Fibrodysplasia Ossificans Progressiva Patient Research Articles

A fibrodysplasia ossificans progressiva patient with a rare missense mutation in ACVR1 detected on 18F-FDG PET/CT

Fibrodysplasia ossificans progressiva (FOP) is an exceedingly rare human genetic disorder characterized by the progressive and incapacitating formation of ectopic bone outside the skeleton. We report a case of FOP patient with mutations within the ACVR1 gene (c.982G>A; p.G328R). 18F-FDG positron emission tomography/computed tomography (PET/CT) was carried out for disease assessment. Previous studies have shown increased FDG uptake in regions of heterotopic ossification (HO) in FOP. However, in our study, the PET/CT features demonstrate that active ossificans exhibit increased 18F-FDG uptake, whereas end-stage ossifications do not. Collectively, 18F-FDG PET/CT emerges as a prospective approach to evaluate medication efficacy in the early stages, directing early intervention and pharmacological management of FOP before ossifications formation.

Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation

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 (N = 1) during active disease phase (flare-up), FOP patients during remission (N = 2), patients after long bone fracture (N = 20) and healthy controls (N = 10). After isolation of EVs – their protein cargo was determined using liquid chromatography / mass spectrometry, after which a functional gene enrichment analysis was performed. Our results show a sizeable difference of the proteomics profiles in which EVs from the bone fracture group show significant activity of integrin interactions, Wnt, VEGF, IGF-1 and PDGF pathways; conversely, FOP patients' EVs indicate that HO occurs via processes of innate immunity and the Ephrin B signaling pathway. We hypothesize that the Ephrin B signaling (expressed in EVs) contributes to HO by aiding in mesenchymal stem cell recruitment and osteogenic differentiation, as well as by contributing to the inflammatory response, including macrophage chemotaxis and activation. This is, to our knowledge, the first published analysis of EV protein cargo in FOP.

P068 Abstract tin soldiers Global FOP patient search

Abstract While looking for one, you may find another: Tin Soldiers and the search for undiagnosed individuals with Fibrodysplasia Ossificans Progressiva (FOP) Background FOP is an ultra-rare condition where heterozygous, gain-of-function missense mutations in the ACVR1 gene result in progressive heterotopic bone formation in ligaments, tendons and muscles and result in severe disability.1 FOP has an estimated incidence of 0.6–1.3 per million individuals 2,3 suggesting that currently there are ∼8000 patients living with FOP worldwide, however only about 900 patients are currently diagnosed worldwide The diagnosis is made clinically by identification of typical malformations of the great toes as well as inflammatory swellings (flare-ups) that result in progressive and episodic ossification of soft connective tissues, often triggered by trauma.4 Muscle biopsies, though contraindicated, are frequently performed mistakenly during the course of diagnosis, as FOP is not a well-known condition. There is an urgent need to identify individuals with FOP across the globe in order to avoid harmful biopsies and to provide a pathway to care for patients with FOP. Tin Soldiers is a global FOP patient search program utilizing multimedia campaigns aimed at educating and bringing attention to FOP, to find individuals across the globe and to connect them to pathways of care. The mission is to identify every person with FOP who is currently undiagnosed, as well as to deliver education and support to those living with a diagnosis, but not connected to support networks. Once found, all people living with FOP are connected to pathways to care. The aim is to describe the Tin Soldiers global FOP patient search program approach and report early results of the program. Methods Tin Soldiers creates multimedia campaigns to create awareness and to educate medical professionals, healthcare workers, general public and local communities on FOP. At the heart of the communication program is story-telling of people living with FOP, from a feature-length documentary to public service announcements, animated short films and an 8-part Global Master Series—all designed to bring attention to FOP in order to find patients and provide a pathway to diagnosis and care. Importantly diagnosis is not the end of the journey, it’s just the beginning. Results Since official operations commenced in March 2020, Tin Soldiers has trained 535 medical professionals; established an African Clinicians Council of 10 doctors with the intention of mentoring others across the continent; increased the number of African patients with a diagnosis from 25 patients in December 2020–32 in April 2021. Connected previously diagnosed (but not connected) patients to a robust support network and held the first African FOP Family Gathering with clinicians from both South Africa and Nigeria. On the journey, patients with other conditions have been discovered including Juvenile Idiopathic Arthritis (JIA), Progressive Osseus Heteroplasia (POH) and Multiple Osteochondromas (MO). These patients have been diagnosed and connected to both medical care and patient support. Another important outcome is the continued education of doctors globally with the uptake of the CME Master Series in Russia and planned rollouts in Algeria, Nigeria, Kenya, Namibia, Sweden (in partnership with the national patient organization) and Brazil (under the First Lady’s patronage). Conclusion Tin Soldiers offers an innovative model of patient identification, diagnosis, support and education at all levels of care, using the power of story-telling and multi-media marketing. Such a model could be considered for raising the profile of other musculoskeletal or rare conditions and connecting patients to a functioning pathway to care.

Generation of an induced pluripotent stem cell line (TRNDi012-B) from Fibrodysplasia Ossificans Progressiva (FOP) patient carrying a heterozygous mutation c. 617G > A in the ACVR1 gene

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.

Activin-A Induces Early Differential Gene Expression Exclusively in Periodontal Ligament Fibroblasts from Fibrodysplasia Ossificans Progressiva Patients.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFβ, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells.

Tailored Teaching for Specialized (Para-)medical Students - Experience From Incorporating a Relevant Genetic Disease Throughout a Course of Molecular Cell Biology.

Worldwide, a mandatory course in Molecular Cell Biology is often part of the (para-) medical curricula. Student audiences are regularly not receptive to such relatively theoretical courses and teachers often struggle to convey the necessary information. Here, positive experience is shared on rigorously embedding a genetic disease that severely affects the movement apparatus, fibrodysplasia ossificans progressiva (FOP), in all aspects of a course for an international group of Research Master Human Movement Sciences students. Various molecular cell biological aspects of FOP were systematically implemented in the course, covering genetics, the biochemical consequences of the mutation, signaling pathways that affect bone formation and lectures on how to clone the mutation or cure the mutation. Students were invited to critically think about how to use the theories learned in the course to analyze a research paper. During the practical part of the course, students assisted in novel, cutting edge research on FOP patient derived or control cells. Research findings were reported in a research paper format. By building a Molecular Cell Biology course around an appealing disease, we managed to increase the general motivation of the students for the course as reflected in two specific questions of the course evaluations (p < 0.05). It convincingly taught the relevance of a course of Molecular Cell Biology to students with a primary background in biomechanics and physiotherapy for their paramedical professional life. This approach of embedding an audience-tailored human disease with a known genetic cause into a course can be implemented to many medical curriculum related courses and will increase students' perception of the relevance of a course.

Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry.

A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare genetic condition of progressive heterotopic ossification (HO) that results in ankylosis of joints and renders most affected individuals immobile by the second decade of life. Here, we present baseline phenotypes on 299 patients (median age 21years; range 0.1 to 78years) from 54 countries based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). The mean current age of the patients is 23.7years (range, 0.1 to 78years). Baseline characteristics are presented for FOP diagnosis, HO, flare-ups and precedent events, system-based prevalent symptomatology, encounters with medical and dental care providers, Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale scores, physical function, as well as the use of aids, assistive devices, and adaptations. Correlations of PROMIS Global Health scores with HO burden and physical function are calculated. Associations of joint mobility with PROMIS Global Health scores, physical function, and use of aids, assistive devices, and adaptations are summarized. Overall, the FOP Registry database contains a broad sample of the global FOP patient population, providing a useful tool for expanding knowledge of FOP, designing clinical trials and facilitating evidence-based decisions about the optimal monitoring and management of affected individuals.

Elevated plasma RANTES in fibrodysplasia ossificans progressiva – A novel therapeutic target?

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C–C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients.

Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP).

Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP.

The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of Registry. Patient-reported, aggregate data are summarized for the first 196 enrolled patients, representing participation from 42 countries and approximately 25% of the world's known FOP population. Fifty-seven percent of the current Registry participants are female with a mean age of 23.8years (median=21years, range=1, 76years). Among the Registry participants who provided their FOP type, 51% reported FOP Classic (R206H), 41% reported FOP Type Unknown, and 8% reported FOP Variant. Patients reported 5.4years (median=3.0years, range=0, 45.8years) as the mean age at which they noticed their first FOP symptoms and a mean age at final FOP diagnosis of 7.5years (median=5.0years, range=0.1, 48.4years). Information on the patients' diagnostic journeys in arriving at a correct diagnosis of FOP is also presented. These early patient-reported data suggest that the IFOPA's vision of one, unified, global, and coordinated approach to the FOP Connection Registry is well underway to being realized. In addition, the positive response from the FOP patient community to the initial launch of the Registry's patient portal has created a solid foundation upon which to build the largest international registry for monitoring the clinical progression of FOP among patients.

AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation

Activin A receptor type I or activin receptor-like kinase 2 (ACVRI/ALK2) belongs to type I TGF-β family and plays an important role in bone development. Activating mutations of ALK2 containing the R206 to H mutation, are present in 95% in the rare autosomal genetic disease fibrodysplasia ossificans progressiva (FOP), which leads to the development of ectopic bone formation in muscle. The effect of AMP-activated protein kinase (AMPK) activation on ALK2R206H-mediated signaling in fibroblasts obtained from a FOP patient was assessed in the present study. The activity of the mutated ALK2 was suppressed by pharmacological AMPK activators such as metformin and aspirin, while their actions were blocked by the dominant negative mutant of AMPK and mimicked by the constitutively active mutant of AMPK. Furthermore, activation of AMPK upregulated Smad6 and Smurf1 and thereby enhanced their interactions, resulting in its proteosome-dependent degradation of ALK2. In contrast, knockdown of Smad6 or Smurf1 prevented metformin-induced reduction of ALK2. To evaluate the biological relevance of AMPK action on ALK2 activity, we induced FOP fibroblasts into iPS cells and found that their osteogenic differentiation in vitro was inhibited by metformin. Our studies provide novel insight into potential approaches to treatment of FOP, since several AMPK activators (e.g. metformin, berberine, and aspirin) are already in clinical use for the treatment of diabetes and metabolic syndromes.

International physician survey on management of FOP: a modified Delphi study

Fibrodysplasia ossificans progressiva (FOP), a disabling disorder of progressive heterotopic ossification (HEO), is caused by heterozygous gain-of- function mutations in Activin receptor A, type I (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Presently, symptomatic management is possible, but no definitive treatments are available. Although extensive guidelines for symptomatic management are widely used, regional preferences exist. In order to understand if there was worldwide consensus among clinicians treating FOP patients, an expert panel of physicians directly involved in FOP patient care was convened. Using a modified Delphi method, broad international consensus was reached on four main topics: diagnosis, prevention of flare-ups, patient and family-centered care and general clinical management issues. This study of physician preferences provides a basis for standardization of clinical management for FOP.

FOP: still turning into stone

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."

Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Patients and Methods: In the present study, we present a case of FOP with marked progressive ossification of extraskeletal tissues. We investigated whether soluble factors in serum would affect the osteoblast phenotype by examining the effects of serum from this patient and control subjects on mouse osteoblastic MC3T3-E1 cells. Results: The clinical findings of this patient were compatible with FOP, and direct sequence analysis of genomic DNA demonstrated the presence of a heterozygous 617G > A (R206H) mutation of activin type 1 receptor (ACVR1). Serum from the FOP patient enhanced the level of alkaline phosphatase (ALP) in Western blotting, compared with serum from the control, in MC3T3-E1 cells. Moreover, serum from the FOP patient enhanced the levels of ALP, osteocalcin and bone morphogenetic protein-2 mRNA in these cells. Conclusion: We presented a case of FOP with progressive ossification in extra-skeletal tissues with ACVR1 mutation. The present data suggest that the serum from this patient includes some soluble factors, which might enhance the osteoblast differentiation and BMP2 expression in mouse osteoblastic cells.

Mutation Analysis and Prenatal Exclusion of Fibrodysplasia Ossificans Progressiva in a Chinese Fetus.

Aims: Fibrodysplasia ossificans progressiva (FOP) is a rare and severely disabling autosomal dominant disorder characterized by congenital malformations of the great toes and progressive postnatal heterotopic ossification. A point mutation in the activin receptor IA (ACVR1) gene is the cause of FOP. Most of the reported cases of FOP are sporadic and caused by de novo mutations; however, some rare cases can also result from parental germline mosaicism associated with a greater risk of recurrence in successive pregnancies. Therefore, once the pathogenic mutation has been identified in the proband, it is relative cheaper and important to perform prenatal diagnostic tests to exclude the recurrence risk of FOP in subsequent pregnancies. In this study, we first investigated the mutation in the ACVR1 gene in a Chinese FOP patient and then performed prenatal tests to exclude the risk of recurrence in the patient's unborn sibling. Methods: A couple visited our clinic with their 4-year-old son, who was clinically diagnosed with FOP, for genetic counseling. Genetic testing was performed by amplifying all the nine exons of the ACVR1 gene using the conventional polymerase chain reaction. Further, DNA sequencing was used to determine the mutation based on the results of a mutation screening using denaturing high-performance liquid chromatography. Subsequently, a prenatal test was performed using the same technique as that used for the proband. Results: A recurrent single nucleotide mutation c.617 G>A (R206H) of the ACVR1 gene was identified in the patient; however, both the parents had a normal ACVR1 gene. Prenatal tests showed that the fetus did not carry the pathogenic mutation. Conclusion: The results confirmed that a recurrent single nucleotide mutation c.617 G>A (R206H) was the genetic cause of FOP and explored the utility of prenatal testing in excluding the risk of recurrence in the successive pregnancy.

Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.

Radiotherapy for management of skin cancers in fibrodysplasia ossificans progressiva: A case report and review of the literature

Fibrodysplasia ossificans progressiva (FOP) is a rare condition of ectopic calcification leading to increasing disability throughout life, with most patients being wheelchair bound by the age of 30. Ectopic calcification can be triggered by trauma and it is therefore important to minimize biopsies and operative procedures in affected individuals. We report a 46-year-old FOP patient who was successfully treated with radiotherapy for a basal cell carcinoma. There are no previous reports in the literature on the management of skin malignancies in these patients and very limited literature on outcome following external beam radiotherapy.

Developmental Anomalies of the Cervical Spine in Patients With Fibrodysplasia Ossificans Progressiva Are Distinctly Different From Those in Patients With Klippel-Feil Syndrome

A radiographic analysis of the cervical spine of 70 patients diagnosed with fibrodysplasia ossificans progressiva (FOP) and 33 diagnosed with Klippel-Feil (KF) syndrome was conducted. The objectives of this study were to describe cervical spine abnormalities in patients with FOP, to compare and contrast those findings with the malformations in patients with KF syndrome, and to examine the possible etiology of these abnormalities. Congenital features of diseases often provide seminal clues to underlying etiology and developmental pathways. While progressive metamorphosis of connective tissue to heterotopic bone is the most dramatic and disabling feature of FOP, less severe congenital anomalies of the skeleton are also present. Vertebral fusions observed in KF are consistent with defects in embryonic segmentation. The cervical spine plain films of 70 FOP patients and 33 KF patients with documented congenital abnormalities were reviewed. Generalized neck stiffness and decreased range of motion were noted in most children with FOP. In the FOP patient group, characteristic anomalies, including large posterior elements, tall narrow vertebral bodies,and fusion of the facet joints between C2 and C7, were observed. Most notably, these characteristic anomalies of the cervical spine in patients with FOP were distinctly different from those of 33 patients with KF that were examined but were strikingly similar to those seen in mice with homozygous deletions of the gene-encoding noggin, a bone morphogenetic protein (BMP) antagonist. FOP patients exhibit a characteristic set of congenital spine malformations. While the noggin gene (NOG) is not mutated in patients who have FOP, these findings extend a growing body of evidence implicating overactivity of the BMP signaling pathway in the molecular pathogenesis of FOP.

Oral and Dental Health Care and Anesthesia for Persons With Fibrodysplasia Ossificans Progressiva

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.