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Background 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 leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine‐Serine rich domain and causing the hyper‐activation of the receptor and the responsivity to the non‐canonical ligand, Activin A. In the present study, we described a 3‐years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution. Methods Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection‐based assays. Results and Conclusions We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A‐mediated signaling, as observed for the gene variants associated with FOP., FOP is a rare genetic disease representing the most severe and disabling condition due to heterotopic ossification associated with gain‐of‐function mutations of the ACVR1 gene. We describe here a little patient with an early clinical presentation of the disease carrying a novel substituton of the ACVR1 causative gene.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of progressive ossification of skeletal muscle, fascia, tendons, and ligaments. Most FOP cases are caused by a heterozygous c. 617G > A mutation in the ACVR1 gene which encodes a gain-of-function of bone morphogenetic protein type I receptor. A human induced pluripotent stem cell (iPSC) line was generated from the dermal skin fibroblasts of a FOP patient who carries the c. 617G > A mutation in the ACVR1 gene. This iPSC line provides an attractive resource for FOP disease modeling.

The human ACVR1 gene encodes a transmembrane protein consisting of 509 amino acids called activin A receptor, type I (ACVR1) or activin receptor-like kinase 2 (ALK2) and has nine coding exons. The ALK2 protein functions as a signaling receptor for ligands of the transforming growth factor-β family. In the human ACVR1 gene, approximately 20 types of heterozygotic mutations in the coding exons have been associated with congenital disorders and somatic cancer, such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma, diffuse idiopathic skeletal hyperostosis and some congenital heart disorders. In the present study, we designed primers for direct sequencing of the nine coding exons in the human ACVR1 gene. The reliability of the primers was examined by PCR and DNA sequencing using genomic DNA prepared from peripheral blood or swab samples of three patients with FOP who had different mutations in the ACVR1 gene. A single nucleotide heterozygotic mutation was identified in each genomic sample without additional mutations in other regions. Therefore, the primers designed for the nine coding exons of the ACVR1 gene could be useful for the genetic diagnosis of patients who may have disorders associated with mutations in the ACVR1 gene.

Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific 'triggers' that push the hypersensitive ALK2-FOP receptor into full signaling mode. Identification of these triggers and their mechanism of action is critical for preventing HO and its devastating consequences in FOP patients. Models of FOP, generated in Drosophila, are shown to activate the highly conserved BMP signaling pathway in both Drosophila cell culture and in developing tissues in vivo. The most common FOP mutation, R206H, in ALK2 and its synonymous mutation, K262H, in the orthologous Drosophila receptor Sax, abolish the ability of wild type receptors to inhibit BMP ligand-induced signaling and lead to ubiquitous pathway activation in both cases but with important differences. When expressed in Drosophila, human ALK2R206H exhibits constitutive signaling. SaxK262H on the other hand can elicit excessive signaling similar to that observed for ALK2R206H in mammalian systems in vivo. For example, hyperactive signaling mediated by SaxK262H is triggered by an increase in ligand or in type II receptors. Interestingly, while the constitutive nature of ALK2R2026H in Drosophila requires activation by the type II receptor, it does not require its ligand binding domain. The differences exhibited by the two Drosophila FOP models enable a valuable comparative analysis poised to reveal critical regulatory mechanisms governing signaling output from these mutated receptors. Modifier screens using these Drosophila FOP models will be extremely valuable in identifying genes or compounds that reduce or prevent the hyperactive BMP signaling that initiates HO associated with FOP.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant severe musculoskeletal disease characterized by extensive new bone formation within soft connective tissues and unique skeletal malformations of the big toes which represent a birth hallmark for the disease. Most of the isolated classic cases of FOP showed heterozygous mutation in theACVR1gene on chromosome 2q23 that encodes a bone morphogenetic protein BMP (ALK2). The most common mutation is (c.617G > A) leading to the amino acid substitution of arginine by histidine (p.Arg206His). We currently report on an Egyptian infant with a sporadic classic FOP in whom c.617G > A mutation had been documented. The patient presented with the unique congenital malformation of big toe and radiological evidence of heterotopic ossification in the back muscles. The triggering trauma was related to the infant's head, however; neither neck region nor sites of routine intramuscular vaccination given during the first year showed any ossifications. Characterization of the big toe malformation is detailed to serve as an early diagnostic marker for this rare disabling disease.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by ectopic bone formation involving the connective tissues leading to severe skeletal manifestations. The genetic defect in this disorder has not been characterized in Indian patients till date. The authors report three cases of FOP along with the molecular defects identified in them. Exon 4 of the ACVR1 gene was amplified and analysed by sequencing. All three cases revealed common heterozygous mutation i.e., c.617(G>A). Identification of this mutation would lead to decrease in misdiagnosis and subsequent iatrogenic harm caused to these children by unnecessary surgical procedures. Also, mutation detection would provide an opportunity for prenatal diagnosis.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and disabling heterotopic ossification in specific anatomic locations with a world wide prevalence of 1 in 2 million population. Nearly 90% of patients with FOP are misdiagnosed and mismanaged. We present a case of a four-year-old boy brought by his parents with the complaints of stiffness of right shoulder, neck and multiple swellings over the upper back noted over the past 4 months. On examination bilateral symmetrical hallux valgus with microdactyly of great toes and multiple bony hard swellings on both the scapulae were noted. Skeletal survey revealed all the classical features of FOP. Mutation of the ACVR1gene on genetic analysis confirmed the diagnosis of FOP. Invasive surgical procedures including biopsy and manipulations for stiff joints were avoided as they strikingly end up in rapid progression of FOP. Congenital hallux valgus with short great toe in a child should be considered as an early diagnostic tool for FOP even before the onset of mass lesions. Genetic analysis for mutation of ACVR1gene is confirmatory. Prevention of injury, medical management of acute painful flare-ups and rehabilitation are the mainstay of treatment.

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare autosomal dominant genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Mutations in the ACVR1 gene (MIM 102576) were identified as a genetic cause of FOP [Shore et al., 2006]. Most patients with FOP have the same recurrent single nucleotide change c.617G>A, p.R206H in the ACVR1 gene. Furthermore, 11 other mutations in the ACVR1 gene have been described as a cause of FOP. Here, we review phenotypic and molecular findings of 130 cases of FOP reported in the literature from 1982 to April 2014 and discuss possible genotype-phenotype correlations in FOP patients.

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare autosomal dominant disorder characterized by postnatal progressive heterotopic ossification of the connective tissue and congenital malformation of the big toes. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. We report the case of a Moroccan patient with FOP carrying a rarely occurring mutation of ACVR1 gene.