3. The Clinical and Basic Science Background of FOP

Jan 6

3-1. Introduction

Here, we provide a brief summary of the clinical and scientific background of FOP in order to place the treatment considerations that follow into a clinical and scientific context. Comprehensive clinical reviews of FOP are available (Kaplan et al., 2008; Shore & Kaplan, 2010; Pignolo et al., 2013; Huning & Gillessen-Kaesbach, 2014; Kaplan et al., 2019).

References

Huning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: Clinical course, genetic mutations and genotype-phenotype correlations. Molec Syndromology 5: 201-211, 2014

Kaplan FS, Pignolo RJ, Al Mukaddam M, Shore EM. Genetic disorders of heterotopic ossification: fibrodysplasia ossificans progressiva and progressive osseous heteroplasia (chapter 112, pp. 865-870). In Bilezikian J (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism – Ninth Edition. The American Society for Bone and Mineral Research, Washington, D.C., 2019

Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008

Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10(S-2): 437-448, 2013

Shore EM, Kaplan FS. Inherited human disease of heterotopic bone formation. Nat Rev Rheumatol 6: 518-527, 2010

3-2. Classic Clinical Features of FOP

Fibrodysplasia ossificans progressiva (FOP: OMIM #135100) is an ultra-rare heritable disorder of connective tissue characterized by congenital malformations of the great toes, and progressive heterotopic ossification (HO) in characteristic anatomic patterns (Kaplan et al., 2005; Pignolo et al., 2019).

Individuals with FOP appear normal at birth except for characteristic malformations of the great toes that are present in all classically affected individuals (Kaplan et al., 2005; Towler, Kaplan, Shore, 2020; Towler, Peck, Kaplan, Shore, 2021). During the first decade of life, most children with FOP develop episodic, painful inflammatory soft tissue swellings (called flare-ups) (Cohen et al., 1993; Pignolo et al., 2016). These are often mistaken for tumors. Misdiagnosis is common and iatrogenic harm is high (Kitterman et al., 2005; Zaghloul et al., 2008).

While some flare-ups regress spontaneously, most transform soft connective tissues - including aponeuroses, fascia, ligaments, tendons, and skeletal muscles - into mature heterotopic bone. Ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues through a process of endochondral ossification that leads to an armament-like encasement of bone and permanent immobility. Minor trauma such as intramuscular immunizations, mandibular blocks for dental work, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses can trigger painful new flare-ups of FOP leading to progressive HO. Attempts to surgically remove heterotopic bone often provoke explosive and painful new episodes of bone growth (Kaplan et al., 2005).

FOP HO progresses in characteristic anatomic and temporal patterns with age, typically first occurring in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions. Recently, investigators noticed that HO in FOP progresses in well-defined but unexplained spatial and temporal patterns that correlate precisely with infrared thermographs of the human body. FOP is caused by gain-of-function pathogenic variants in Activin A receptor type I (ACVR1/ALK2), encoding a bone morphogenetic protein (BMP) type I receptor kinase.

As with all enzymes, the activity of ACVR1 is temperature dependent. Investigators hypothesized that connective tissue progenitor cells (CTPCs) that express the common heterozygous ACVR1R206H variant 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. BMP pathway signaling was compared at a range of physiologic temperatures in primary CTPCs isolated from FOP patients and unaffected controls. BMP pathway signaling and resultant chondrogenesis were amplified in FOP CTPCs compared to control CTPCs (p < 0.05). Thus, the anatomic distribution of HO in FOP may be due, in part, to a dysregulated 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, the 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 FOP (Wang et al., 2021).

The severe pain that commonly accompanies appendicular flare-ups is often ascribed to compartment syndrome (Kaplan et al., 2020). A unique case documented compartment syndrome during an acute flare-up of FOP (Kaplan et al., 2020).

In a large prospective, international, natural history study on FOP, individuals aged ≤65 years with classic FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. Results from individuals receiving standard care for up to 3 years in this natural history study showed the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood (Pignolo et al., 2022).

Several skeletal muscles including the diaphragm, intrinsic muscles of the tongue, and extra-ocular muscles are spared from HO in FOP. Cardiac muscle and smooth muscle are also notably spared from HO (Cohen et al., 1993; Kaplan et al., 2005; Pignolo et al., 2018).

HO in FOP is episodic, but disability is cumulative. Most patients with FOP are confined to a wheelchair by the third decade of life and require lifelong assistance in performing activities of daily living (Cohen et al., 1993; Rocke et al., 1994; Kaplan et al., 2018a; Kaplan et al., 2018b). Severe weight loss may result following ankylosis of the jaw. Severe restrictive chest wall disease and decrease in pulmonary function due to developmental arthropathy of the costo-vertebral joints and heterotopic ossification of the chest wall develops early (Towler, Shore, Kaplan, 2020; Botman et al., 2021). Pneumonia or right-sided heart failure may complicate rigid fixation of the chest wall. The severe disability of FOP results in low reproductive fitness. Fewer than ten multigenerational families showing inheritance of FOP are known worldwide. The median age at death is approximately 40 years, but the median estimated life expectancy is 56 years. Death often results from complications of thoracic insufficiency syndrome or pneumonia (Kaplan et al., 2010).

A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with FOP. Baseline phenotypes on 299 patients from 54 countries are reported based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). Overall, the FOP Registry database provides 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 (Pignolo et al., 2020).

References

Botman E, Smilde BJ, Hoebink M, Treurniet S, Raijmakers P, Kamp O, Teunissen BP, Bökenkamp A, Jak P, Lammertsma AA, van den Aardweg JG, Boonstra A, Eekhoff EMW. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva. Bone Rep 2021 Feb 25;14:100758

Cohen RB, Hahn GV, Tabas J, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 215-219, 1993

Kaplan FS, Glaser DL, Shore EM, Deirmengian GK, Gupta R, Delai P, Morhart P, Smith R, Le Merrer M, Rogers JG, Connor JM, Kitterman JA. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 183-188, 2005

Kaplan FS, Zasloff MA, Kitterman JA. Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92: 686-691, 2010

Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP). Bone 101: 123-128, 2018a

Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 109: 150-161, 2018b

Kaplan FS, Al Mukaddam M, Pignolo RJ. Compartment syndrome of the thigh in a patient with fibrodysplasia ossificans progressiva. J Orthopaedic Case Reports 10: 103-107, 2020

Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: 654-661, 2005

Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, Keen R, Al Mukaddam M, Sang KLQ, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis 2019 May 3;14(1):98

Pignolo RJ, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Al Mukaddam M, Le Quan Sang KH, Wilson A, Marino R, Strahs A, Kaplan FS. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genet Med 24:2422-2433, 2022

Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016

Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109: 124-133, 2018

Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De Cunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the international fibrodysplasia ossificans progressiva (FOP) association global registry. Bone 2020 May;134:115274

Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 301: 243-248, 1994

Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116

Towler OW, Kaplan FS, Shore EM. The developmental phenotype of the great toe in fibrodysplasia ossificans progressiva. Front Cell Dev Biol 2020 Dec 8;8:612853

Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021

Wang H, De Cunto CL, Pignolo RJ, Kaplan FS. Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. Bone 149:115978, 2021

Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neursurg Pediatrics 1: 91-94, 2008

3-3. Other Skeletal Anomalies of FOP

While malformations of the great toes are characteristic of FOP, other developmental anomalies are frequently observed. The pathogenic ACVR1 receptor in FOP has a clear effect on the induction of extra-skeletal bone formation. However, this 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 (Towler et al., 2020).

There is widespread evidence for developmental arthropathy throughout the axial and appendicular skeleton at all ages in individuals with FOP. Asymmetric narrowing and subchondral sclerosis are present throughout the joints of the normotopic skeleton and osteophytes are 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 show partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic with short and wide femoral necks, small growth plates and intra-articular synovial osteochondromas. There is also evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacroiliac joints, and lower limbs (Towler et al., 2020).

Thus, the effects of the 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 (Towler et al., 2020).

Thus, 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 (Towler et al., 2020; Kaplan et al., 2020; Pignolo et al., 2020).

Stiffness of the neck is an early finding in most patients and can precede the appearance of HO at that site. Characteristic anomalies of the cervical spine include large posterior elements, tall narrow vertebral bodies, and variable fusion of the facet joints between C2 and C7 (Schaffer et al., 2005). Although the cervical spine often becomes ankylosed early in life, any minimal residual movement may eventually result in chronic headaches and painful arthritic symptoms.

Other skeletal anomalies associated with FOP include short malformed thumbs with interphalangeal joint fusion, clinodactyly, malformation of the temporomandibular joints, variable and often asymmetric fusions of the costovertebral and costotransverse joints, short broad femoral necks, and osteochondromas, most notably of the proximal medial tibias and femurs, but variably present throughout the normotopic skeleton (Deirmengian et al., 2008; Kaplan et al., 2009; Bauer et al., 2018; Kaplan et al., 2018; Towler et al., 2020). A common face signature is often noted (Hammond et al., 2012).

In summary, multiple skeletal abnormalities and joint malformations are often seen in individuals with FOP, and the following plain radiographs can aid in rapid phenotypic screening and clinical diagnosis:

Anterior-Posterior (AP) of hands
AP of both feet
Lateral of cervical spine
AP & lateral of chest
AP of pelvis
AP & lateral of both knees

References

Bauer AH, Bonham J, Gutierrez L, Hsiao EC, Motamedi D. Fibrodysplasia ossificans progressiva: a current review of imaging findings. Skeletal Radiol 47: 1043-1050, 2018

Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 90: 366-374, 2008

Hammond P, Suttie M, Hennekam RC, Allanson J, Shore EM, Kaplan FS. The face signature of fibrodysplasia ossificans progressiva. Am J Med Genet 158A: 1368-1380, 2012

Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009

Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva. Bone 109: 115-119, 2018

Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva: a disorder of osteochondrogenesis. Bone 2020 Jul;140:115539

Pignolo RJ, Wang H, Kapan FS. Fibrodysplasia ossificans progressiva (FOP): A segmental progeroid syndrome. Front Endocrinol (Lausanne) 2020 Jan 10;10:908

Schaffer AA, Kaplan FS, Tracy MR, O’Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome. Spine 30: 1379-1385, 2005

Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116

3-4. Radiographic Features of FOP

Radiographic evaluation of heterotopic bone in FOP shows normal modeling and remodeling (Kaplan et al., 1994). Individuals with FOP are at increased risk of fractures of both the normotopic and heterotopic skeleton due to the increased risk of falls, immobility and prednisone use (Pignolo et al., 2016). Fractures appear to heal normally in FOP. Bone scans are abnormal before HO can be detected by conventional radiographs (Kaplan et al., 1994; Mahboubi et al., 2001). Computed tomography, magnetic resonance imaging, and 18F-NaF Positron Emission Tomography (PET) scans of early lesions have been described (Eekhoff et al., 2018; Botman et al., 2019; Botman et al., 2020). While these evaluation methods are generally superfluous from a diagnostic standpoint, they can provide a useful research perspective of the disease process and are being incorporated into evaluation schemes in contemporary clinical trials with various quantitative assessments (Rajapakse et al., 2017; Al Mukaddam et al., 2018; Eekhoff et al., 2018). The clinical diagnosis of FOP can be made by simple clinical evaluation that associates rapidly appearing soft tissue lesions with malformations of the great toes.

References

Al Mukaddam M, Rajapakse CS, Pignolo RJ, Kaplan FS, Smith SE. Imaging assessment in fibrodysplasia ossificans progressiva: Qualitative, quantitative and questionable. Bone 109: 147-152, 2018

Botman E, Raijmakers PGHM, Yaqub M, Teunissen B, Netelenbos C, Lubbers W, Schwarte LA, Micha D, Bravenboer N, Schoenmaker T, de Vries TJ, Pals G, Smit JM, Koolwijk P, Trotter DG, Lammertsma AA, Eekhoff EMW. Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: An [(18)F]NaF PET/CT study. Bone 124: 1-6, 2019

Botman E, Teunissen BP, Raijmakers P, de Graaf P, Yaqub M, Treurniet S, Schoenmaker T, Bravenboer N, Micha D, Pals G, Bökenkamp A, Netelenbos JC, Lammertsma AA, Eekhoff EM. Diagnostic value of magnetic resonance imaging in fibrodysplasia ossificans progressiva. JBMR Plus 2020 Apr 28;4(6):e10363

Eekhoff EMW, Botman E, Coen Netelenbos J, de Graaf P, Bravenboer N, Micha D, Pals G, de Vries TJ, Schoenmaker T, Hoebink M, Lammertsma AA, Raijmakers PGHM. [18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone 109: 143-146, 2018

Kaplan FS, Strear CM, Zasloff MA. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin Orthop 304: 238-247, 1994

Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva. Pediatr Radiol 31: 307-314, 2001

Rajapakse CS, Lindborg C, Wang H, Newman BT, Kobe EA, Chang G, Shore EM, Kaplan FS, Pignolo RJ. Analog method for radiographic assessment of heterotopic bone in fibrodysplasia ossificans progressiva. Acad Radiol 24: 321-327, 2017

3-5. Pathology of FOP Lesions

Early pre-osseous FOP lesions consist of an intense aggregation of mononuclear inflammatory cells including lymphocytes, macrophages, and mast cells in the perivascular spaces of edematous muscle (Gannon et al., 1998; Gannon et al., 2001). Mast cells, macrophages, and cellular hypoxia play a direct role in the generation of FOP lesions (Wang et al., 2016; Convente et al., 2018). Following the catabolic phase of muscle cell death, a highly anabolic fibroproliferative phase (often mistaken for aggressive juvenile fibromatosis) consists, in part, of Sca1+/PDGFRα+/Tie2+/CD34- fibroadipogenic progenitor (FAP) cells that differentiate through an endochondral pathway into mature heterotopic bone (Kaplan et al.,1993; Lounev et al., 2009; Wosczyna et al., 2012; Lees-Shepard et al., 2018).

References

Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of Mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018

Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva (FOP). Hum Pathol 32: 842-848, 2001

Gannon FH, Valentine BA, Shore EM, Zasloff MA, Kaplan FS. Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346: 19-25, 1998

Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG, Hematopoietic stem cell contribution to ectopic skeletogenesis. J Bone Joint Surg 89: 347-357, 2007

Kaplan FS, Tabas J, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J Bone Joint Surg Am 75-A: 220-230, 1993

Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 9:471, 2018

Lounev VY, Ramachandran R, Wosczyna MN, Yamamoto M, Maidment AD, Shore EM, Glaser DL, Goldhamer DJ, Kaplan FS. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91: 652-663, 2009

Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016

Wosczyna MN, Biswas AA, Cogswell CA, Goldhamer DJ. Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification. J Bone Miner Res 27: 1004-1017, 2012

3-6. Laboratory Findings in FOP

Routine biochemical studies are usually normal, although serum prostanoids, urinary basic fibroblast growth factor, cartilage-derived retinoic acid protein (CD-RAP), and alkaline phosphatase levels may be increased during the inflammatory, fibroproliferative, chondrogenic, and osteogenic phases of flare-ups, respectively (Kaplan et al., 1998; Lindborg et al., 2018). Elevated numbers of circulating osteoprogenitor cells have been noted during early flare-ups.

In a case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, investigators reported the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Although these findings require further study, plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation (Pignolo, McCarrick-Walmsley et al., 2022).

References

Kaplan FS, Sawyer J, Connors S, Keough K, Shore E, Gannon F, Glaser D, Rocke D, Zasloff M, Folkman J. Urinary basic fibroblast growth factor: a biochemical marker for preosseous fibroproliferative lesions in patients with FOP. Clin Orthop 346: 59-65, 1998

Lindborg CM, Brennan TA, Wang H, Kaplan FS, Pignolo RJ. Cartilage-derived retinoic acid-sensitive protein (CD-RAP): A stage-specific biomarker of heterotopic endochondral bone ossification (HEO) in fibrodysplasia ossification progressiva (FOP). Bone 109: 153-157, 2018

Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res 37: 475-483, 2022

3-7. Etiology & Pathogenesis of FOP

Early observations in flies and vertebrates led to the hypothesis that the bone morphogenetic protein (BMP) signaling pathway was dysregulated in FOP (Kaplan et al., 1990). In fact, the BMP signaling pathway is highly dysregulated in FOP. FOP cells over-express BMP4, cannot up-regulate expression of multiple BMP antagonists in response to a BMP challenge, and exhibit a defect in BMP receptor internalization with increased activation of downstream targets, suggesting that altered BMP receptor signaling participates in HO formation in FOP (reviewed in Kaplan et al., 2009b).

Genome-wide linkage analysis localized the causative gene for FOP to chromosome 2q23-24, a locus containing the Activin A receptor, type 1 (ACVR1) gene encoding a BMP type 1 receptor. A recurrent heterozygous missense mutation (c.617G>A; p.R206H) in the glycine-serine (GS) activation domain of ACVR1 was identified in all affected individuals with classic features of either sporadic or inherited FOP, establishing mutation of this gene as the definitive cause of FOP and making molecular confirmation possible (Shore et al., 2006; Couzin, 2006; Kaplan et al., 2009a). A knock-in mouse model was used to confirm that this single nucleotide substitution is sufficient to induce all features associated with FOP (Chakkalakal et al., 2012).

Protein modeling predicted destabilization of the GS domain, consistent with enhanced activation of ACVR1 signaling as the underlying pathogenesis of the ectopic chondrogenesis, osteogenesis, and joint fusion of FOP (Shore et al., 2006; Groppe et al., 2007; Shen et al., 2009; van Dinther et al., 2010; Chaikaud et al., 2012; Culbert et al., 2014). The GS domain is a specific binding site for FKBP12, a highly conserved inhibitory protein that prevents leaky activation of type I receptors in the absence of ligand. ACVR1 (R206H) interacts less with FKBP12 in the absence of BMP, suggesting this impaired FKBP12-ACVR1 interaction contributes in part to BMP-independent pathway signaling (Shen et al., 2009; Groppe et al., 2011).

Basal and ligand-stimulated dysregulation of BMP pathway signaling are characteristic of connective tissue progenitor cells from FOP patients, and in vitro and in vivo FOP models. ACVR1R206H causes FOP through dysregulation of the BMP signaling pathway, in part, by receptor activation independently of ligands, but also by being hyper-responsive to BMP ligands, and by responding to the normally antagonistic ligand Activin A (Billings et al., 2008; Shen et al., 2009; Culbert et al., 2014; Hatsell et al., 2015; Hino et al., 2015; Haupt et al., 2018; Wang et al., 2018; Allen et al., 2020). In addition, FOP ACVR1 signals in the absence of a normally required type I receptor partner and has reduced GS domain serine/threonine phosphorylation site requirements, further demonstrating the loss of normal regulatory constraints on ACVR1 receptor activation (Allen et al., 2020; Allen et al., 2023). Ramachandran and colleagues showed that pathogenic signaling of ACVR1R206H is mediated predominantly by Activin A-dependent receptor clustering, which induces auto-activation of the mutant receptor (Ramachandran et al., 2021).

Additionally, early FOP lesions dramatically amplify BMP pathway signaling through an intracellular ligand-independent HIF-1α mechanism thus establishing cellular hypoxia as a central mechanism for the stimulation and amplification of FOP lesions (Wang et al., 2016). Recent studies also show that the ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification (Haupt et al., 2019; Stanley et al., 2019), and that in parallel with inducing ectopic bone formation, ACVR1R206H impairs regeneration of the skeletal muscle where HO forms (Barruet et al., 2021; Stanley et al., 2022).

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. In murine models of FOP, Towler and colleagues showed that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, localization of Growth Differentiation Factor-5 (Gdf5+) joint progenitor cells, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and also 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 ACVR1R206H in impaired joint development (Towler, Peck, Kaplan, Shore, 2021).

References

Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020

Allen, RS, Jones WD, Hale M, Warder BN Shore EM, and Mullins MC. Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish. J Bone Miner Res 38: 1364-1385, 2023

Barruet E, Garcia SM, Wu J, Morales BM, Tamaki S, Moody T, Pomerantz JH, Hsiao EC. Modeling the ACVR1R206H mutation in human skeletal muscle stem cells. eLife 2021 Nov 10;10:e66107

Billings PC, Fiori JL, Bentwood JL, O'Connell MP, Jiao X, Nussbaum B, Caron RJ, Shore EM, Kaplan FS. Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res 23: 305-313, 2008

Chaikuad A, Alfano I, Kerr G, Santivale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem 287: 36990-36998, 2012

Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res 27: 1746-1756, 2012

Couzin J. Bone disease gene finally found. Science 312: 514-515, 2006

Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore EM. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells 32: 1289-1300, 2014

Groppe JC, Shore EM, Kaplan FS. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res 462: 87-92, 2007

Groppe JC, Wu J, Shore EM, Kaplan FS. In vitro analysis of dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP. Cells Tissues Organs 194: 291-295, 2011

Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015

Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232-240, 2018

Haupt J, Stanley A, McLeod CM, Cosgrove BD, Culbert AL, Wang L, Mourkioti F, Mauck RL, Shore EM. ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification. Mol Biol Cell 30: 17-29, 2019

Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015

Kaplan FS, Pignolo RJ, Shore EM. The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. Cytokine Growth Factor Rev 20: 399-407, 2009b

Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990

Ramachandran A, Mehić M, Wasim L, Malinova D, Gori I, Blaszczyk BK, Carvalho DM, Shore EM, Jones C, Hyvönen M, Tolar P, Hill CS. Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation. EMBO J 2021 Jul 15;40(14):e106317.

Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embargo ventralization. J Clin Invest 119: 3462-3472, 2009

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38: 525-527, 2006

Stanley A, Heo SJ, Mauck RL, Mourkioti F, Shore EM. Elevated BMP and Mechanical Signaling Through YAP1/RhoA Poises FOP Mesenchymal Progenitors for Osteogenesis. J Bone Miner Res 34: 1894-1909, 2019

Stanley, A., E.D. Tichy, J. Kocan, D.W. Roberts, E.M. Shore, F. Mourkioti. Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva. npj Regenerative Medicine 7(1);5, 2022

Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021

van Dinther M, Visser N, de Gorter DJJ, Doorn J, Goumans M-J, de Boer J, ten Dijke P. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res 25: 1208-1215, 2010

Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induced chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone 109: 218-224, 2018

3-8. The Developmental Molecular Biology of the Great Toe Malformation in FOP

Children with FOP characteristically exhibit malformation of their great toes at birth, indicating that the ACVR1 mutation acts during embryonic development to alter skeletal formation. The great toes are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. 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.

Towler et al. (2020) 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.

In order to elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, Towler et al. (2021) used an FOP knock-in mouse model that mimics the first digit phenotype of human FOP and determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit. Altered BMP signaling, Growth Differentiation Factor-5 (Gdf5) joint progenitor cell localization, and joint development occur in a manner that affects individual digits during embryogenesis. The Acvr1R206H 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 (Towler et al., 2021; Towler & Shore, 2022).

References

Towler OW, Kaplan FS, Shore EM. The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva. Front Cell Dev Biol. 2020;8:612853, 2020

Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021

Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn 251: 164-177, 2022

3-9. FOP Variants

All patients with classic clinical features of FOP (great toe malformations and progressive HO) have the same heterozygous mutation (c.617G>A; p.R206H) in the glycine-serine activation domain of ACVR1 (~97% of all FOP patients worldwide). Approximately 3% of FOP patients have been identified with clinical features unusual compared to classical FOP, most notably greater or lesser severity of the great toe malformations. These patients with “variant” clinical presentation of FOP have novel non-R206H activating mutations in the ACVR1 gene. Genotype-phenotype correlations have been observed between some ACVR1 pathogenic variants and the age of onset of HO or on embryonic skeletal development (Kaplan et al., 2009; Kaplan et al., 2015; Haupt et al., 2018; Kaplan et al., 2022; reviewed in Huning & Gillessen-Kaesbach, 2014). A more detailed discussion of FOP variants is found in Section 5.

References

Haupt, J., M. Xu, and E.M. Shore. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232-240, 2018

Huning I, Gillessen-Kaesbach G. Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlations. Molec Syndromology 5: 201-211, 2014

Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167: 2265-2271, 2015

Kaplan FS, Groppe JC, Xu M, Towler OW, Grunvald E, Kalunian K, Kallish S, Al Mukaddam M, Pignolo RJ, Shore EM. An ACVR1R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A 188: 806-817, 2022

3-10. The Immune System & FOP

In all affected individuals, FOP is caused by a heterozygous missense gain-of-function variant in ACVR1. Loss of autoinhibition of the mutant receptor results in dysregulated BMP pathway signaling and is necessary for the myriad developmental features of FOP but may not be sufficient to induce the episodic flare-ups that lead to disabling post-natal HO and that are a hallmark of the disease. Evidence from all levels of investigation in humans and animal models strongly support that the innate immune system plays a key role in inducing episodes of HO.

Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system (reviewed in Kaplan et al., 2016; Matsuo et al., 2019). Recent studies implicate mast cells, macrophages and hypoxia as well as canonical and non-canonical TGFβ/BMP family ligands in the amplification of mutant ACVR1 signaling leading to the formation of FOP lesions and resultant HO (Kaplan et al., 2016; Wang et al., 2016; Convente et al., 2018). BMP and Activin ligands that stimulate mutant ACVR1 signaling also have critical regulatory functions in the immune system (reviewed in Kaplan et al., 2016; Barruet et al., 2018). Macrophages derived from patients with FOP show prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, resulting in dampened responses to additional LPS stimulation, identifying macrophages as a source of Activin A that may drive heterotopic ossification in FOP (Matsuo et al., 2021).

A case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, reported the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation (Pignolo et al., 2022). Crosstalk between the morphogenetic and immunological pathways that regulate tissue maintenance and repair identifies potential robust therapeutic targets for FOP (Wang et al., 2018).

Lounev et al. recently reported that an otherwise healthy 35-year-old man (patient-R) with the classic congenital great toe malformation of FOP and the canonical pathogenic ACVR1R206H mutation had extreme paucity of post-natal heterotopic ossification and nearly normal mobility. The authors hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for heterotopic ossification. Extensive studies in the patient and in multiple mouse models of FOP revealed that deficiency of MMP-9 confers resilience in FOP, that MMP-9 orchestrates a critical role in the pathogenesis of FOP by linking inflammation to heterotopic ossification, and importantly illustrates that a single patient's clinical phenotype can unveil novel treatment strategies (Lounev et al., 2024; Wein & Yang, 2024).

References

Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958

Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018

Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016

Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024

Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019

Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129

Wang H, Behrens EM, Pignolo RJ, Kaplan FS. ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. Bone 109: 201-209, 2018

Wein MN, Yang Y. Actionable disease insights from bedside-to-bench investigation in fibrodysplasia ossificans progressiva. J Bone Miner Res 39: 375-376, 2024

3-11. Epidemiologic, Genetic, & Environmental Factors in FOP

FOP is among the rarest of human afflictions (Connor & Evans, 1982; Morales Piga et al., 2012; Baujat et al., 2017). Prevalence estimates for FOP have been hindered by the rarity of the condition and the heterogeneity of disease presentation. A study of disease prevalence was conducted in the United States, based on contact with one of 3 major treatment centers for FOP (University of Pennsylvania, Mayo Clinic, or University of California San Francisco), the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) membership list, or the IFOPA FOP Registry through July 22, 2020. The results of the study suggested that the prevalence of FOP is higher than the often-cited value of 0.5 per million (Pignolo, Hsiao et al., 2021).

All races are affected with FOP. There is no ethnic, racial, gender, or geographic predisposition. Autosomal dominant transmission with complete penetrance but variable expression is established. Inheritance can be from either mothers or fathers (Kaplan et al., 1993; Shore et al., 2005). Most cases arise as a result of a spontaneous new mutation (reviewed in Shore et al., 2005). A paternal age effect has been reported (Rogers & Chase, 1979). Maternal mosaicism may exist. Fewer than ten small families with multigenerational members with FOP are known worldwide. Phenotypic heterogeneity is observed (Shore et al., 2005).

Both genetic and environmental factors affect the phenotype of FOP. A study of three pairs of monozygotic twins with FOP found that within each pair, congenital toe malformations were identical. However, postnatal HO varied greatly depending on life history and environmental exposure to viral illnesses and to soft tissue trauma. Genetic factors appear to be the key determinants during prenatal development while environmental factors strongly influence postnatal progression of HO (Hebela et al., 2005).

References

Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis 12:123, 2017

Connor JM, Evans DA. Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet 19: 35-39, 1982

Hebela N, Shore EM, Kaplan FS. Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva: the role of environment in the progression of heterotopic ossification. Clin Rev Bone Miner Metab 3: 205-208, 2005

Kaplan FS, McCluskey W, Hahn G, Tabas J, Muenke M, Zasloff MA. Genetic transmission of fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 1214-1220, 1993

Morales Piga A, Bachiller-Corral J, Trujillo-Tiebas MJ, Villaverde-Hueso A, Gamir-Gamir ML, Alonso-Ferreira V, et al. Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects. Bone 51:748–755, 2012

Pignolo RJ, Hsiao EC, Baujat G, Lapidus D, Sherman A, Kaplan FS. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis 16:350, 2021

Rogers JG, Chase GA. Paternal age effect in fibrodysplasia ossificans progressiva. J Med Genet 16: 147-148, 1979

Shore EM, Feldman GJ, Xu M, Kaplan FS. The genetics of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 201-204, 2005

3-12. Genetic Testing & FOP

Definitive genetic testing of FOP by DNA sequence analysis of the ACVR1 locus can confirm a diagnosis of FOP prior to the appearance of HO (Kaplan et al., 2008). Clinical suspicion of FOP early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing (if appropriate), and the avoidance of harmful diagnostic and treatment procedures. Clinicians should be aware of the early diagnostic signs of FOP - congenital malformation of the great toes and episodic soft tissue swelling even before the appearance of HO. This awareness should prompt genetic consultation and testing and the institution of assiduous precautions to prevent injury and iatrogenic harm.

References

Kaplan FS, Xu M, Glaser DL, Collins F, Connor M, Kitterman J, Sillence D, Zackai E, Ravitsky V, Zasloff M, Ganguly A, Shore EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 121: e1295-e1300, 2008

3-13. Animal Models of FOP

Animal models of FOP are important in deciphering the pathophysiology of FOP and in testing possible therapies. Laboratory-generated animal models of FOP in Drosophila, zebrafish and mice with features of FOP have provided the opportunity to better understand the biology of BMP pathway-associated HO and to study the effectiveness and safety of currently available and emerging therapies (Kaplan et al., 1990; Shen et al., 2009; Chakkalakal et al., 2012; Kaplan et al., 2012; Le et al., 2012; LaBonty & Yelick, 2018; Le & Wharton, 2018; Mucha et al., 2018; LaBonty & Yelick, 2019; Allen et al., 2020; Allen et al., 2023). Mouse conditional knock-in models of the classic FOP mutation have been developed and are critical in establishing specificity of treatment for FOP as well as investigating many previously unexplored aspects of the condition (Hatsell et al., 2015; Chakkalakal et al, 2016; Lees-Shepard et al., 2018; Chakkalakal & Shore, 2019). FOP was confirmed clinically and genetically in two domestic shorthaired cats (Casal et al., 2019).

References

Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020

Casal ML, Engiles JB, Zakošek Pipan M, Berkowitz A, Porat-Mosenco Y, Mai W, Wurzburg K, Xu MQ, Allen R, ODonnell PA, Henthorn PS, Thompson K, Shore EM. Identification of the identical human mutation in ACVR1 in two cats with fibrodysplasia ossificans progressiva. Vet Pathol 56: 614-618, 2019

Chakkalakal SA, Shore EM. Heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 247-255, 2019

Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016

Kaplan FS, Chakkalakal SA, Shore EM. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech 5: 756-762, 2012

Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990

LaBonty M, Yelick PC. Animal models of fibrodysplasia ossificans progressiva. Dev Dyn 247: 279-288, 2018

LaBonty M, Yelick PC. An adult zebrafish model of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 155-163, 2019

Le VQ, Anderson E, Akiyama T, Wharton KA. Drosophila models of FOP provide mechanistic insight. Bone 109: 192-200, 2018

Le VQ, Wharton KA. Hyperactive BMP signaling induced by ALK2 (R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva. Dev Dyn 241: 200-214, 2012

Mucha BE, Hashiguchi M, Zinski J, Shore EM, Mullins MC. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109: 225-231, 2018

3-14. Prognosis of FOP

Despite widespread HO and severe disability, some patients live productive lives into their seventh decade. Most, however, succumb earlier from cardiopulmonary complications of severe restrictive chest wall involvement (Kaplan, 2006; Kaplan, 2013).

Tools to construct a conceptual framework for the clinical staging of FOP have been proposed. 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 of functional loss 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. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage when disease-modifying therapies may be most efficacious (reviewed in Pignolo & Kaplan, 2018).

Over the past decade, FOP research has identified robust genetic, molecular and cellular targets for therapy. Clinical trials are underway, and more are set to occur. There is hope for the future.

References

Kaplan FS. The key to the closet is the key to the kingdom: a common lesson of rare diseases. Orphan Disease Update 24(3): 1-9, 2006

Kaplan FS. The skeleton in the closet. Gene 528: 7-11, 2013

Pignolo RJ, Kaplan FS. Clinical staging of fibrodysplasia ossificans progressiva. Bone 109: 111-114, 2018

3-15. Challenges of Therapeutic Assessment in FOP

Flare-ups of FOP are sporadic and unpredictable, and there is great individual variability in the rate of disease progression. Several large studies on the natural history of FOP have confirmed that it is impossible to predict the occurrence, duration or severity of an FOP flare-up, although characteristic anatomic patterning has been described. The rarity of FOP and the unpredictable nature of the condition make it extremely difficult to assess any therapeutic intervention, a fact recognized as early as 1918 by Julius Rosenstirn (Rosenstirn, 1918):

“The disease was attacked with all sorts of remedies and alternatives for faulty metabolism; every one of them with more or less marked success observed solely by its original author but pronounced a complete failure by every other follower. In many cases, the symptoms of the disease disappear often spontaneously, so the therapeutic effect (of any treatment) should not be unreservedly endorsed.”

These words ring true today as they did when they were written a century ago. With the discovery of the FOP gene and emerging understanding of the pathology and molecular genetics of FOP, new pharmacologic strategies are emerging to definitively treat FOP. Presently, physicians are faced with an increasing number of potential medical interventions. At present, clinical experience using these medications for FOP is mostly anecdotal (Kaplan et al., 2017).

In the next section of this report, we will review the major classes of medications that are being used to manage symptoms in patients who have FOP. We will provide a perspective on indications and contraindications for the use of such medications.

References

Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017

Rosenstirn J. A contribution to the study of myositis ossificans progressiva. Ann Surg 68: 485-520, 591-637, 1918

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