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Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in ACVR1 c.772A>G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent αC helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild-type ACVR1 kinase. The high fidelity phenotype-genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare catastrophic genetic condition of extraskeletal (heterotopic) ossification. One in every two million people is affected worldwide, with no ethnic, racial, gender, or geographic predisposition. Most cases of FOP arise from a spontaneous missense mutation in the gene encoding bone morphogenic protein (BMP) type II receptor (ACVR1/ALK2). Affected individuals are normal at birth apart from malformed great toes. Onset of clinical symptoms is usually in the first decade of life, presenting with episodic emergence of painful rapidly appearing tumor-like soft tissue swellings (flare-ups). Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Most affected individuals are confined to wheelchair in the third decade of life. Worldwide rate of misdiagnosis of FOP is very high; clinicians often fail to associate the two classic clinical features of FOP: rapidly developing soft tissue swellings and the abnormal great toes. The current case presents a previously undiagnosed 39-year-old FOP patient, sadly a victim of lack of clinical awareness of this rare condition. As a result of repetitive iatrogenic harm, he has tragically 'turned into stone.' [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare, congenital disorder caused by heterozygous mutation of the bone morphogenetic protein type I receptor ACVR1. Various forms of atypical FOP have recently been identified, and a novel mutation, ACVR1 (587T>C), was reported in 2011. We report on the second patient worldwide with ACVR1 (587T>C) mutation. A 22-year-old Japanese male with no family history of heterotopic ossification did not show any malformation of the great toes and showed normal development from birth to the age of 17 years, when heterotopic ossification appeared in the lumbar area. The clinical symptoms were similar to those reported previously: the delayed onset with a slower and mild clinical course and little finger camptodactyly. Gene analysis revealed that the patient was heterozygous for ACVR1 (587T>C) mutation, the same one as reported in 2011, suggesting a correlation between the location of the mutation and the clinical symptoms. This second report of ACVR1 (587T>C) mutation worldwide is particularly meaningful in that it highlights the difference between clinical symptoms of the first reported patient with ACVR1 (587T>C) mutation and those of classic FOP. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder of skeletal malformations and progressive heterotopic ossification. The worldwide prevalence is estimated to be one in 2 million. This report outlines the management of a patient with FOP limited to the maxillofacial region where the FOP lesion produced a fusion between the mandibular ramus and the zygomatic complex and trismus. The patient underwent three surgical procedures and various medical treatments during a 19-year period in attempts to manage the trismus, all in vain. The initial difficulty in establishing the diagnosis and ignorance of the true nature of the disease led to unsuccessful surgery. [Copyright &y& Elsevier]

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. The present article reports the long-term oral outcomes of three Japanese patients with FOP, in whom the teeth were deliberately extracted to avoid the risk of oral inflammation causing further heterotopic ossification. The extractions were conducted under local or general anesthesia, and healing of sockets was nonproblematic with the formation of new bone. Undesirable events, including progression of heterotopic ossification in the oral and maxillofacial region and further restriction of mouth opening, were not apparent. The extractions also alleviated the existing inflammation, contributing to maintaining their oral hygiene. These cases suggest that deliberate planning and judicious surgery could induce favorable healing after tooth extractions in patients with FOP, leading to long-term stability of their oral health status.

Abstract: The origins of fibrodysplasia ossificans progressiva (FOP) in human history are unknown but the condition has been well described since Freke's account in 1740. Important contributions by physicians and scientists in the past two and a half centuries have converged on the remarkable skeleton of Harry Eastlack at The Mutter Museum of The College of Physicians in Philadelphia. [Copyright &y& Elsevier]

Background: The ACVR1 gene encodes a type I receptor for bone morphogenetic proteins (BMPs). Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues. Several aspects of FOP pathophysiology are still poorly understood, including mechanisms regulating ACVR1 expression. This work aimed to identify regulatory elements that control ACVR1 gene transcription. Methods and results: We first characterized the structure and composition of human ACVR1 gene transcripts by identifying the transcription start site, and then characterized a 2.9 kb upstream region. This region showed strong activating activity when tested by reporter gene assays in transfected cells. We identified specific elements within the 2.9 kb region that are important for transcription factor binding using deletion constructs, co-transfection experiments with plasmids expressing selected transcription factors, site-directed mutagenesis of consensus binding-site sequences, and by protein/DNA binding assays. We also characterized a GC-rich minimal promoter region containing binding sites for the Sp1 transcription factor. Conclusions: Our results showed that several transcription factors such as Egr-1, Egr-2, ZBTB7A/LRF, and Hey1, regulate the ACVR1 promoter by binding to the -762/-308 region, which is essential to confer maximal transcriptional activity. The Sp1 transcription factor acts at the most proximal promoter segment upstream of the transcription start site. We observed significant differences in different cell types suggesting tissue specificity of transcriptional regulation. These findings provide novel insights into the molecular mechanisms that regulate expression of the ACVR1 gene and that could be targets of new strategies for future therapeutic treatments. [ABSTRACT FROM AUTHOR]

Abstract: Heterotopic ossification (HO), acquired or hereditary, is the formation of true bone outside the normal skeleton. Although the lineages of cells contributing to bone formation during normal development are well defined, the precise lineages of cells that contribute to HO are not clear. This study utilized Cre-lox based genetic lineage tracing to examine the contribution to HO of cells that expressed either FoxD1 or Glast. Both lineages contributed broadly to different normal tissues, and FoxD1-cre labeled cells contributed to normal bone formation. Despite the similarity in labeling patterns of normal tissues, and the significant contribution of FoxD1-cre labeled cells to normal bone, only Glast-creERT labeled progenitors contributed significantly to HO at all stages, suggesting that the cell populations that normally contribute to physiological bone formation, such as the Foxd1-cre labeled cells, may not participate in pathological HO. Further, identification of Glast-expressing cells as precursors that give rise to HO should help with the molecular targeting of this population both for the prevention and for the treatment of HO. [Copyright &y& Elsevier]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through non-invasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP. [ABSTRACT FROM AUTHOR]

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by postnatal heterotopic ossification (HO). When HO affects the masticatory muscles, mouth opening becomes restricted. This paper presents the changes in facial morphology and occlusion of a patient with FOP who was followed from the age of 8 to age 21. At the initial examination, he had a severely protruded maxilla and Angle Class II Division 1 malocclusion. His mouth opening was restricted (5.0 mm). He had a large overjet and this enabled him to clean his teeth and to eat. Orthodontic correction was not planned, and his facial growth was closely followed with attention to his oral hygiene. The maxillary protrusion and a low mandibular plane angle became more prominent as the patient aged. His mandible rotated in a counterclockwise direction. His molars had delayed eruption or were impacted and seven were extracted. His mouth opening increased slightly and his oral hygiene improved to excellent. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Progressive osseous heteroplasia (POH) is a rare genetic disorder characterized by dermal ossification during infancy and progressive ossification into deep connective tissue during childhood. POH is at the severe end of a spectrum of GNAS-associated ossification disorders that include osteoma cutis and Albright Hereditary Osteodystrophy (AHO). Here we describe two girls who have different clinical presentations that reflect the variable expression of GNAS-associated disorders of cutaneous ossification. Each girl had a novel heterozygous inactivating mutation in the GNAS gene. One girl had POH limited to the left arm with severe contractures and growth retardation resulting from progressive heterotopic ossification in the deep connective tissues. The other girl had AHO with widespread, superficial heterotopic ossification but with little functional impairment. While there is presently no treatment or prevention for GNAS-associated ossification disorders, early diagnosis is important for genetic counselling and for prevention of iatrogenic harm. [Copyright &y& Elsevier]

Abstract: 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 studying FOP. [Copyright &y& Elsevier]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification of soft tissue. As heterotopic bone accumulates, range of motion is progressively lost and leads, eventually, to near-complete immobility. Proper rehabilitation helps to preserve health and function despite great impairment. Present and future rehabilitation approaches to enhance activities of daily living, mobility, education, vocation, and sexuality are discussed. [ABSTRACT FROM AUTHOR]

The ultimate goal of research on fibrodysplasia ossificans progressiva (FOP) is the development of treatments that will prevent, half, or even reverse the progression of the condition. Despite advances in understanding the pathophysiology of FOP, there are no therapies with scientifically proven benefits for the prevention or treatment of FOP. Insights obtained from the research laboratory and from the treatment of hundreds of patients world wide have allowed us to identify targets for potential therapies. Some of these therapies involve the use of currently available medications, whereas others involve novel therapeutic approaches that are in preclinical testing. In this article, we will review the scientific basis for considering various therapeutic options based on the known pathophysiology of FOP. Because there are presently no proven preventions or treatments for the condition, this article is intended to represent an opinion of the authors that may be helpful to others who face similar situations. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a devastating genetic disorder with profound oral and dental health care issues. Most patients with FOP eventually develop heterotopic ossification of the chewing muscles with resultant ankylosis of the temporom andibular joints. Preventive and restorative dental care, as well as endodontic, periodontic, and orthodontic care present therapeutic challenges to the dental practitioner, the anesthesiologist, and to the FOP patient throughout his or her life. [ABSTRACT FROM AUTHOR]

Animal models of fibrodysplasia ossificans progressiva (FOP) are important for understanding the pathophysiology of FOP and for testing possible therapies. Laboratory-generated genetic animal models, each with features of FOP, provide the opportunity to better understand the biology of FOP, and to study the effectiveness and safety of currently available and emerging therapies. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant genetic disorder of aberrant joint formation and heterotopic bone formation, and is the result of a mutation in an as-yet-unidentified gene. Dysregulated signaling pathways can be investigated as a method to identify the consequences of the mutated gene responsible for FOP and to identify potential therapeutic targets. Candidate signaling pathways for FOP are those whose dysregulation during embryonic development could account for the malformation of the great toes and whose postnatal dysregulation could explain the progressive heterotopic endochondral ossification that is such a disabling feature of the disorder. Signaling pathways that fit these criteria are the bone morphogenic protein (BMP)-signaling pathway and its interacting pathways. A large body of data suggests that the BMP4-signaling pathway is dysregulated in FOP. [ABSTRACT FROM AUTHOR]

Patients with fibrodysplasia ossificans progressiva (FOP) develop thoracic insufficiency syndrome (TIS), which can lead to life-threatening complications. Features contributing to TIS in patients with FOP include costovertebral malformations with orthotopic ankylosis of the costovertebral joints; ossification of intercostal muscles, paravertebral muscles, and aponeuroses; and progressive spinal deformity, including kyphoscoliosis or thoracic lordosis. Pneumonia and right-sided congestive heart failure are the major life-threatening hazards that result from TIS in patients with FOP. Prophylactic measures to maximize pulmonary function, minimize respiratory compromise, and prevent influenza and pneumonia may be helpful in decreasing the morbidity and mortality from TIS in patients with FOP. [ABSTRACT FROM AUTHOR]

Patients with fibrodysplasia ossificans progressiva (FOP) develop a craniofacial phenotype characterized most notably by mandibular hypoplasia. Other less well-defined features of FOP include invol vement of the joints, muscles, and associated fascia of the head and neck. Although absent at birth, the craniofacial phnotype generally emerges during the second decade of life. The cranofacial features of FOP may provide important insight into underlying molecular signaling pathways involved in the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Genetic and environmental factors affect the phenotype of fibrodysplasia ossificans progressiva (FOP) but their relative effects are unknown. We studied three pairs of monozygotic twins with FOP and found that, within each pair, congenital toe malformations were identical. However, postnatal beterotopic ossification varied greatly depending on life history and environmental exposure. This study shows that genetic determinants strongly influence disease phenotype during prenatal development and that environmental factors strongly influence postnatal progression of the disease. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare, heritable disorder with infrequent genetic transmission of the condition owing to low reproductive, fitness. The recent identification of several small, additional families with inheritance of classic features of FOP has provided the opportunity to expand positional cloning efforts to identify the mutated gene in FOP through whole-genome linkage nnalyses. Candidate gene studies using both genetic (linkage), and molecular (gene expression) approaches also are contributing to information about the genetic and cellular, causes of FOP. [ABSTRACT FROM AUTHOR]

Clinically, the lesions in fibrodysplasia ossificans progressiva (FOP) follow spontaneous or injury-induced exacerbations and are characterized by painful swellings in soft connective tissue that progress to form mature heterotopic bone. Heterotopic ossification (HO) progresses in characteristic anatomic and temporal patterns, and the location of HO dictates the severity of functional consequences. The histological stages of lesion formation are well described and include, in order of progression: perivascular lymphocytic infiltration (stage 1A), lymphocytic migration into affected muscle and myonecrosis (stage 1B), early reactive fibroproliferation (stage 1C), intense fibroproliferation, neovascularity, and angiogenesis (stage 2A), cartilage formation (stage 2B), and endochondral bone formation (stage 2C). Possible mechanisms for FOP lesion formation, including the origin of bone-forming cells, are discussed. [ABSTRACT FROM AUTHOR]

Dysregulation of the bone morphogenic protein (BMP)4-signaling pathway can explain many developmental and postnatal features of fibrodysplasia ossificans progressive (FOP). However, many puzzling clinical features of the disease strongly implicate an underlying immunological component to the disorder. In this article, we review features of the BMP4 signaling pathway that regulate the immune system, and suggest an integrated hypothesis for FOP that accounts for both BMP-related abnormalities and immunological features of the condition. [ABSTRACT FROM AUTHOR]

The phenotype of fibrodysplasia ossificans progressiva (FOP) includes two defining features: congenital malformation of the great toes and progressive heterotopic ossification in characteristic anatomic patterns. Additional common features include proximal medial tibial osteochondromas, orthotopic fusions of the posterior elements of the cervical spine, broad short femoral necks, and conductive hearing loss. The FOP phenotype supports that the primary molecular pathology involves the bone morphogenetic protein (BMP)-signaling pathway directly or a BMP-interacting pathway. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene of a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP. [ABSTRACT FROM AUTHOR]

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain-of-function pathogenic variant (codon 375, Arginine > Proline; ACVR1 R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1 R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1 R375P variant greatly expands the scope and understanding of this rare disorder., (© 2021 Wiley Periodicals LLC.)

The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2–3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study. • In fibrodysplasia ossificans progressiva (FOP) clinical trial enrollment is difficult. • Off-on-off-on (O4) designs rapidly assess drug efficacy and tolerability with limited subjects. • We report 3 FOP children who had recalcitrant back flare-ups treated with an imatinib O4 regimen. • Fewer flare-ups, decreased swelling and improved function were found "on" imatinib than "off". • The median time to improvement on imatinib was 2–3 weeks. [ABSTRACT FROM AUTHOR]

Progressive heterotopic ossification (HO) is a hallmark of fibrodysplasia ossificans progressiva (FOP); however, this tissue transformation is not random. Rather, we noticed that HO in FOP progresses in well-defined but inexplicable spatial and temporal patterns that correlate precisely with infrared thermographs of the human body. FOP is caused by gain-of-function mutations in Activin A receptor type I (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor kinase. As with all enzymes, the activity of ACVR1 is temperature-dependent. We hypothesized that connective tissue progenitor cells that express the common heterozygous ACVR1R206H mutation (FOP CTPCs) exhibit a dysregulated temperature response compared to control CTPCs and that the temperature of FOP CTPCs that initiate and sustain HO at various anatomic sites determines, in part, the anatomic distribution of HO in FOP. We compared BMP pathway signaling at a range of physiologic temperatures in primary CTPCs isolated from FOP patients (n = 3) and unaffected controls (n = 3) and found that BMP pathway signaling and resultant chondrogenesis were amplified in FOP CTPCs compared to control CTPCs (p < 0.05). We conclude that the anatomic distribution of HO in FOP may be due, in part, to a dyregulated temperature response in FOP CTPCs that reflect anatomic location. While the association of temperature gradients with spatial patterns of HO in FOP does not demonstrate causality, our findings provide a paradigm for the physiologic basis of the anatomic distribution of HO in FOP and unveil a novel therapeutic target that might be exploited for this disabling condition. • Thermographs correlate with patterns of heterotopic ossification in FOP. • FOP connective tissue progenitor cells exhibit a dysregulated temperature response. • BMP pathway signaling and resultant chondrogenesis are amplified in FOP. • We provide a paradigm for anatomic distribution of heterotopic ossification in FOP. [ABSTRACT FROM AUTHOR]

[Display omitted] Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity. [ABSTRACT FROM AUTHOR]

Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity to bone morphogenetic proteins (BMPs) and a neoceptor response to Activin A. There is extensive literature on the skeletal phenotypes in FOP, but a much more limited understanding of non-skeletal manifestations of this disease. Emerging evidence reveals important cardiopulmonary and neurologic dysfunctions in FOP including thoracic insufficiency syndrome, pulmonary hypertension, conduction abnormalities, neuropathic pain, and demyelination of the central nervous system (CNS). Here, we review the recent research and discuss unanswered questions regarding the cardiopulmonary and neurologic phenotypes in FOP. [ABSTRACT FROM AUTHOR]

The article describes the case of a 48-year-old woman with fibrodysplasia ossificans progressiva (FOP) who was given rosiglitazone for 14 months. Findings show that the patient did not experience new flare-ups during rosigliatizone therapy in comparison to her previous episodes while on prednisone. The results theorize that the patient's skin becomes softer and will have improved articular mobility with lowered dose administration. The data suggest that rosiglitazone therapy in combination with prednisone helps FOP patients' conditions.

The International Fibrodysplasia Ossificans Progressiva (FOP) Association was, founded by patient Jeannie Peeper in June of 1988 to educate patients, doctors, and the public about FOP: to raise funds and provide a patient base to support medical research into FOP: and to support patients with FOP and their families by providing a network of communication to help end the isolation that accompanies this rare and severely disabling condition. [ABSTRACT FROM AUTHOR]