Publications by authors named "Frederick S Kaplan"

116 Publications

The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva.

Front Cell Dev Biol 2020 8;8:612853. Epub 2020 Dec 8.

Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which extensive heterotopic ossification (HO) begins to form during early childhood and progresses throughout life. Although HO does not occur during embryonic development, children who carry the mutation that causes most cases of FOP characteristically exhibit malformation of their great toes at birth, indicating that the mutation acts during embryonic development to alter skeletal formation. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature. In this study, we examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.
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http://dx.doi.org/10.3389/fcell.2020.612853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753048PMC
December 2020

Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP).

Dev Biol 2021 Feb 17;470:136-146. Epub 2020 Nov 17.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, Clinical Research Building, Philadelphia, PA 19104, United States; Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. Electronic address:

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 Acvr1;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 Acvr1 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 Acvr1 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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http://dx.doi.org/10.1016/j.ydbio.2020.11.004DOI Listing
February 2021

Fibrodysplasia ossificans progressiva (FOP): A disorder of osteochondrogenesis.

Bone 2020 11 27;140:115539. Epub 2020 Jul 27.

Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

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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http://dx.doi.org/10.1016/j.bone.2020.115539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502483PMC
November 2020

Patients with ACVR1 mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva.

Orphanet J Rare Dis 2020 07 29;15(1):193. Epub 2020 Jul 29.

Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, University of California- San Francisco, 513 Parnassus Ave., HSE901G, San Francisco, CA, 94143-0794, USA.

Background: Genetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status.

Methods: The NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2 FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients.

Results: Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality.

Conclusions: We found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2 affects cardiac health will help elucidate the underlying mechanism.
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http://dx.doi.org/10.1186/s13023-020-01465-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389682PMC
July 2020

Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome.

Front Endocrinol (Lausanne) 2019 10;10:908. Epub 2020 Jan 10.

Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Segmental progeroid syndromes are commonly represented by genetic conditions which recapitulate aspects of physiological aging by similar, disparate, or unknown mechanisms. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in the gene for ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor, and results in the formation of extra-skeletal ossification and a constellation of others features, many of which resemble accelerated aging. The median estimated lifespan of individuals with FOP is approximately 56 years of age. Characteristics of precocious aging in FOP include both those that are related to dysregulated BMP signaling as well as those secondary to early immobilization. Progeroid features that may primarily be associated with mutations in ACVR1 include osteoarthritis, hearing loss, alopecia, subcutaneous lipodystrophy, myelination defects, heightened inflammation, menstrual abnormalities, and perhaps nephrolithiasis. Progeroid features that may secondarily be related to immobilization from progressive heterotopic ossification include decreased vital capacity, osteoporosis, fractures, sarcopenia, and predisposition to respiratory infections. Some manifestations of precocious aging may be attributed to both primary and secondary effects of FOP. At the level of lesion formation in FOP, soft tissue injury resulting in hypoxia, cell damage, and inflammation may lead to the accumulation of senescent cells as in aged tissue. Production of Activin A, platelet-derived growth factor, metalloproteinases, interleukin 6, and other inflammatory cytokines as part of the senescence-associated secretory phenotype could conceivably mediate the initial signaling cascade that results in the intense fibroproliferative response as well as the tissue-resident stem cell reprogramming leading up to ectopic endochondral bone formation. Consideration of FOP as a segmental progeroid syndrome offers a unique perspective into potential mechanisms of normal aging and may also provide insight for identification of new targets for therapeutic interventions in FOP.
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http://dx.doi.org/10.3389/fendo.2019.00908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966325PMC
January 2020

Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva.

Bone 2020 01 23;130:115116. Epub 2019 Oct 23.

Departments of Orthopaedic Surgery, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of Medicine, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. Electronic address:

Rationale: Fibrodysplasia ossificans progressiva (FOP) is primarily a disease of progressive heterotopic ossification (HO) leading to impaired mobility throughout life. An additional diagnostic feature is a characteristic malformation of the great toes. The culpable gene for FOP,ACVR1 (activin A receptor type 1) has a clear effect on the induction of extra-skeletal bone formation. However, this bone morphogenetic protein (BMP) pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations.

Materials And Methods: We analyzed baseline whole body (minus skull) computed tomographic (CT) scans of 113 individuals with classic clinical features of FOP and the ACVR1 (R206H) mutation who were enrolled in a non-interventional natural history study ((NCT02322255)) for skeletal malformations, atypical morphology, intra-articular synovial osteochondromatosis, developmental arthropathy, and associated degenerative joint phenotypes. Individuals were evaluated in three age groups: 4-13; 14-25; and 25-56 years old, based on historical models of FOP disease progression.

Results: We found widespread evidence of developmental arthropathy throughout the axial and appendicular skeleton in all age groups (61M, 52F; ages: 4-56 years). Asymmetric narrowing and subchondral sclerosis were present throughout the joints of the normotopic skeleton and osteophytes were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic. We also found evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacro-iliac joints, and lower limbs.

Conclusions: The effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease.

Significance: FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.
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http://dx.doi.org/10.1016/j.bone.2019.115116DOI Listing
January 2020

Correction to: Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes.

Orphanet J Rare Dis 2019 May 23;14(1):113. Epub 2019 May 23.

Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The original version of this article [1] unfortunately included an error to an author's name. Author Maja Di Rocco was erroneously presented as Maja DiRocco.The correct author name has been included in the author list of this Correction article and is already updated in the original article.
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http://dx.doi.org/10.1186/s13023-019-1096-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532205PMC
May 2019

Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes.

Orphanet J Rare Dis 2019 05 3;14(1):98. Epub 2019 May 3.

Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP.

Methods: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed.

Results: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52).

Conclusions: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients.

Trial Registration: This study ( NCT02322255 ) was first posted on 23 December, 2014.
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http://dx.doi.org/10.1186/s13023-019-1068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499994PMC
May 2019

Severe digital malformations in a rare variant of fibrodysplasia ossificans progressiva.

Am J Med Genet A 2019 07 22;179(7):1310-1314. Epub 2019 Apr 22.

Department of Orthopaedic Surgery, Center for Research in FOP & Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.

A 16-year-old girl with a history of nontraumatic swelling of both forearms, osteochondromas of the knees, heterotopic ossification of the neck and back, severe malformations of all digits with hypoplastic or absent nails, alopecia partialis of the scalp, and moderate cognitive impairment was seen for diagnostic evaluation. Whole exome sequencing identified an activating mutation of ACVR1 (c.983G > A; p.Gly328Glu) which confirmed a suspected FOP variant. The delayed diagnosis of an FOP variant in this patient could have been avoided if the significance of severe digital malformations had been recognized, especially in the setting of progressive heterotopic ossification.
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http://dx.doi.org/10.1002/ajmg.a.61153DOI Listing
July 2019

Heterotopic Ossification: The Keys to the Kingdom.

Bone 2018 04;109:1-2

Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104; Department of Genetics, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104; Department of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104. Electronic address:

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http://dx.doi.org/10.1016/j.bone.2018.03.001DOI Listing
April 2018

A case report of mesenteric heterotopic ossification: Histopathologic and genetic findings.

Bone 2018 04 7;109:56-60. Epub 2018 Jan 7.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c.690G>A; E230E) in the causative gene for FOP (ACVR1/ALK2). However, no frameshift, missense, or nonsense mutations in ACVR1, or in the causative gene for POH (GNAS), were found. Although genetic predisposition may play a role in MHO, our data suggest that mutations which occur in known hereditary conditions of HO are not the primary cause.
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http://dx.doi.org/10.1016/j.bone.2018.01.006DOI Listing
April 2018

ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells.

Bone 2018 04 27;109:201-209. Epub 2017 Dec 27.

Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions.
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http://dx.doi.org/10.1016/j.bone.2017.12.024DOI Listing
April 2018

Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases.

Bone 2018 04 11;109:281-284. Epub 2017 Dec 11.

Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.
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http://dx.doi.org/10.1016/j.bone.2017.12.011DOI Listing
April 2018

Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva.

Bone 2018 04 11;109:120-123. Epub 2017 Dec 11.

Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States; The Center for Research in FOP & Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States. Electronic address:

The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age-weighted prevalence of 4.5% (p=4×10) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition.
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http://dx.doi.org/10.1016/j.bone.2017.12.010DOI Listing
April 2018

Reply to: Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms.

J Bone Miner Res 2018 02 27;33(2):367-368. Epub 2017 Dec 27.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1002/jbmr.3349DOI Listing
February 2018

Ablation of Gsα signaling in osteoclast progenitor cells adversely affects skeletal bone maintenance.

Bone 2018 04 26;109:86-90. Epub 2017 Nov 26.

Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Gsα, the alpha stimulatory subunit of heterotrimeric G proteins that activates downstream signaling through the adenylyl cyclase and cAMP/PKA pathway, plays an important role in bone development and remodeling. The role of Gsα in mesenchymal stem cell (MSC) differentiation to osteoblasts has been demonstrated in several mouse models of Gsα inactivation. Previously, using mice with heterozygous germline deletion of Gsα (Gnas), we identified a novel additional role for Gsα in bone remodeling, and showed the importance of Gnas in maintaining bone quality by regulating osteoclast differentiation and function. In this study, we show that postnatal deletion of Gsα (CreERT2;Gnas) leads to reduction in trabecular bone quality parameters and increased trabecular osteoclast numbers. Furthermore, mice with deletion of Gsα specifically in cells of the macrophage/osteoclast lineage (LysM-Cre;Gnas) showed reduced trabecular bone quality and increased trabecular osteoclasts, but to a reduced extent compared to the CreERT2;Gnas global knockout. This demonstrates that while Gsα has a cell autonomous role in osteclasts in regulating bone quality, Gsα expression in other cell types additionally contribute. In both of these mouse models, cortical bone was more subtly affected than trabecular bone. Our results support that Gsα is required postnatally to maintain trabecular bone quality and that Gsα function to maintain trabecular bone is regulated in part through a specific activity in osteoclasts.
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http://dx.doi.org/10.1016/j.bone.2017.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866199PMC
April 2018

Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP).

Expert Opin Orphan Drugs 2017 17;5(4):291-294. Epub 2017 Mar 17.

Cali-Weldon Professor of FOP Research; Professor of Orthopaedic Surgery and Genetics, Co-Director, Center for Research in FOP and Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1080/21678707.2017.1304211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697787PMC
March 2017

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

Bone 2018 04 21;109:218-224. Epub 2017 Nov 21.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Background: 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.

Objective: 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).

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.bone.2017.11.014DOI Listing
April 2018

Clinical-pathological correlations in three patients with fibrodysplasia ossificans progressiva.

Bone 2018 04 13;109:104-110. Epub 2017 Oct 13.

Division of Endocrinology, Diabetes, and Metabolism, Institute for Human Genetics, Department of Medicine, University of California, San Francisco, CA, United States. Electronic address:

Objective: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which heterotopic bone forms in the soft tissues. This often occurs in response to injury or inflammation, leading to joint immobilization and significant disability. There are currently no definitive treatment options for this devastating disease. Although the most dramatic phenotype in FOP is the episodic and progressive heterotopic ossification, patients report a number of symptoms that affect other organ systems. Post-mortem examination of FOP patients may contribute to our understanding of the underlying pathophysiology and complications of this disease. Here, we present the autopsy findings from three patients with FOP.

Findings: Autopsy findings in two of the three patients confirmed that the cause of death was cardiorespiratory failure in the setting of severe thoracic insufficiency from heterotopic ossification. Both of these patients also had evidence of right ventricular dilatation likely secondary to thoracic insufficiency. The third patient died from complications of a traumatic head injury after a fall but also had post-mortem evidence of thoracic insufficiency syndrome. All three patients had extensive, widespread heterotopic ossification and joint deformities consistent with FOP. There was extensive ossification of the spinal ligament in these patients, which may contribute to cervical spine rigidity. One patient was diagnosed post-mortem with a brainstem malformation. No additional significant abnormalities were noted in the other organ systems. Finally, we also demonstrate that cadaveric skin fibroblasts can be isolated for use as a potential source for future in vitro cell culture studies.

Conclusions: This autopsy case series provides valuable information about the underlying complications of FOP and contributes significantly to our knowledge of this rare yet debilitating disorder. Thoracic insufficiency syndrome, right heart dysfunction, widespread heterotopic ossification, spinal ligament ossification, and CNS malformations were clearly evident; however, most other non-bone tissues appeared to be spared from gross malformations. Finally, the ability to isolate live cells from cadaveric skin is an important technique that will facilitate future studies, particularly as induced pluripotent stem cells and other cell-based technologies evolve. This case series highlights the importance of post-mortem examinations and their contribution to our current knowledge of disease pathophysiology and comorbidities.
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http://dx.doi.org/10.1016/j.bone.2017.10.009DOI Listing
April 2018

Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1 Mouse Model of Fibrodysplasia Ossificans Progressiva.

J Bone Miner Res 2018 02 3;33(2):269-282. Epub 2018 Jan 3.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1 (referred to as Acvr1 ) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1 lesions and in Acvr1 mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1 mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1 in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737844PMC
February 2018

Cartilage-derived retinoic acid-sensitive protein (CD-RAP): A stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP).

Bone 2018 04 28;109:153-157. Epub 2017 Sep 28.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints.

Results: Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations.

Conclusions: These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.
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http://dx.doi.org/10.1016/j.bone.2017.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680581PMC
April 2018

Clinical staging of Fibrodysplasia Ossificans Progressiva (FOP).

Bone 2018 04 21;109:111-114. Epub 2017 Sep 21.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Fibrodyplasia ossificans progressiva (FOP) is an ultra-rare genetic condition of heterotopic ossification (HO) that results in progressive loss of joint function, ultimately rendering movement impossible. Death is most commonly the result of thoracic insufficiency syndrome, or complications related to recurrent respiratory infections. There are no current treatments for FOP, but early and emerging clinical trials offer hope for this devastating disease. With the recent reporting of a comprehensive global natural history study, scales to assess joint dysfunction, and a more accurate prediction of joint survival, it is now possible to construct a conceptual framework for the clinical staging of FOP. Based on assessment of FOP features in seven areas, it is possible to assign five clinical stages. FOP features include flare-up activity, body regions affected, thoracic insufficiency, other complications, activities of daily living (ADLs), ambulatory status, and the cumulative joint involvement scale (CAJIS) score. Assessments of these features assign an individual with FOP to early/mild, moderate, severe, profound, or late-stage disease. These criteria seek to be flexible enough to be used by clinicians without reliance on advanced imaging or specialized testing, as well as by investigators involved in research or clinical trial studies who would have these tools available. These staging measures for FOP assess the influence of HO and accelerated joint dysfunction (due to congenital abnormalities) on the ability to perform common functional activities, and thus a delay or lack of progression from one stage to the next represents the ultimate test of efficacy for drug trials. This framework will serve both as a prediction tool for FOP progression as well as a critical opportunity to substantiate therapeutic interventions. The staging system proposed here will permit an accurate assessment of severity to appropriately develop or revise clinical plans of care, define operational research criteria, and identify the effectiveness of interventions. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage where disease-modifying therapies may be most efficacious.
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http://dx.doi.org/10.1016/j.bone.2017.09.014DOI Listing
April 2018

Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP).

Bone 2018 04 26;109:259-266. Epub 2017 Aug 26.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies.

Results: Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions.

Conclusions: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition.
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http://dx.doi.org/10.1016/j.bone.2017.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805128PMC
April 2018

Imaging assessment of fibrodysplasia ossificans progressiva: Qualitative, quantitative and questionable.

Bone 2018 04 16;109:147-152. Epub 2017 Aug 16.

Department of Radiology, Division of Musculoskeletal Imaging and Intervention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address:

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant genetic disorder of heterotopic ossification (HO) characterized by skeletal anomalies and episodic soft tissue swelling (flare-ups) that can transform into heterotopic bone. The progressive development of heterotopic bone and progressive arthropathy leads to significant limitation of mobility. This paper will review various imaging modalities used in evaluating episodic soft tissue swelling (flare-ups), heterotopic bone and skeletal anomalies. Different imaging modalities are required at different stages of the disease. Ultrasound and MRI can be useful for evaluating edema in early stages of a flare-up; MRI being superior to ultrasonography. Plain radiographs and computed tomography (CT) can evaluate heterotopic bone in later stages of HO, but CT scan is better at evaluating presence and the volume of heterotopic bone. Functional imaging demonstrates increased activity at sites of flare-ups, their utility in determining disease progression need to be further evaluated. Cost, radiation exposure, availability of various imaging modalities and the ability of FOP patients to fit in the scanner are all considerations when requesting radiographic tests in a patient with FOP. Future studies are required to determine if early radiographic findings can determine disease progression and response to treatment in this disorder.
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http://dx.doi.org/10.1016/j.bone.2017.08.011DOI Listing
April 2018

Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP).

Bone 2018 04 16;109:115-119. Epub 2017 Aug 16.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Flare-ups of the hips are among the most feared and disabling complications of fibrodysplasia ossificans progressiva (FOP) and are poorly understood. In order to better understand the nature of hip flare-ups in FOP, we evaluated 25 consecutive individuals with classic FOP (14 males, 11 females; 3-56years old, median age, 17years old) who presented with acute unilateral hip pain.

Results: All 25 individuals were suspected of having a flare-up of the hip based on clinical history and a favorable response to a four day course of high-dose oral prednisone. Ten individuals (40%) experienced rebound symptoms of pain and/or stiffness within seven days after discontinuation of prednisone and all ten subsequently developed heterotopic ossification (HO) or decreased mobility of the affected hip. None of the 14 individuals who experienced sustained relief of symptoms following a course of oral prednisone experienced HO or decreased mobility. Incidental radiographic findings at the time of presentation were multifactoral and included osteochondromas of the proximal femur (18/25; 72%), degenerative arthritis (17/25; 68%), developmental hip dysplasia (15/25; 60%), previously existing heterotopic ossification (12/25; 48%), intra-articular synovial osteochondromatosis (8/25; 32%) or traumatic fractures through pre-existing heterotopic bone (1/25; 4%).

Conclusions: Developmental joint pathology may confound clinical evaluation of hip pain in FOP. The most useful modality for suspecting an ossification-prone flare-up of the hip was lack of sustained response to a brief course of oral prednisone. Evaluation of soft tissue edema by ultrasound or magnetic resonance imaging showed promise in identifying ossification-prone flare-ups and warrants further analysis in prospective studies.
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http://dx.doi.org/10.1016/j.bone.2017.08.009DOI Listing
April 2018

Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases.

Bone 2018 04 20;109:276-280. Epub 2017 Jul 20.

Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases.

Results: Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication.

Conclusions: These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease.
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http://dx.doi.org/10.1016/j.bone.2017.07.019DOI Listing
April 2018

Vascular ossification: Pathology, mechanisms, and clinical implications.

Bone 2018 04 5;109:28-34. Epub 2017 Jul 5.

Department of Medicine, Cardiovascular Division, Section of Vascular Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address:

In recent years, the mechanisms and clinical significance of vascular calcification have been increasingly investigated. For over a century, however, pathologists have recognized that vascular calcification is a form of heterotopic ossification. In this review, we aim to describe the pathology and molecular processes of vascular ossification, to characterize its clinical significance and treatment options, and to elucidate areas that require further investigation. The molecular mechanisms of vascular ossification involve the activation of regulators including bone morphogenic proteins and chondrogenic transcription factors and the loss of mineralization inhibitors like fetuin-A and pyrophosphate. Although few studies have examined the gross pathology of vascular ossification, the presence of these molecular regulators and evidence of microfractures and cartilage have been demonstrated on heart valves and atherosclerotic plaques. These changes are often triggered by common inflammatory and metabolic disorders like diabetes, hyperlipidemia, and chronic kidney disease. The increasing prevalence of these diseases warrants further research into the clinical significance of vascular ossification and future treatment options.
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http://dx.doi.org/10.1016/j.bone.2017.07.006DOI Listing
April 2018

Joint-specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP).

Bone 2018 04 13;109:124-133. Epub 2017 Jun 13.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) causes progressive disability due to heterotopic ossification from episodic flare-ups. Using data from 500 FOP patients (representing 63% of all known patients world-wide), age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods.

Results: Compared to data from a 1994 survey of 44 individuals with FOP, our current estimates of age- and joint-specific risks of new joint involvement are more accurate (narrower confidence limits), based on a wider range of ages, and have less bias due to its greater comprehensiveness (captures over three-fifths of the known FOP patients worldwide). For the neck, chest, abdomen, and upper back, the estimated hazard decreases over time. For the jaw, lower back, shoulder, elbow, wrist, fingers, hip, knee, ankle, and foot, the estimated hazard increases initially then either plateaus or decreases. At any given time and for any anatomic site, the data indicate which joints are at risk.

Conclusions: This study of approximately 63% of the world's known population of FOP patients provides a refined estimate of risk for new involvement at any joint at any age, as well as the proportion of patients with uninvolved joints at any age. Importantly, these joint-specific survival curves can be used to facilitate clinical trial design and to determine if potential treatments can modify the predicted trajectory of progressive joint dysfunction.
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http://dx.doi.org/10.1016/j.bone.2017.06.009DOI Listing
April 2018

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

Orphanet J Rare Dis 2017 06 12;12(1):110. Epub 2017 Jun 12.

Department of Orthopaedic Surgery, Center for Research in FOP & Related Disorders, The Perelman School of Medicine, The University of Pennsylvania, 3737 Market Street, Philadelphia, PA, 19104, USA.

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.
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http://dx.doi.org/10.1186/s13023-017-0659-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468985PMC
June 2017

Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP).

Bone 2018 04 6;109:158-161. Epub 2017 Jun 6.

Department of Medicine, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic disorder characterized by episodic soft tissue swelling (flare-ups) that leads to progressive heterotopic ossification and restricted joint mobility.

Methods: Here we present the first longitudinal patient-reported mobility assessment (PRMA) in FOP based on a simple evaluation tool. At initial presentation and follow-up (1-11year span; median: 6 year span), 64 patients (36 females; 28 males) with classic FOP completed a questionnaire designed to rapidly assess mobility at 15 sites (three axial; six upper limb, and six lower limb). In order to validate this instrument, twenty-one of 64 patients (33%) underwent a cumulative analogue joint involvement scale (CAJIS) evaluation by two physicians within six months of their second self-assessment.

Results: We found that: 1) mobility changes were episodic and regional, occurring first in the neck and trunk, followed by the upper limbs and finally the lower limbs; 2) interval improvements in mobility did occur, most notably in the lower limbs (18%), and less so in the upper limbs (12%) and trunk (3%), and 3) patient-reported mobility assessments correlate highly (R=0.81) with physician-reported CAJIS evaluations.

Conclusion: This is the first longitudinal PRMA in FOP and provides a simple and valid tool that can be used in the design and evaluation of clinical trials in this progressively disabling disease.
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http://dx.doi.org/10.1016/j.bone.2017.06.005DOI Listing
April 2018