Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP).
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ABSTRACT:
SUBMITTER: Shore EM
PROVIDER: S-EPMC2601573 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
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Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP).
Shore Eileen M EM Kaplan Frederick S FS
Bone 20080528 3
Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder of extensive and debilitating extra-skeletal bone formation. While the challenges of investigating a rare condition are many, the potential benefits are also great - not only for the specific disease under investigation, but also for the unique perspective on how cells normally function and the mechanisms that underlie more common disorders. This review will illustrate some of the many insights that we have gained by st ...[more]
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Project description:Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of extraskeletal bone formation, but could appropriately be viewed as a seminal disorder of osteochondrogenesis. Many, if not most, of the musculoskeletal features of FOP are related to dysregulated chondrogenesis including abnormal articular cartilage formation, abnormal diarthrodial joint specification, growth plate dysplasia, osteochondroma formation, heterotopic endochondral ossification (HEO), and precocious arthropathy. In FOP, causative activating mutations of Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the osteochondrodysplasia that impacts developmental phenotypes as well as postnatal features of this illustrative disorder. Here, we highlight the myriad developmental and postnatal effects on osteochondrogenesis that emanate directly from mutant ACVR1 and dysregulated bone morphogenetic protein (BMP) signaling in FOP.
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Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Extraskeletal bone formation associated with inflammation preceding the osseous conversion usually begins in the first decade, predominantly in the head, neck, and shoulders. All patients have malformed great toes. Most patients have a spontaneous mutation of the ACVR1 gene. We report a 17-year-old girl with malformed great toes who had her first episode of heterotopic ossification and impaired mobility of the left hip at the age of 13 years. No inflammatory fibroproliferative masses preceded the onset of heterotopic ossification. Radiographic studies demonstrated myositis ossificans, but failure to associate the great toe malformation with heterotopic ossification led to a failure to diagnose FOP. She underwent repeated and unnecessary operative procedures to remove a recurrent lesion. FOP was finally suspected when the great toe malformation was correlated with the trauma-induced heterotopic ossification. Genetic analysis confirmed the presence of the classic FOP mutation (ACVR1 c.617G>A; R206H). This case highlights the importance of examining the great toes in anyone with heterotopic ossification. The association of malformations of the great toe with heterotopic ossification in all cases of classic FOP will lead to prompt clinical diagnosis and the prevention of iatrogenic harm.
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Project description:Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.
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Project description:Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis. It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO) postnatally, which leads to the formation of a second skeleton of heterotopic bone. Individuals with these classic clinical features of FOP have the identical heterozygous activating mutation (c.617G>A; R206H) in the gene encoding ACVR1 (also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Disease activity caused by this ACVR1 mutation also depends on altered cell and tissue physiology that can be best understood in the context of a high-fidelity animal model. Recently, we developed such a knock-in mouse model for FOP (Acvr1(R206H/+)) that recapitulates the human disease, and provides a valuable new tool for testing and developing effective therapies. The FOP knock-in mouse and other models in Drosophila, zebrafish, chickens and mice provide an arsenal of tools for understanding BMP signaling and addressing outstanding questions of disease mechanisms that are relevant not only to FOP but also to a wide variety of disorders associated with regenerative medicine and tissue metamorphosis.
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Project description:The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP.
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Project description: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). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms of flare-ups were swelling (93%), pain (86%), or decreased mobility (79%). Seventy-one percent experienced a flare-up within the preceding 12 months (52% spontaneous; 48% trauma-related). Twenty-five percent of those who had received an intramuscular injection reported an immediate flare-up at the injection site, 84% of whom developed HO. Axial flare-ups most frequently involved the back (41.6%), neck (26.4%), or jaw (19.4%). Flare-ups occurred more frequently in the upper limbs before 8 years of age, but more frequently in the lower limbs thereafter. Appendicular flare-ups occurred more frequently at proximal than at distal sites without preferential sidedness. Seventy percent of patients reported functional loss from a flare-up. Thirty-two percent reported complete resolution of at least one flare-up and 12% without any functional loss (mostly in the head or back). The most disabling flare-ups occurred at the shoulders or hips. Surprisingly, 47% reported progression of FOP without obvious flare-ups. Worldwide, 198 treatments were reported; anti-inflammatory agents were most common. Seventy-five percent used short-term glucocorticoids as a treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids. This study is the first comprehensive global assessment of FOP flare-ups and establishes a critical foundation for the design and evaluation of future clinical trials.
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