Fibrodysplasia Ossificans Progressiva

The pathophysiology of fibrodysplasia ossificans progressiva (FOP) is unknown. It is an inherited autosomal dominant disorder with complete penetration but variable gene expressivity. Findings suggest that fibrodysplasia ossificans progressiva maps to band 4q27-31, a region that contains at least 1 gene involved in the bone morphogenic protein (BMP) signaling pathway.[5] BMPs are members of the transforming growth factor-beta superfamily and play a role in the development of bone and other tissues.[6] The condition is multifocal, starting to develop usually after traumatization. The genetic cause of fibrodysplasia ossificans progressiva lies within the ACVR1 gene, which encodes a type I BMP transmembrane receptor. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.[7] In one study, it was mapped to 2q23-24 by linkage analysis.[8]

A number of mutations have been documented. A mutation of the noggin (NOG) gene in a fibrodysplasia ossificans progressiva family has been described.[9] The FOP gene in the 17q21-22 region had been observed with several mutations described in the NOG gene (located in 17q22) in 4 fibrodysplasia ossificans progressiva patients, including the G91C mutation, which was transmitted dominantly in a Spanish fibrodysplasia ossificans progressiva family. This mutation is a guanine to adenine change at nucleotide 283 (283G–>A) of the NOG gene and was transmitted by the affected mother to her 2 affected children. A novel mutation in the activin A type 1 receptor gene was described in one patient.[10] Analysis showed that the patient was heterozygous for a mutation, G356D.[11]

Patients with fibrodysplasia ossificans progressiva–like heterotopic ossification and/or toe malformations have been described in 2 categories: fibrodysplasia ossificans progressiva–plus (classic defining features of fibrodysplasia ossificans progressiva plus one or more atypical features) and fibrodysplasia ossificans progressiva variants (major variations in one or both of the 2 classic defining features of fibrodysplasia ossificans progressiva)[12] While the typical mutation was found in all cases of classic fibrodysplasia ossificans progressiva and most cases of fibrodysplasia ossificans progressiva–plus, novel ACVR1 mutations were identified in the fibrodysplasia ossificans progressiva variants and some with fibrodysplasia ossificans progressiva–plus.

Two unique mutations in the ACVR1 gene have also been identified in 2 fibrodysplasia ossificans progressiva patients from the United Kingdom with some atypical digit abnormalities and other clinical features[13] . A patient from Japan with an ACVR1 gene mutation had normal development until age 17 years and a mild clinical course.[14] The resultant mutations were interpreted to result in local structural changes in the ACVR1 protein, as revealed by interrogating homology models of the native and mutated ACVR1 kinase domains.

Impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may activate osteogenic BMP-signaling in extraskeletal sites, leading to delayed and progressive ectopic bone formation.[15]

A novel ALK2 mutation, L196P, was identified in a mild form of fibrodysplasia ossificans progressiva.[16]

Frequency

The prevalence of fibrodysplasia ossificans progressiva (FOP) has been estimated at 1 case per 1.64 million persons in the United Kingdom. A prevalence of 1.36 per million inhabitants has been calculated for France.[17] Worldwide, approximately 800 fibrodysplasia ossificans progressiva patients have been delineated with prevalence of 0.6-1.3 per million individuals.[1, 2] Fibrodysplasia ossificans progressiva has approximately the same prevalence in Japan.[18]

Race

Fibrodysplasia ossificans progressiva mainly occurs in Whites, but it is also reported in Blacks.

Sex

Fibrodysplasia ossificans progressiva is more common in females than in males. The observed male-to-male transmission of the disorder excludes X-linked inheritance. Because few individuals who are affected choose to have children, most patients are considered to have new mutations.

Age

Fibrodysplasia ossificans progressiva usually starts in early infancy; however, reports exist of in utero involvement and skeletal deformations are present at birth.

In most cases, fibrodysplasia ossificans progressiva (FOP) starts in early infancy with episodes of soft tissue swelling; however, reports exist of in utero involvement. It may be first evident in an infant as recurrent diffuse soft-tissue scalp and periorbital swelling.[19]

Ectopic bone formation is usually first evident in early childhood in children aged 2-6 years. The main target is the axial musculature, but eventually ectopic bone formation occurs in the ligaments, the fascia, the aponeuroses, the tendons, and the joint capsules. Involvement often demonstrates a proximal-to-distal predilection. Approximately half of the flare-ups seem to be spontaneous, while the other half appear to be trauma related.[20]

Most patients become bedridden by time they are in their 30s.

Chronic neurological symptoms are common in these patients.[21] These findings include neuropathic pain, especially in females (15%). Many had other sensory abnormalities.

Fibrodysplasia ossificans progressiva (FOP) lesions are characterized by painful, tender, rubbery, soft-tissue indurations, usually precipitated by a trauma. Lesions mainly develop in the paraspinal muscles of the back and in the limb girdles. Some of the tumors undergo ossification, which can also affect the tendons, the ligaments, and the fascia. Widespread arthropathy throughout the axial and appendicular skeleton may be evident.[22]

Characteristics of diagnostic value are a hallus valgus deformity (present at birth), torticollis (due to involvement of the sternocleidomastoid muscle), joint immobilization (due to periarticular ossificans), and a thorax deformity (both lateral and anteroposterior).

Fibrodysplasia ossificans progressiva limited to the maxillofacial region has been described.[23] It may produce a fusion between the mandibular ramus and the zygomatic complex and trismus.

All proximal tibial osteochondromas are a common phenotypic feature.[24, 25] Mobility is restricted because of ankylosis of the spine and the rib cage.

Fibrodysplasia ossificans progressiva is sometimes associated with alopecia and deafness.[26]

Aslan et al reported ankylosis of the jaw and van der Meij et al reported restricted mandibular movement, both associated with fibrodysplasia ossificans progressiva.[27, 28]

Note the images below.

Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.

Typical hallus valgus deformity.

The clinical presentation (especially the additional presence of a hallus valgus deformity) is suggestive of fibrodysplasia ossificans progressiva (FOP). Routine biochemical study results of mineral metabolism are usually within the reference range. In fibrodysplasia ossificans progressiva, increased alkaline phosphatase levels are characteristic for children (physiologic growth of the bones).

Changes associated with fibrodysplasia ossificans progressiva (FOP) include abnormal formation of the great toe, abnormally shaped long bones with exostoses, and developmental fusion of cervical vertebrae.

The most characteristic features are areas of bony masses penetrating into muscles (mainly the paraspinal region).

CT scanning is the best method for detection of early fibrodysplasia ossificans progressiva lesions.[32] Bone scintigraphy shows an increased uptake of radiolabeled diphosphonate before ossification can be demonstrated by radiographic examination.

CT evaluation may demonstrate heterotopic ossification of the pterygoid muscles, a likely cause jaw restriction and retrognathia in older patients.[33]

A biopsy is generally not indicated in fibrodysplasia ossificans progressiva (FOP) because of the frequent development of the lesions in the traumatization area.

Histologic examination shows a pronounced proliferation of fibroblasts within the muscles in several areas, leading to destruction of muscle fibers. Predominate mononuclear cell infiltrates are present within the muscles and in the subcutaneous connective tissue, with extensive proliferation of connective tissue fibroblasts replacing damaged muscle fibers, plus areas of newly formed bone tissue. In the center of fibrous material, bone or cartilage tissue may be detected. The well-developed osseous lesions show a typical picture of mature bone with Haversian systems. The muscle fibers usually secondarily degenerate. Smooth muscles are not involved. Note the image below.

Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.

A therapeutic option that may lower the number of body regions with new ossification or the formation of new ossification may substantially enhance a patient’s quality of life.[1, 2] Palovarotene was approved by the FDA in Auguest 2023 and is an oral selective retinoic acid receptor γ agonist developed to diminish FOP heterotopic ossification formation.[34] Patients require close monitoring, as Hsiao et al have illuminated,[35] as adverse events may produce depression or/and anxiety and, potentially, heighten pain perception.[36]

Fibrodysplasia ossificans progressiva (FOP) should be diagnosed during the neonatal period.[37] Early treatment of fibrodysplasia ossificans progressiva helps avoid the factors of aggravation, slow the progression of the disease, and provide the children with improved quality of life. The first effective medical therapy, palovarotene, was approved by the FDA for fibrodysplasia ossificans progressiva in August 2023. Bisphosphonates and corticosteroids are only beneficial during the flares. Systemic steroids are sometimes used for acute flare-ups. Iontophoresis with steroids or acetic acid may improve diminished range of motion. 

Palovarotene

Palovarotene (Sohonos) was the first drug approved for fibrodysplasia ossificans progressiva (FOP). It is indicated for reduction in volume of new heterotopic ossification in adults and pediatric patients aged ≥8 years for females and ≥10 years for males with fibrodysplasia ossificans progressiva (FOP). 

In patients with fibrodysplasia ossificans progressiva, abnormal bone formation, including heterotrophic ossification, is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). Palovarotene is an orally bioavailable retinoic acid receptor agonist, with particular selectivity at the gamma subtype of RAR. 

Approval was based on 18-month data from the phase 3 multicenter, open-label MOVE trial that included 107 adult and pediatric patients, over 10% of the world's population with FOP. All received oral palovarotene and were compared with untreated individuals from a prior natural history study of the condition. Palovarotene reduced annualized heterotopic ossification volume by 54% (p = 0.039).[38]    

Other therapies

Gene therapy may hold promise in fibrodysplasia ossificans progressiva treatment. Inflammatory mediators play a role in fibrodysplasia ossificans progressiva and represent a possible therapeutic target.[39] The discovery of the FOP gene reveals a highly conserved target in the transforming growth factor-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small-molecule signal transduction inhibitors for activinlike kinase-2.[40] Effective therapies for fibrodysplasia ossificans progressiva may be based on blocking activinlike kinase-2 or blocking of activin receptor IA/activin–like kinase 2 signaling.[41]

One report (involving 3 patients) suggested that a combined formulation of propranolol and ascorbic acid (known as FOPCon) may be beneficial in the prophylaxis of flare-ups.[42] However, the International Clinical Counsel (ICC) on Fibrodysplasia Ossificans Progressiva, which seeks to help delineate best practices,[35] recommends that FOPCon not be promoted as or purported to be a definitive therapy for fibrodysplasia ossificans progressiva.[43] The ICC has determined the evidence for efficacy and safety is insufficient. The organization strongly recommends caution for both patients and medical practitioners against making therapeutic conclusions for current practice; however, it suggests further insights may be gained from continued investigation and validation. Further, until the safety and efficacy of FOPCon has been further investigated, it should be considered investigational and patients receiving it should be treated under protocols associated with formal clinical trials, including discussion of potential risks and benefits.

A summary of the ICC treatment guidelines for medical professionals is as follows[44] :

• Deep tissue trauma: Deep tissue trauma must be avoided. This includes intramuscular injections, if at all possible.
• Stabilization and treatment: For stabilization and procedures, venipuncture, subcutaneous medications, and intravenous medications are acceptable; again, intramuscular infections should be avoided if possible.
• Intubation precautions: Significant precautions should be taken with intubation procedures. The jaw should be protected. Expert anesthesiologist consultation should be obtained because the jaw and neck may be completely or partially locked.
• Further consultations: It is strongly recommended to obtain further consultations with expert physicians regarding the significant potential risks of any surgical or medical interventions being considered.

A complete version of these guidelines is available at The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations.

Patients with fibrodysplasia ossificans progressiva (FOP), a rare disorder, may require oral surgical and anesthetic procedures to control oral pain. The importance of a minimally invasive surgical technique and appropriate anesthetic management has been stressed.[45]

The experience using general anesthesia has been favorable, with awake nasal fiberoptic intubation evaluated as desirable for airway management.[46]

Palovarotene was the first drug approved for fibrodysplasia ossificans progressiva (FOP).[38]  Clinical trials have been underway with fidresertib, saractinib, garetosmab (REGN 2477), and rapamycin.[47, 48]

Class Summary

In patients with fibrodysplasia ossificans progressiva, abnormal bone formation, including heterotrophic ossification, is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). By binding to RARγ, palovarotene decreases the BMP/ALK2 downstream signaling pathway by inhibiting phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation. 

Palovarotene (Sohonos)

Indicated for reduction in volume of new heterotopic ossification in adults and pediatric patients aged ≥8 years for females and ≥10 years for males with fibrodysplasia ossificans progressiva (FOP).