggestive clinical features of FOP, despite the absence of the recurrent p.R206H substitution commonly found in FOP patients.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Clinical Neurology
Shinichiro Mori, Satoshi O. Suzuki, Hiroyuki Honda, Hideomi Hamasaki, Nobutaka Sakae, Naokazu Sasagasako, Hirokazu Furuya, Toru Iwaki
Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease characterized by progressive ossification of skeletal muscles. The causative gene for FOP has been identified as the ACVR1 gene, with mutations like R206H being common. Additionally, rare mutations like G356D have been found in some FOP patients.
Article
Biochemistry & Molecular Biology
Yeon-Suk Yang, Chujiao Lin, Hong Ma, Jun Xie, Frederick S. Kaplan, Guangping Gao, Jae-Hyuck Shim
Summary: Gene therapy using adeno-associated virus has been developed to suppress trauma-induced heterotopic ossification in mice with fibrodysplasia ossificans progressiva (FOP), while limiting expression in non-skeletal organs. The therapy effectively inhibits aberrant signaling pathway activation and osteogenic differentiation in skeletal progenitor cells.
Review
Pharmacology & Pharmacy
Edward C. Hsiao, Maja Di Rocco, Amanda Cali, Michael Zasloff, Mona Al Mukaddam, Robert J. Pignolo, Zvi Grunwald, Coen Netelenbos, Richard Keen, Genevieve Baujat, Matthew A. Brown, Tae-Joon Cho, Carmen De Cunto, Patricia Delai, Nobuhiko Haga, Rolf Morhart, Christiaan Scott, Keqin Zhang, Robert J. Diecidue, Clive S. Friedman, Fredrick S. Kaplan, Elisabeth M. W. Eekhoff
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2019)
Article
Genetics & Heredity
Zoran Gucev, Velibor Tasic, Dijana Plaseska-Karanfilska, Marija Dimishkovska, Nevenka Laban, Zoran Bozinovski, Marko Kostovski, Alek Saveski, Momir Polenakovic, O. Will Towler, Eileen M. Shore, Frederick S. Kaplan
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2019)
Article
Endocrinology & Metabolism
O. Will Towler, Eileen M. Shore, Frederick S. Kaplan
Review
Endocrinology & Metabolism
Robert J. Pignolo, Haitao Wang, Frederick S. Kaplan
FRONTIERS IN ENDOCRINOLOGY
(2020)
Article
Endocrinology & Metabolism
Robert J. Pignolo, Kin Cheung, Sammi Kile, Mary Anne Fitzpatrick, Carmen De Cunto, Mona Al Mukaddam, Edward C. Hsiao, Genevieve Baujat, Patricia Delai, Elisabeth M. W. Eekhoff, Maja Di Rocco, Zvi Grunwald, Nobuhiko Haga, Richard Keen, Benjamin Levi, Rolf Morhart, Christiaan Scott, Adam Sherman, Keqin Zhang, Fredrick S. Kaplan
Article
Genetics & Heredity
Samuel Kou, Carmen De Cunto, Genevieve Baujat, Kelly L. Wentworth, Donna R. Grogan, Matthew A. Brown, Maja Di Rocco, Richard Keen, Mona Al Mukaddam, Kim-Hanh Le Quan Sang, Umesh Masharani, Frederick S. Kaplan, Robert J. Pignolo, Edward C. Hsiao
ORPHANET JOURNAL OF RARE DISEASES
(2020)
Article
Cell Biology
O. Will Towler, Frederick S. Kaplan, Eileen M. Shore
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2020)
Article
Developmental Biology
O. Will Towler, Sun H. Peck, Frederick S. Kaplan, Eileen M. Shore
Summary: The development of joints in mammals and the formation of skeletal structures are greatly influenced by the BMP pathway and mutations in the ACVR1 gene can lead to FOP, affecting both joint and skeletal development.
DEVELOPMENTAL BIOLOGY
(2021)
Article
Genetics & Heredity
Diana Martin-Garcia, O. Will Towler, Meiqi Xu, Osmany Alfonso-Hernandez, Paula R. Oliveira, Marleny Alonso-Clavo, Eileen M. Shore, Frederick S. Kaplan
Summary: This case report describes a three-year-old girl from Angola with a nonclassic FOP presentation, characterized by complex malformations of the toes and fingers, reduction defects of the digits, absence of nails, progressive heterotopic ossification, and a confirmed heterozygous ACVR1 variant at c.983G > A. The emerging knowledge of FOP can help increase awareness of the disease in under-represented medical communities, improve access to clinical trials for FOP patients, and enhance their ability to connect with the international FOP community.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2021)
Article
Endocrinology & Metabolism
Frederick S. Kaplan, David T. Teachey, Jeffrey R. Andolina, David M. Siegel, Edna E. Mancilla, Edward C. Hsiao, Mona Al Mukaddam, David M. Rocke, Robert J. Pignolo
Summary: This study reported improvements in symptoms in three children with FOP treated with imatinib, supporting the design of further clinical trials.
Article
Endocrinology & Metabolism
Haitao Wang, Carmen L. De Cunto, Robert J. Pignolo, Frederick S. Kaplan
Summary: Progressive heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP) exhibits distinctive spatial and temporal patterns, correlating with infrared thermographs of the human body. Dysregulated temperature response of connective tissue progenitor cells in FOP patients influences the anatomical distribution of HO initiation and sustainment at various sites. This provides insights into potential therapeutic targets for this disabling condition.
Article
Genetics & Heredity
Frederick S. Kaplan, Jay C. Groppe, Meiqi Xu, O. Will Towler, Eduardo Grunvald, Kenneth Kalunian, Staci Kallish, Mona Al Mukaddam, Robert J. Pignolo, Eileen M. Shore
Summary: Genetic variants play a crucial role in clinical phenotyping, physical diagnosis, genetic counseling, understanding disease at the molecular level, and possibly advancing drug development. This study highlights two families with an ultra-rare ACVR1 gain-of-function variant responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype, expanding the understanding of this rare disorder.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Genetics & Heredity
Sreedhara Sangadala, Eileen M. Shore, Meiqi Xu, Clemens Bergwitz, Santiago A. Lozano-Calderon, Angela E. Lin, Scott D. Boden, Frederick S. Kaplan
Summary: A 54-year-old man with a history of heterotopic ossification (HO) and normal genetic analysis had variants of unknown significance (VUS) in the gene encoding LMP-1. In vitro experiments showed that the LMP-1 variants had increased BMP-reporter activity and induced higher levels of osteoblast markers and mineralization. These findings suggest a possible relationship between the LMP-1 variants and the patient's HO.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Medicine, General & Internal
Michelle Ho, Beau Y. Park, Norman G. Rosenblum, Mona Al Mukaddam, Frederick S. Kaplan, Victor Kucherov, Scott G. Hubosky, Gregory Kane, Vishal Desai, Michael R. Kramer, Bon S. Ku, Eric S. Schwenk, Jaime L. Baratta, Deepti Harshavardhana, Zvi Grunwald
Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that causes decreased joint mobility and the formation of a second skeleton. Utilizing 3D models for preoperative planning is crucial to avoid unnecessary surgical risks. Postoperatively, a multimodal analgesic regimen and steroid course are recommended, along with early ambulation.
AMERICAN JOURNAL OF CASE REPORTS
(2021)
Review
Endocrinology & Metabolism
Frederick S. Kaplan, Mona Al Mukaddam, Alexandra Stanley, O. Will Towler, Eileen M. Shore