Ossification In Fibrodysplasia Ossificans Progressiva Research Articles

Primary cilia mediate skeletogenic BMP and Hedgehog signaling in heterotopic ossification.

Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy-treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.

Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles, tendons, and ligaments. FOP is caused by a missense mutation in the ACVR1 gene (activin A receptor type I), an important signaling receptor involved in endochondral ossification. The ACVR1R206H mutation induces increased downstream canonical SMAD-signaling and drives tissue-resident progenitor cells with osteogenic potential to participate in endochondral HO formation. In this article, we review aberrant ACVR1R206H signaling and the cells that give rise to HO in FOP. FOP mouse models and lineage tracing analyses have been used to provide strong evidence for tissue-resident mesenchymal cells as cellular contributors to HO. We assess how the underlying mutation in FOP disrupts muscle-specific dynamics during homeostasis and repair, with a focus on muscle-resident mesenchymal cells known as fibro-adipogenic progenitors (FAPs). Accumulating research points to FAPs as a prominent HO progenitor population, with ACVR1R206H FAPs not only aberrantly differentiating into chondro-osteogenic lineages but creating a permissive environment for bone formation at the expense of muscle regeneration. We will further discuss the emerging role of ACVR1R206H FAPs in muscle regeneration and therapeutic targeting of these cells to reduce HO formation in FOP.

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.

ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages.

Macrophages play crucial roles in many human disease processes. However, obtaining large numbers of primary cells for study is often difficult. We describe 2D and 3D methods for directing human induced pluripotent stem cells (hiPSCs) into macrophages (iMACs). iMACs generated in 2D culture showed functional similarities to human primary monocyte-derived M2-like macrophages, and could be successfully polarized into a M1-like phenotype. Both M1- and M2-like iMACs showed phagocytic activity and reactivity to endogenous or exogenous stimuli. In contrast, iMACs generated by a 3D culture system showed mixed M1- and M2-like functional characteristics. 2D-iMACs from patients with fibrodysplasia ossificans progressiva (FOP), an inherited disease with progressive heterotopic ossification driven by inflammation, showed prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, resulting in dampened responses to additional LPS stimulation. These results demonstrate a simple and robust way of creating hiPSC-derived M1- and M2-like macrophage lineages, while identifying macrophages as a source of Activin A that may drive heterotopic ossification in FOP.

Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients.

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

Clinical Aspects and Current Therapeutic Approaches for FOP.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Heterotopic ossification is usually progressive leading to severe deformities in the trunk and extremities. Early clinical diagnosis is important to prevent unnecessary iatrogenic harm or trauma. Clinicians should become aware of early detectable skeletal malformations, including great toe deformities, shortened thumb, neck stiffness associated with hypertrophy of the posterior elements of the cervical spine, multiple ossification centers in the calcaneus, and osteochondroma-like lesions of the long bones. Although there is presently no definitive medical treatment to prevent, stop or reverse heterotopic ossification in FOP, exciting advances of novel pharmacological drugs focusing on target inhibition of the activated ACVR1 receptor, including palovarotene, REGN 2477, rapamycin, and saracatinib, have developed and are currently in clinical trials.

Palovarotene inhibits the development of new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP)

Palovarotene inhibits the development of new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP)

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.

Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva – How Does One Tissue Become Another?

The development and maintenance of tissues and organ systems depend on precise coordination of cellular events and mechanisms. During embryonic development, the induction of bone formation is spatially and temporally regulated to specify the skeletal elements. After birth, new bone formation is normally limited to regeneration during fracture repair, a process that is also precisely regulated.Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which extensive and progressive heterotopic ossification – the formation of bone outside of the normal skeleton – occurs in soft connective tissues such as skeletal muscle. At birth, there is usually little indication of the disease, except for a characteristic malformation of the great toes. However during early childhood, episodes of bone formation that are frequently associated with swelling and inflammation begin within soft tissues. In most patients examined to date, FOP is caused by a single nucleotide change in the BMP type I receptor ACVR1 (Activin A receptor, type 1; alias, ALK2) that causes enhanced pathway activation. All patients with a classic clinical presentation of the disease possess a recurrent heterozygous c.617G&gt;A (R206H) mutation.Heterotopic ossification in FOP frequently forms in response to tissue injury, although also develops in the absence of overt tissue trauma. Within the tissue, heterotopic bone formation in FOP patients progresses through well‐described changes in affected tissue: initial catabolic events are followed by an anabolic stage and formation of endochondral bone. In vivo mouse models have been instrumental in providing a more detailed understanding of the tissue, cellular, and molecular impact of the ACVR1 R206H mutation and the structural changes in the soft connective tissues that are transitioning to cartilage and bone. In response to injury, initial steps of wound healing in mutant tissue appear to be normal, including an early immune response that leads to tissue degradation and removal of damaged tissue. However this tissue repair trajectory rapidly diverges and, instead of repairing and regenerating the injured muscle tissue, ectopic cartilage and bone are formed. Our investigations of these events are providing a more detailed understanding of the tissue, cellular, and molecular impact of the ACVR1 R206H mutation and of the mechanisms that regulate tissue maintenance, repair, and regeneration.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease with a progressive course characterized by episodically local flare-ups, which often but not always leads to heterotopic bone formation (HO). Recently, we showed that [18F]NaF PET/CT may be the first tool to monitor progression of a posttraumatic flare-up leading to new HO, which was demonstrated in a patient with FOP who underwent a maxillofacial surgery. This paper evaluates [18F]NaF PET/CT as a marker of FOP disease activity, comparing its use with other imaging modalities known in literature. In addition, the follow-up of a spontaneous flare-up in a 19-year old patient is presented showing high muscle [18F]NaF uptake in one defined part within the flare-up area after three weeks. During follow-up [18F]NaF PET /CT scan revealed newly formed heterotopic bone but only in this previously active [18F]NaF region. In conclusion, increased muscle [18F]NaF uptake may predict future HO development in FOP patients. At present [18F]NaF PET/CT appears to be a sensitive imaging modality to serve as a noninvasive marker for bone formation and to monitor disease activity during flare-ups in FOP.

Myositis ossificans in children: a review.

The formation of lamellar bone in the soft tissues, where bone normally does not exist, is called myositis ossificans. However, it would be more accurate to describe as myositis ossificans the involvement of skeletal muscles and as ectopic or heterotopic ossification the involvement of soft tissues in general. The lesion is subdivided in genetic and non-genetic or acquired types. Myositis or fibrodysplasia ossificans progressiva is a debilitating rare genetic disorder. Clinical suspicion of the disease in the newborn on the basis of malformed great toes may lead to early clinical diagnosis, confirmatory diagnostic genetic testing and avoidance of iatrogenic harmful procedures. Acquired lesions involve the neurogenic myositis ossificans and the non-neurogenic disorder. The latter is defined either as circumscribed myositis ossificans that is post-traumatic or as idiopathic/pseudomalignant myositis ossificans that is non-traumatic and may be a form fruste of fibrodysplasia ossificans progressiva. Ossification in fibrodysplasia ossificans progressiva is irreversible, unlike other forms of heterotopic ossification. In this retrospective study, a total of 22 children with myositis ossificans treated in a 20-year period were identified and classified. Two patients were diagnosed with myositis/fibrodysplasia ossificans progressiva, one with neurogenic myositis ossificans, one with idiopathic/pseudomalignant myositis ossificans and 18 patients with circumscribed myositis ossificans. The clinical features, imaging and histological findings as well as treatment modalities and complications of myositis ossificans in our patients are presented and discussed.

A 'Y-shaped' soft tissue ossification in fibrodysplasia ossificans progressiva.

A 16-year-old girl developed multiple painful and tender soft tissue swellings over her neck, trunk and extremities since 2 years of age. These swellings appeared spontaneously or after trivial injury and either used to resolve spontaneously or they ossified into mature bone. These flares of heterotopic ossification resulted in gradual restriction of movements of neck, trunk, shoulder, elbow, hip and knee joints. There was associated congenital hallux valgus bilaterally (Fig. 1a). There was no history of similar illness in her family. The radiographs of the girl showed certain characteristic features of fibrodysplasia ossificans progressiva (FOP). The cervical skiagram showed characteristic anomalies of the cervical spine in form of large posterior elements and fusion of the facet joints between C2 and C7 (Fig. 1b) [1]. A CT scan of dorso-lumbar spine showed a peculiar

Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by heterotopic endochondral ossification in soft tissue. A mutation in the bone morphogenetic protein (BMP) receptor ALK2, R206H, has been identified in patients with typical FOP. In the present study, we established murine embryonic stem (ES) cells that express wild-type human ALK2 or typical mutant human ALK2 [ALK2(R206H)] under the control of the Tet-Off system. Although wild-type ALK2 and mutant ALK2(R206H) were expressed in response to a withdrawal of doxycycline (Dox), BMP signaling was activated only in the mutant ALK2(R206H)-expressing cells without the addition of exogenous BMPs. The Dox-dependent induction of BMP signaling was blocked by a specific kinase inhibitor of the BMP receptor. The mutant ALK2(R206H)-carrying cells showed Dox-regulated chondrogenesis in vitro, which occurred in co-operation with transforming growth factor-β1 (TGF-β1). Overall, our ES cells are useful for studying the molecular mechanisms of heterotopic ossification in FOP in vitro and for developing novel inhibitors of chondrogenesis induced by mutant ALK2(R206H) associated with FOP.

Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification. FOP is caused by a gain-of-function mutation in ACVR1 encoding the bone morphogenetic protein type II receptor, ACVR1/ALK2. The mutant receptor causes upregulation of a transcriptional factor, Id1. No therapy is available to prevent the progressive heterotopic ossification in FOP. In an effort to search for clinically applicable drugs for FOP, we screened 1,040 FDA-approved drugs for suppression of the Id1 promoter activated by the mutant ACVR1/ALK2 in C2C12 cells. We found that that two antianginal agents, fendiline hydrochloride and perhexiline maleate, suppressed the Id1 promoter in a dose-dependent manner. The drugs also suppressed the expression of native Id1 mRNA and alkaline phosphatase in a dose-dependent manner. Perhexiline but not fendiline downregulated phosphorylation of Smad 1/5/8 driven by bone morphogenetic protein (BMP)-2. We implanted crude BMPs in muscles of ddY mice and fed them fendiline or perhexiline for 30days. Mice taking perhexiline showed a 38.0% reduction in the volume of heterotopic ossification compared to controls, whereas mice taking fendiline showed a slight reduction of heterotopic ossification. Fendiline, perhexiline, and their possible derivatives are potentially applicable to clinical practice to prevent devastating heterotopic ossification in FOP.

Early Clinical and Radiographic Characteristics in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva is an extremely rare and disabling genetic condition characterized by progressive heterotopic ossification of soft tissues such as muscles, ligaments, tendons, fasciae, and aponeuroses. The prevalence of fibrodysplasia ossificans progressiva is estimated to be about one in 2 million individuals1. Heterotopic ossification in fibrodysplasia ossificans progressiva usually begins in the first decade of life with the episodic development of inflammatory fibroproliferative masses in the axial skeleton. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed as having soft-tissue sarcoma or aggressive juvenile fibromatosis before the definitive appearance of heterotopic ossification and undergo invasive procedures that usually lead to the acceleration of ossification2. Early correct diagnosis of fibrodysplasia ossificans progressiva is necessary to prevent additional iatrogenic harm or trauma. At the molecular level, dysregulated bone morphogenetic protein (BMP) signaling is associated with the formation of heterotopic ossification in fibrodysplasia ossificans progressiva. Patients with classical features of the disease have the same heterozygous missense mutation in the glycine-serine activation domain of activin A receptor type-I gene (ACVR1), a BMP type-I receptor3. The causative mutation of fibrodysplasia ossificans progressiva is a recurrent single-nucleotide substitution at position 617 (c.617G>A; R206H) in the ACVR1 gene, which is one of the most specific disease-causing mutations in the human genome. This mutant receptor constitutively activates BMP signaling without binding of ligands4. A unique and recurrent mutation has great relevance for diagnostic purposes in the case of fibrodysplasia ossificans progressiva. Definitive molecular diagnosis of fibrodysplasia ossificans progressiva is now available at early stages of disease development, when misdiagnosis is most likely to occur. Clinical awareness of the preosseous features of the disease is necessary for the early diagnosis of fibrodysplasia ossificans progressiva. In the present study, we describe the cases of two patients in whom fibrodysplasia ossificans progressiva …

In vitro Analyses of the Dysregulated R206H ALK2 Kinase-FKBP12 Interaction Associated with Heterotopic Ossification in FOP

A single recurrent mutation in the regulatory subdomain of a bone morphogenetic protein type I receptor kinase has been linked to heterotopic ossification in classic fibrodysplasia ossificans progressiva (FOP). As a result of a substitution at 1 residue by only 1 other side chain (Arg206His) in just 1 of the 4 type I BMP receptors (ALK2/ACVR1), soft connective tissues progressively metamorphose through an endochondral process into cartilage that is replaced by bone. The substitution of arginine for histidine, also a basic residue yet with the singular property of ionization/protonation over the physiological pH range, led to the hypothesis of an aberrant, pH-sensitive switch mechanism for the ligand-independent activation of BMP signaling through the mutant receptor kinase in patients presenting with classic FOP. To test a potential aspect of the putative pH-dependent mechanism, i.e. loss of autoinhibition of the kinase mediated by the inhibitory protein FKBP12, in vitrointeraction analyses with purified wild-type and R206H ALK2 kinase and FKBP12 proteins were performed. Interactions between the kinases and inhibitory proteins were analyzed qualitatively and quantitatively by native gel electrophoresis and HPLC size exclusion chromatography and with an optical biosensor (Octet; ForteBio). Binding of inhibitory protein by the R206H mutant was diminished 3-fold relative to the wild type kinase at a physiological pH, yet below this value (<∼7.5) pronounced nonspecific interactions, particularly with the mutant, prevented comparative evaluations. In conclusion, substitution with histidine leads to partial loss of inhibition of the mutant type I receptor through diminished binding of FKBP12, which may act as a gradient reader in morphogenetic contexts.

Deformity of the great toe in fibrodysplasia ossificans progressiva

BackgroundAs invasive medical procedures can induce permanent heterotopic ossification in fibrodysplasia ossificans progressiva (FOP), caution should be exercised in clinical practice. The present study was conducted to examine the characteristics of the great toe deformity in patients with FOP, which may lead to an early diagnosis of this condition. MethodsThe subjects consisted of 31 feet from 16 FOP patients (8 males, 8 females) with an average age of 17.3 years (range 1–47 years) at the time of this study. Gross and radiographic findings, including the hallux valgus angles (HVA), intermetatarsal angles (IMA), and the deformity of the proximal phalanx and metatarsal bone, were examined. ResultsOf the 31 feet, 29 (93.5%) showed several degrees of great toe deformity. A shortened great toe was the typical gross finding and was observed in 20 feet (64.5%). The mean HVA and IMA were 19.7° and 8.5°, respectively; and 22 (71.0%) feet satisfied the radiographic definition of hallux valgus (HVA ≥ 20° or IMA ≥ 10°). The proximal phalanx was consistently shortened but morphologically dissimilar from case to case. The metatarsal bone was also shortened and sharpened to the medial side, deviating the proximal phalanx laterally from the metatarsal axis. Fusion between the distal and proximal phalanx occurred with advancing age. Only two feet in one patient showed no obvious deformity of the great toe. ConclusionsA shortened great toe and hallux valgus were frequently found in patients with FOP. Shortening and sharpening of the proximal phalanx and metatarsal bone consistently existed and contributed to the great toe deformity. These findings were thought to exist from birth and may be a key to an early diagnosis.

Nonhereditary Heterotopic Ossification: Implications for Injury, Arthropathy, and Aging

Nonhereditary heterotopic ossification (NHHO) usually arises in the setting of trauma, certain arthropathies, or following injury, often in the setting of common age-related conditions. In this article, we discuss the pathophysiology, diagnosis, and clinical findings in periarticular NHHO and the relevance to age-related pathology, as well as the prevention and treatment of NHHO. Except for the precipitating events or clinical conditions in which NHHO occurs, primary etiological mechanisms remain unknown. Many forms of NHHO develop in the context of injury and inflammation, suggesting that the formation of extraskeletal bone may share similar initiating events with ectopic ossification in fibrodysplasia ossificans progressiva.

Mast cell involvement in fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic genetic disorder of progressive heterotopic ossification associated with dysregulated production of bone morphogenetic protein 4 (BMP4), a potent osteogenic morphogen. Postnatal heterotopic ossification in FOP is often heralded by hectic episodes of severe post-traumatic connective tissue swelling and intramuscular edema, followed by an intense and highly angiogenic fibroproliferative mass. The abrupt appearance, intense size, and rapid intrafascial spread of the edematous preosseous fibroproliferative lesions implicate a dysregulated wound response mechanism and suggest that cells and mediators involved in inflammation and tissue repair may be conscripted in the growth and progression of FOP lesions. The central and coordinate role of inflammatory mast cells and their mediators in tissue edema, wound repair, fibrogenesis, angiogenesis, and tumor invasion prompted us to investigate the potential involvement of mast cells in the pathology of FOP lesions. We show that inflammatory mast cells are present at every stage of the development of FOP lesions and are most pronounced at the highly vascular fibroproliferative stage. Mast cell density at the periphery of FOP lesional tissue is 40- to 150-fold greater than in normal control skeletal muscle or in uninvolved skeletal muscle from FOP patients and 10- to 40-fold greater than in any other inflammatory myopathy examined. These findings document mobilization and activation of inflammatory mast cells in the pathology of FOP lesions and provide a novel and previously unrecognized target for pharmacologic intervention in this extremely disabling disease. HUM PATHOL 32:842-848. This is a US government work. There are no restrictions on its use.

Acute Lymphocytic Infiltration in an Extremely Early Lesion of Fibrodysplasia Ossificans Progressiva

A 2-year-old child with fibrodysplasia ossificans progressiva underwent a muscle biopsy of a very early lesion, and had findings that showed the earliest stage ever seen in the histopathology of fibrodysplasia ossificans progressiva. This very early stage consisted of intense perivascular lymphocytic infiltration into normal appearing skeletal muscle. A nearly identical histopathologic sequence was noted in a cat with phenotypic features similar to those of fibrodysplasia ossificans progressiva in humans. These new findings represent the earliest documented changes that have ever been noted in fibrodysplasia ossificans progressiva, and provide further histopathologic support for the recent discovery that lymphocytes may play a role in the pathogenesis of heterotopic ossification in fibrodysplasia ossificans progressiva.