Fibrodysplasia Ossificans Progressiva

An autosomal dominant disorder, almost always de novo, caused by gain-of-function variants in the bone morphogenetic protein type I receptor ACVR1 (ALK2), combining a congenital malformation of the great toe with inflammatory flare-ups of soft tissues followed by cumulative and irreversible endochondral heterotopic ossification.

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder of connective tissue and skeletal muscle in which normal soft tissues (striated muscle, tendons, ligaments, fasciae and aponeuroses) are transformed, through successive episodes, into mature extraskeletal bone. This heterotopic bone forms by the endochondral route, that is, it passes through a cartilaginous phase before ossifying, and accumulates as bridges and plates linking the parts of the normal skeleton until they form an irreversible “exoskeleton” [1, 4]. The disease has two components: a congenital component, present at birth, consisting of malformations of the first rays of the extremities (short great toe in valgus, sometimes short thumbs), and a postnatal component, consisting of inflammatory flare-ups that precede, though not always, heterotopic ossification [4, 11]. The ICC describes it as the most catastrophic disorder of heterotopic ossification in humans, ultra-rare and fully penetrant [11].

1.2. Historical overview

The first recognisable description is attributed to a letter by the French physician Guy Patin, in 1692 [13]. The PNDS supporting document refers to descriptions dating back to Antiquity and to the publication of clinical details in 1740, in a 14-year-old adolescent with ossifications, according to the 2008 review by Kaplan and colleagues [4]. In 1918, Rosenstirn extensively reviewed the cases published under the name myositis ossificans progressiva, which dominated the literature until the 20th century; the term still appears as a synonym in databases [1, 13]. The current name, fibrodysplasia ossificans progressiva, better reflects the histology of the lesions, which show a fibroproliferative and angiogenic reaction of connective tissue followed by endochondral ossification, rather than a primary myositis [13]. In 2022, Smith's Recognizable Patterns of Human Malformation counted more than 500 published cases [13], and GeneReviews, in its 2024 revision, referred to more than 800 individuals with more than 20 pathogenic ACVR1 variants [1].

Formal genetics was established between the 1960s and 1980s: most cases are sporadic, there are concordant monozygotic twins and triplets and vertical transmission over two or three generations, and sporadic cases are associated with advanced paternal age (Tünte 1967; Rogers and Chase 1979, cited in OMIM) [5]. Connor and Evans (1982) estimated, in the United Kingdom, a point prevalence of 0.61 per million and a direct mutation rate of 1.8 per million gametes per generation [5].

1.3. Milestones of molecular discovery

The search for the gene had two false starts. Between 1999 and 2007, variants of NOG (encoding noggin, an antagonist of bone morphogenetic protein, BMP) were published in patients with FOP; these observations were attributed to nested polymerase chain reaction artefacts, and the patient described with a “NOG deletion” carried the recurrent ACVR1 variant [5]. In 2000, Feldman and colleagues published linkage to 4q27–q31 (lod 3.10) that was not confirmed [5, 19]. In 2006, Shore and colleagues mapped the disease to 2q23–q24 by linkage analysis in families with vertical transmission and identified the same heterozygous variant, 617G>A (p.Arg206His), in the GS activation domain of the BMP type I receptor ACVR1, in all patients examined from seven families and in 32 of 32 sporadic cases; modelling predicted destabilisation of the GS domain and constitutive activation of the receptor [6, 9]. In 2009, Kaplan and colleagues studied 112 patients, 21 of them with an atypical phenotype, and showed that classic and atypical forms all result from heterozygous missense variants of conserved amino acids of ACVR1, proposing the classification into classic FOP, FOP-plus and FOP-variants [6, 10]. The later demonstration that the mutant receptor responds to activin A, a ligand that does not normally activate it, underpinned the development of the anti-activin A antibody garetosmab [7, 23]. The first targeted drug, palovarotene, was authorised in Canada in January 2022 and in the United States in August 2023, and garetosmab was authorised in the United States in August 2026 [20, 21, 23].

1.4. Nomenclature, classification and entities within scope

In the 2023 revision of the Nosology of Genetic Skeletal Disorders, the disease is designated “ACVR1-related FOP” and included in the group of disorders of the organised development of skeletal components [1, 2]. The clinical classification used in the French and international guidelines derives from Kaplan 2009 [4, 10]:

The three forms belong to a single genetic entity; this article covers them together and indicates the differences where they exist. Progressive osseous heteroplasia (POH, GNAS), hereditary multiple osteochondromas (EXT1/EXT2) and multiple synostoses (NOG/GDF5) are included only as differential diagnoses.

2. Molecular Genetics and Pathophysiology

2.1. The ACVR1 gene and the ALK2 protein

ACVR1 lies at 2q24.1 (GRCh38 2:157,736,446–157,876,330) and encodes activin A receptor type 1, also designated ALK2 (activin receptor-like kinase 2), ACVRLK2, SKR1 or ACVR1A, a 509-amino-acid protein (HGNC:171; Entrez 90; UniProt Q04771) [6, 7]. The MANE Select transcript is NM_001111067.4 (NP_001104537.1); the French PNDS uses NM_001105.5 and GeneReviews NM_001105.4, transcripts that are not MANE but have the same c. and p. numbering for FOP variants [1, 4, 8]. The protein is a transmembrane serine/threonine kinase with an extracellular binding domain, a transmembrane segment, an intracellular glycine- and serine-rich domain (GS domain) and a kinase domain [1, 6].

ALK2 forms heterotetrameric complexes with type II receptors (ACVR2A, ACVR2B, AMHR2). After binding of a BMP, the type II receptor transphosphorylates the GS domain of the type I receptor, which in turn phosphorylates the intracellular mediators SMAD1, SMAD5 and SMAD8; these enter the nucleus and activate genes of the osteochondrogenic pathway [4, 7]. At rest, the GS domain binds the inhibitory protein FKBP12 (FKBP1A), which prevents “leaky” activation of the receptor in the absence of ligand [6].

2.2. Molecular mechanism: gain of function and activin A neo-agonism

All pathogenic variants described in FOP are heterozygous gain-of-function missense variants; no intragenic deletions or duplications or loss-of-function variants (nonsense, frameshift, splicing) have been described [1, 11]. Codon 206 lies at the end of the GS domain, at the junction with the kinase domain; the p.(Arg206His) substitution destabilises intramolecular interactions that keep the receptor inactive and alters FKBP12 binding, which makes the receptor hypersensitive and partially active without ligand [6, 9]. GeneReviews summarises the mechanism as hyperactive BMP signalling, induced independently of BMP and responsive to BMP; the activation is milder than in murine models of pathway hyperactivation, which are embryonic lethal, which would explain compatibility with life [1]. The property with the greatest therapeutic consequence is neo-agonism: the mutant receptor responds to activin A, which is not an agonist at the normal receptor, and drives progenitor cells of connective tissue and muscle through an endochondral programme [7]. Smith's adds increased mTOR (mechanistic target of rapamycin) signalling downstream of this response to activin A [13]. The antibody garetosmab binds activin A and prevents activation of the mutant receptor [23].

Animal models confirmed the mechanism. The Acvr1 R206H knock-in mouse reproduces the classic phenotype (Chakkalakal 2012, according to the PNDS supporting document) [4]. Expression of a constitutively active ALK2 (Q207D) generates ectopic endochondral bone and joint fusions dependent on an inflammatory environment, which corticosteroids inhibit (Yu 2008, according to OMIM) [6]. A finding with practical implications is that of Aykul and colleagues (2022): anti-ACVR1 monoclonal antibodies blocked heterotopic ossification in mice with normal Acvr1, but worsened it in the R206H model, because they induced artificial, ligand-independent dimerisation that activates the mutant receptor; the observation explains the caution with antibodies targeting the receptor itself [6]. Older observations, such as increased BMP4 in patient lymphoblastoid lines (26 of 32 patients versus 1 of 12 controls) and greater cell-surface presence of BMPR1A, are now interpreted as downstream consequences [5].

2.3. From flare-up to ossification: tissue pathophysiology

The lesion begins with intramuscular oedema, often after trauma, followed by an intensely angiogenic, mast-cell-rich fibroproliferative reaction; some lesions regress, but most progress to cartilage and then to lamellar bone with marrow, by endochondral ossification [13]. On histology of 11 paediatric biopsies performed to exclude neoplasia, 6 were interpreted as fibromatosis or sarcoma; ossification was normal endochondral apart from its location, and biopsy uniformly worsened the disease [5]. The progenitors involved reside in connective tissue and muscle and respond to trauma, hypoxia and inflammation; imatinib has been used for its action on targets of the hypoxic inflammatory phase (HIF1-α, platelet-derived growth factor receptor alpha, c-KIT and several mitogen-activated kinases) [4, 11]. Heterotopic bone forms preferentially in the ligaments and the paraspinal, girdle and masticatory muscles, and the diaphragm, tongue, extraocular muscles, cardiac muscle and smooth muscle are spared [4, 13, 19].

The same receptor is involved outside the skeleton. ACVR1-dependent hyperexcitability of sensory neurons, demonstrated by quantitative sensory testing (Yu 2023), explains neuropathic pain; autopsy of one patient showed ectopia of the pedunculopontine nucleus and thickening of the subventricular zone (Tanaka 2022), and the BMP pathway appears to participate in central nervous system demyelination (Kan 2012) [4].

2.4. Variant spectrum

About 97% of patients have the recurrent variant c.617G>A p.(Arg206His); GeneReviews indicates more than 97% and the ICC about 97%, with the remaining 3% distributed among other variants, some more severe and others milder [1, 11]. Worldwide recurrence (Japanese, Taiwanese, Italian, American and European patients) is explained by the transition occurring at a CpG dinucleotide [6]. There are no founder variants: the same variant arises de novo in all populations. The following variants were normalised in VariantValidator (GRCh38 genome assembly; MANE Select transcript) and, where available, in ClinVar:

OMIM describes the Gly356Asp variant as “1097G-A”; this numbering does not correspond to the MANE transcript (VariantValidator rejects c.1097G>A because of a mismatch with the reference sequence), and the correct description is c.1067G>A [6, 8]. The review by De Brasi and colleagues adds c.974G>C p.(Gly325Ala) (g.157766013C>G) among the FOP-variant variants [8, 30]. The PNDS states that all variants are located in the catalytic kinase domain; GeneReviews and the location of Arg206 in the GS domain indicate that they are distributed across the GS and kinase domains [1, 4, 6].

2.5. Genotype-phenotype correlations, penetrance and expressivity

The p.(Arg206His) variant is associated with the classic phenotype: bilateral malformed great toe, heterotopic ossification beginning before the age of 10 and few extramuscular or extraskeletal signs [1, 4, 10]. Codon 328 variants are associated with limb reduction defects, which may be confused with amniotic bands or brachydactyly type B before ossification appears [1]. GS domain variants proximal to Arg206 (Arg202Ile, Leu196Pro) and some kinase domain variants (Gly356Asp, Arg375Pro) are associated with late onset and slow progression, but the number of patients per variant is very small [5, 6]. Penetrance is estimated to be complete or near-complete: no carrier of p.(Arg206His) without disease is known [1]. Expressivity varies greatly between patients and within the same family, from the adult with only great toe malformation to disabling disease (Connor 1993: five people in three generations), and the guidelines identify no prognostic factors [4, 5].

2.6. Allelic disorders, somatic variants and associations under study

GeneReviews recognises no other germline phenotypes associated with ACVR1 [1]. OMIM records as a provisional association ACVR1 variation in atrioventricular septal defects (AVSD1, OMIM 606215) [6]. Somatic gain-of-function variants in ACVR1 (including Arg206His, Arg258Gly, Gly328Glu/Val/Trp and Gly356Asp) are present in 20–25% of diffuse intrinsic pontine gliomas (DIPG) of childhood, with a broader spectrum than the germline one; no increase in DIPG has been described in patients with FOP [1, 30]. ALK2 inhibitors have shown only preclinical benefit in DIPG [7].

3. Clinical Spectrum and Manifestations by System

3.1. Frequency of manifestations

The table brings together the frequencies compiled by GeneReviews from Kaplan 2009, the French national registry of Piram 2011 and the Kaplan 2019 review; the percentages refer to patients in series from expert centres and registries, mostly with the classic variant, and some are age-dependent [1].

3.2. Congenital component: extremities and skeleton

The great toe is the key to diagnosis. The 1st metatarsal is short, with a malformed head and lateral deviation, and the proximal phalanx is short, triangular or trapezoidal, sometimes absent (monophalangism) or fused with the metatarsal or the distal phalanx; the metaphyseal line of the 1st phalanx is oblique, and brachymesophalangy of the 5th toe is frequent [4, 19]. The great toe is always affected in the classic form, but the thumb may be normal; when involved, the 1st metacarpal is short and ovoid, with hypoplasia of the phalanges, and some children have early fusion of the metacarpophalangeal and interphalangeal joints of the thumb [4, 19]. In the newborn, the great toe may only be short and go unnoticed if the paediatric team is unfamiliar with the disease; prenatal ultrasound may identify it from 23 weeks, although prenatal diagnosis is exceptional [1, 4]. Some newborns have reduction anomalies of several rays in the upper and lower limbs, and at the opposite extreme there are patients with normal great toes [4].

Other congenital or developmental skeletal changes include tall, narrow cervical vertebrae with fusion of the facets from C2 to C7 and limitation of neck movement before any flare-up, broad femoral necks with small proximal femoral epiphyses, developmental dysplasia of the hip (found in 60% of patients assessed for acute hip pain) and enchondromas of unknown prevalence [1, 4]. Osteochondromas begin as subtle prominences of the proximal tibial and distal femoral metaphyses in the 1st decade and evolve into sessile or pedunculated formations; they are less bulky than in hereditary multiple osteochondromas, matter for distinguishing knee pain from a flare-up and should not be excised [4]. The facial signature, studied by three-dimensional photogrammetry in 55 patients of European phenotype (mean age 21.9 years), consists of a narrow, elongated face, particularly in males, a small mandible, low-set ears and flattening of the upper orbital rim with prominence of the lower rim [4, 13].

3.3. Postnatal component: flare-ups and heterotopic ossification

A flare-up is defined, in the PNDS, by the presence of at least 2 of 6 signs: pain, swelling, induration, increased local warmth, redness and reduced segmental mobility [4]. In the worldwide survey of Pignolo 2016 (78 questions in 15 languages, sent to 685 classic patients from 45 countries; 500 responses, 73%; ages 1–71 years, median 23), the most frequent symptoms were oedema (93%), pain (86%) and reduced mobility (79%); 71% had had a flare-up in the preceding 12 months, 52% spontaneous and 48% post-traumatic [18]. Axial flare-ups were most frequent in the back (41.6%), neck (26.4%) and jaw (19.4%); the upper limbs were affected before the age of 8 and the lower limbs later, with proximal predominance; 70% of flare-ups caused functional loss, 32% of patients had complete resolution of at least one flare-up, flare-ups of the shoulders and hips were the most disabling and 47% of patients reported progression without apparent flare-ups [18]. The PNDS stresses that not all flare-ups lead to ossification and that ossification may occur without an evident flare-up [4].

The mean age at first flare-ups is 6.9 years (Pignolo 2016, according to the PNDS); in the series of Cohen 1993 (44 patients aged 3 to 69 years), the first ossification appeared on average at 5 years (from birth to 25 years) and Smith 1996 (28 patients followed up to 24 years) observed onset between birth and 16 years (mean 4.6) [4, 5, 19]. In p.Arg206His patients, ossification begins between 1 and 10 years; in atypical FOP it may begin later [1]. The first sites are the neck, spine and shoulder girdle, and progression follows the axial→appendicular, cranial→caudal, dorsal→ventral and proximal→distal axes, which reproduce the order of development of the embryonic skeleton [4, 5, 19]. Heterotopic bone forms pseudotumours, irregular sheets, bony bridges and small confluent clumps in the joint capsules, and exostosis-like projections at ligament insertions [4, 19]. Surgical removal of an inflammatory or bony lesion may trigger a volley of flare-ups for months [4]. The documented triggers are intramuscular injections (25% of patients who received one had an immediate flare-up at the site, and 84% of these progressed to ossification), biopsies, surgery, mandibular blocks, muscle fatigue, blunt trauma and influenza-like viral infections [11, 18].

3.4. Functional course and stages

Ossification is cumulative. In the series of Cohen 1993, 80% (35 of 44) had restrictive ossification by age 7 and more than 95% (42 of 44) had severely limited arm mobility by age 15; Smith's indicates 85% by age 7, with most patients wheelchair-bound in the 3rd decade [5, 11, 13]. The HAS summary describes the need for one and then two people for activities of daily living from the start of the 3rd decade [4]. In the prospective natural history study (Pignolo 2019: 114 patients, 36 months, mean age 17.6 years, 54% male, seven centres in Buenos Aires, Woolloongabba, Paris, Genoa, Stanmore, Philadelphia and San Francisco), flare-ups were most frequent between the ages of 8 and 15, the cumulative analogue joint involvement scale (CAJIS) was worst between 25 and 65 years and the volume of ossification correlated with the course [4]. CAJIS increased, on average, by 1 point every 2 years in the natural history study preceding the palovarotene trial [4]. The five clinical stages of Pignolo and Kaplan (2018) and their use in follow-up are given in section 11 [31].

3.5. Respiratory and cardiovascular system

Lung disease is restrictive, with reduced vital capacity without obstruction. Thoracic insufficiency syndrome results from thoracic kyphoscoliosis or hyperlordosis, costovertebral fusions and ossification of the intercostal and paravertebral muscles; advanced patients breathe only with the diaphragm and accumulate atelectasis, retained secretions, hypoxaemia, hypercapnia, pneumonia, pulmonary embolism, pulmonary hypertension and right heart failure [1, 4, 27]. It is the predominant cause of death (section 11) [25]. Early cardiac involvement was revealed by natural history studies: in the study of Kou 2020 (R206H patients), 45.3% of baseline electrocardiograms had conduction disturbances, mainly non-specific intraventricular conduction delay (37.7%); the frequency was 22.2% in adults versus 5.9% in a healthy population (n = 3978; p < 0.00001) and 62.3% in those under 18, without correlation with thoracic deformity, scoliosis, function tests or CAJIS; 8 of 22 echocardiograms showed structural anomalies [27]. The PNDS considers these changes generally without consequence in children and young adults, but recommends screening for them, particularly before trials of drugs with possible cardiac effects [4].

3.6. Head, neck, jaw, hearing and teeth

Temporomandibular joint (TMJ) dysfunction results from constitutional anomalies of the joint and ossification of the masticatory and pterygoid muscles; in the British series of Connor 1982, 34 of 44 patients had ossification of the masticatory muscles, 6 preceded by local trauma [4]. Mandibular ankylosis, spontaneous or post-traumatic, causes feeding and swallowing difficulties, poor oral hygiene and risk of aspiration in the event of vomiting [4, 13]. In the series of Luchetti 1996, 5 of 21 patients who received dental local anaesthesia had an immediate flare-up with ossification and ankylosis of the jaw [4]. Maxillodental disharmony and progressive retrognathia are frequent [4]. Submandibular flare-ups may cause dyspnoea due to oedema and are emergencies [4, 11]. Conductive hearing loss affects about 50% of patients, begins in childhood and progresses slowly, possibly due to ossification of the middle ear; mixed and sensorineural forms have been described, tympanostomy tubes and middle ear surgery have not improved the course, and acute hearing loss requires another cause to be sought [1, 4, 11].

3.7. Nervous system and pain

In the survey of Kitterman 2012 (168 patients from 30 countries, 1.5–68 years), 51% had at least one chronic neurological symptom: headache (26.2%), neuropathic pain (10.1%) and other sensory disturbances (36.3%), such as allodynia, numbness and tingling, mainly in the legs, feet, arms and hands [4, 13]. Myoclonus and tremor, headaches mainly in post-pubertal women, malformations of the cerebellum and corpus callosum, craniopharyngioma and obstructive hydrocephalus due to a brainstem mass in a 15-month-old child, without progression up to the age of 10, have been described [4, 13]. In the magnetic resonance imaging (MRI) series of Severino 2016 (13 patients, 11 R206H and 2 R258S), all had small asymptomatic hamartoma-like lesions in the dorsal medulla and ventral pons with brainstem dysmorphism, 10 (77%) had an enlarged origin of the vestibulocochlear nerves and 8 had calcifications of the basal ganglia or dentate nuclei, correlated with age and disability [5]. This dorsal medullary protuberance is one of the forms of hooded medullary tegmental dysplasia, which has other causes and enters the differential diagnosis of brainstem malformations. White matter changes and signs of focal inflammation have no evident clinical correlate [4]. Chronic pain may be neuropathic or nociceptive and is worsened by poorly fitted chairs, footwear and aids [11].

3.8. Kidney, skin, limbs, digestive system and other manifestations

The risk of kidney stones is about 3 times that of the population; in the study of Gupta 2018, 19 of 207 patients (9.2%; mean age 38 years) had urolithiasis, to which immobility, the BMP pathway, bone remodelling, a low-fibre diet and urinary tract infections contribute [1, 4]. In the skin, seborrhoeic dermatitis and hypotrichosis (sparse eyebrows, reduced hair density) are frequent, and joint limitation favours bacterial intertrigo and fungal infections; in advanced forms, pressure ulcers, maceration and lesions over bony prominences increase, portals of entry for sepsis [4, 11]. Limb oedema is a feared complication: in the series of Moriatis 1997 (74 patients), 64% had lower limb lymphoedema and 4% deep vein thrombosis; oedema associated with an acute flare-up may persist for 3 to 6 months, with risk of compression, blisters and streptococcal cellulitis [4]. Nausea and vomiting are frequent and of unknown cause, and weight loss with very low body mass index and severe scoliosis is associated with intestinal obstruction and superior mesenteric artery syndrome [11]. In a body composition study in Amsterdam (18 patients), 6 had low body mass index, mainly those with very restricted mouth opening, fat-free mass was low and fat high, worse with high CAJIS, and resting energy expenditure was lower than predicted by the World Health Organization formula (1211 versus 1437 kcal/day; p = 0.003) [32]. The risk of fractures of normotopic and heterotopic bone increases with falls, immobility and corticosteroid-induced osteopenia; fractures heal with little heterotopic formation when managed conservatively [1, 11]. Hernias, widely spaced teeth, hypogenitalism or delayed puberty, easy bruising and cardiac conduction anomalies have been described as occasional findings; malignancy is not part of the disease [13].

3.9. Atypical forms

FOP-variants may present without great toe malformation and with late onset, which delays diagnosis: a woman with p.(Arg202Ile) presented with a “stiff back” at age 21, was treated for years as spondyloarthropathy and ankylosing spondylitis and was diagnosed only at age 27, in the presence of ossification of the ligamenta flava and interspinous ligaments; she was only the fifth published patient with both great toes normal [5]. At the opposite extreme, codon 328 variants cause severe digital reductions, absent nails and, in some patients, mild cognitive impairment and cerebellar anomalies [6]. In the series of Kaplan 2009, 21 of 112 patients had an atypical phenotype (FOP-plus or FOP-variant) [6, 10].

3.10. Natural history and treated disease

The data in the preceding sections describe mainly the natural history, with symptomatic treatment. Short courses of corticosteroids relieve flare-ups, but there is no proof that they prevent ossification: in the 2016 survey, 75% of patients used glucocorticoids for appendicular flare-ups, 55% reported occasional improvement and 31% consistent improvement, only 12% had complete resolution and 43% had a rebound effect 1 to 7 days after the course; in a series of 25 patients with hip flare-ups treated with a short course of oral corticosteroid, all developed ossification [4, 18]. The effects of targeted drugs on new ossification are given in section 7.

4. Clinical Recognition and Warning Signs

4.1. The problem of late diagnosis and iatrogenic harm

Early recognition is the intervention with the greatest impact, because the usual diagnostic procedures for a soft tissue mass (biopsy, excision, injections) worsen the disease. In the survey of Kitterman 2005 of IFOPA members (138 responses from 25 countries, 51% of 269; ages 2–71 years), 87% had received an incorrect initial diagnosis, most often cancer (32%); the correct diagnosis came on average 4.1 years later, after a median of 6 doctors; 67% had undergone unnecessary invasive procedures, mainly biopsies, 68% inappropriate therapies and 49% were left with permanent loss of mobility caused by these interventions; only 8% of 184 medical textbooks described the disease adequately [5, 33]. The problem persists: in the Chinese national registry (114 patients with molecular confirmation, 23 provinces), FOP was not considered at the first consultation in 74.6%, the initial diagnosis was wrong in 63.2% (tumour hypotheses in 50.0%), 44.7% were biopsied, with subsequent worsening in 80.4%, and 22 of 25 excisions of heterotopic bone (88.0%) were followed by recurrence or new lesions at the site [34]. In a scoping review of 369 case publications (541 patients from 57 countries, 2000–2024), 35.1% of patients had undergone surgery, 34.1% of these interventions were biopsies, and only 5.5% had been followed by multidisciplinary teams [35]. In France, the mean age at diagnosis was 10 years, with 14.9% diagnosed after the age of 18 [14]; the PNDS reports a mean age of 5 years in the natural history cohort, probably falling [4].

4.2. When to suspect

The Oxford Desk Reference summarises the practical rule: in the presence of ectopic soft tissue ossification, look for the short great toe, and avoid surgery and dental treatment because they accelerate ossification [36]. The recommendation common to the guidelines is that, when FOP is suspected, all elective procedures (surgery, biopsy, intramuscular immunisation) should be postponed until genetic confirmation [1, 11].

4.3. Warning signs and emergencies

The following are emergencies: submandibular and anterior cervical flare-ups, because of the risk of airway and swallowing compromise; any head injury, even without loss of consciousness, because ankylosed shoulders prevent protection of the head in falls and epidural haematomas are common; respiratory difficulty during an infection in a patient with restrictive syndrome; acute oedema of a limb (deep vein thrombosis, compartment syndrome); nausea and vomiting in a patient with an ankylosed jaw (risk of aspiration); and acute abdominal pain in a patient on anti-inflammatory drugs, in whom an abdominal flare-up, the pain of abdominal ossification and gastrointestinal perforation may be confused [4, 11]. The management of each is given in section 7.

4.4. Newborn screening

There is no biochemical or genetic newborn screening. Early detection depends on examination of the newborn's feet and on awareness of the disease among neonatal and paediatric teams [4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal diagnostic criteria. The clinical diagnosis rests on the combination of congenital great toe malformation and progressive heterotopic ossification, but requires genetic confirmation of a pathogenic ACVR1 variant [1, 11]. GeneReviews considers the diagnosis established in a proband with great toe malformations and heterotopic ossification and/or a heterozygous pathogenic or likely pathogenic ACVR1 variant; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. In children without ossification, detection of c.617G>A allows diagnosis before any harm (Kaplan 2008: 7 children without ossification), and early diagnosis avoids invasive investigations [4].

5.2. Genetic testing

The proportion of variants detected by sequencing is not equivalent to the clinical sensitivity of the test: a negative result in a patient with a typical phenotype requires the phenotype to be reviewed and mosaicism or a variant outside the regions analysed to be considered, before the disease is excluded. The report should state the gene, the versioned transcript (NM_001111067.4 is MANE Select), the Human Genome Variation Society (HGVS) description, c. and p., zygosity (heterozygous) and classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); c.617G>A is classified as pathogenic in ClinVar by several submitters, without conflicts [8, 12]. There is no ClinGen actionability assertion for ACVR1 [7].

5.3. Imaging

Foot radiography is the most useful investigation: the earliest radiological sign is monophalangism of the 1st toe with a stubby, broadened 1st metacarpal (Al Mukaddam 2018) [4]. The French initial work-up includes conventional radiographs (not EOS, the low-dose biplanar radiography system) of all four extremities with bone age, AP pelvis and knees and lateral cervical spine, and of the affected segments [4]. Ultrasound and MRI identify the oedema of a flare-up at an early stage, for example in the abdominal region, but MRI is not always feasible; radiography and computed tomography (CT) assess ossification and its volume [4]. Low-dose whole-body CT with bone reconstruction and positron emission tomography with fluorine-18-labelled sodium fluoride (¹⁸F-NaF PET-CT) are used mainly in trials, and EOS radiography reduces irradiation in the follow-up of deformities [4]. There is no international recommendation on the frequency of imaging; the French schedule is given in section 11 [4].

5.4. Biomarkers

There is no biochemical marker of diagnosis or disease activity [4, 7]. In research, adiponectin and tenascin-C correlated strongly with the FOP genotype and kallikrein-7 with acute heterotopic ossification (Pignolo 2022), without clinical use [4]. Routine tests are normal; C-reactive protein may be raised during a flare-up (52.76 mg/L in the case in section 10) [30]. Histopathology is not an available test in practice because biopsy is contraindicated [7].

5.5. Algorithm

The algorithm that follows from the guidelines is sequential. In a newborn with malformed great toes, or a child with soft tissue swelling and a malformed great toe, the first step is to examine and radiograph the feet and to suspend biopsies, elective surgery and intramuscular injections. The second step is testing for c.617G>A, followed by sequencing of ACVR1 if negative, or exome/genome when the phenotype is atypical. Once the variant is confirmed, parental testing follows, together with characterisation of the form and stage (Pignolo and Kaplan stages and CAJIS), the initial multidisciplinary work-up and referral to an expert centre, with immediate education on prevention and the management of flare-ups [1, 4, 11]. The initial assessments recommended by GeneReviews include staging, functional assessment of the great toe (which rarely requires intervention), the extent of ossification, pulmonary and sleep studies if mechanical insufficiency is suspected, the history and examination of swellings and a genetics clinic appointment [1].

5.6. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible; the PNDS adds that non-invasive prenatal diagnosis is possible when the carrier parent is the father [1, 4]. The ultrasound finding of fetal hallux valgus is rare and does not replace testing [4].

6. Differential Diagnosis

6.1. Comparative table

AD, autosomal dominant.

6.2. The main differential diagnoses

The most important distinction is from progressive osseous heteroplasia, the other genetic disorder of progressive heterotopic ossification. In POH, bone forms by membranous ossification and begins in the dermis, as osteoma cutis, before reaching the subcutaneous tissue and muscle; there is no great toe malformation or inflammatory swelling, bone formation is not triggered by trauma, infection or puncture, and the disease stabilises after adolescence. In FOP, bone is endochondral, forms in muscle and deep connective tissues, the skin and subcutaneous tissue are spared and each trauma may trigger a flare-up [1, 37]. The two diseases share the contraindication to surgery, because the lesions recur [37].

Osteochondromas are the second point of confusion, because about 90% of patients with FOP have them and because they are sometimes the presenting finding at the end of the 1st decade [1, 4]. The osteochondromas of FOP are smaller and less symptomatic, are located mainly in the medial proximal tibia and the distal femur and coexist with the malformed great toe; in hereditary multiple osteochondromas, the great toe is normal and there is no soft tissue ossification [4, 38]. The error of confusing them leads to excision, which in FOP triggers flare-ups.

FOP-variants with severe digital reduction (codon 328) may be classified as brachydactyly type B or as amniotic band sequence before ossification appears, and patients with late onset and normal great toes as ankylosing spondylitis [1, 5]. The early cervical fusions of FOP resemble Klippel-Feil syndrome, which has no heterotopic ossification or great toe malformation [19]. NOG-related multiple synostoses syndrome shares conductive deafness, fusions and a short 1st metacarpal, but does not form bone in soft tissues; the association of NOG with FOP has been refuted [5, 40].

In a child with a soft tissue mass, a diagnosis of sarcoma, aggressive juvenile fibromatosis or desmoid tumour should be investigated by biopsy only after examining the feet and, if the great toe is abnormal, after ACVR1 testing: in the histological series of Kaplan 1993, FOP had never been considered before the 11 biopsies, 6 were read as fibromatosis or sarcoma and all worsened the disease [5, 33]. The case of Brance 2022 illustrates the opposite limit: a 55-year-old man with congenital bilateral hallux valgus developed extensive ossification after severe COVID-19 with no ACVR1 variant identified, which shows that the phenotype alone does not replace genetic confirmation [4].

7. Treatments and Risk Management Strategies

7.1. Objectives, organisation and reference documents

The objectives defined by the PNDS are to limit the formation of new heterotopic bone, relieve pain and improve comfort and quality of life, prevent and detect complications early, increase survival in severe forms, preserve cardiorespiratory, skeletal and oral function, growth, mobility and autonomy, and support the patient and family in the medical, school and professional dimensions [4]. Coordination is the responsibility of a doctor at an FOP expert centre, in liaison with the general practitioner: in children, a paediatrician, clinical geneticist or paediatric rheumatologist; in adults, a rheumatologist and/or a physical and rehabilitation medicine physician [4]. The ICC recommends that the treating doctor consult an FOP expert and coordinate the local team, that the patient and family be informed at diagnosis about the ICC, the IFOPA and national associations, and that emergency care follow the recommendations for first responders [11]. The two main guidelines are the 2024 HAS PNDS, French in scope, and the ICC medical guidelines published in 2025, developed by 21 members and 7 consultants from 15 countries by a modified Delphi method, from more than 2900 articles, with evidence generally moderate to low and expert opinion where data are lacking, without industry funding [4, 11]. The ICC classifies drugs into four groups: approved by a regulatory authority (palovarotene); class I, of accepted use (prednisone/prednisolone, ibuprofen, indometacin, celecoxib); class II, off-label and with caution (montelukast, oral cromoglicate, pamidronate, zoledronate, imatinib, tofacitinib, canakinumab); and class III, investigational [11]. The PNDS, written before the recent authorisations, uses the previous ICC classification and places palovarotene and garetosmab in class 3, «non utilisables en pratique courante» in France [4].

7.2. Prevention of trauma and invasive procedures

Prevention is the cornerstone of treatment and begins at diagnosis. Fall prevention measures include light, non-slip footwear (sometimes with a raise), removal of obstacles at home, secure handrails and rugs, walking aids, cautious proprioceptive physiotherapy and a helmet for children with affected upper limbs and for adults who still walk [1, 4, 11]. Contact sports, muscle stretching, muscle fatigue and passive mobilisation should be avoided; physical activity is encouraged, and singing, aquatic exercise and breathing activities are strongly recommended [11]. The procedures to avoid are intramuscular injections (including vaccines), biopsies, removal of heterotopic bone, all non-urgent surgery, mandibular anaesthetic blocks and stretching of the jaw [1, 11]. Venepuncture and superficial peripheral intravenous access are acceptable when performed by an experienced professional, with a brief tourniquet and without excessive cuff inflation; central venous catheters, peripherally inserted central catheters and arterial punctures may cause ossification and are used only if critical [11]. Intradermal and subcutaneous injections are possible outside flare-ups, with caution [4].

7.3. Vaccination

Vaccination is a balance between the risk of a flare-up at the injection site and the risk of potentially fatal respiratory infections in a patient with restrictive syndrome. The ICC 2025 recommendations are: subcutaneous route for all vaccines that allow it; avoid all intramuscular vaccines and the live attenuated intranasal influenza vaccine; do not vaccinate during a flare-up or for up to 8 weeks after its resolution; and vaccinate all household contacts against influenza, pertussis and COVID-19; no flare-ups have been reported after subcutaneous measles, mumps and rubella vaccines, with or without varicella [11]. The PNDS details the vaccines by group, according to the ICC and French experience; the original numbering jumps from group 6 to group 8, with no group 7 [4]:

The PNDS table has two internal inconsistencies. It contraindicates the oral rotavirus vaccine because it contains live virus, but accepts in group 1 the live subcutaneous vaccines against measles, mumps, rubella and varicella; the risk of flare-up associated with vaccines results from the muscle injury of the injection, which the oral route does not cause [4, 11]. And it places the Haemophilus influenzae b vaccine among the toxoid-conjugated vaccines to be avoided (Hiberix® and Act-HIB® are conjugated with tetanus toxoid) and, in group 8, among those possible by the subcutaneous route [4]. The reference for these decisions is the ICC 2025 rule: subcutaneous route whenever the vaccine allows it, no intramuscular vaccine, and a case-by-case decision in the face of respiratory risk [11].

The HAS summary describes the French position as avoidance of vaccinations from the time of diagnostic suspicion until the appearance of restrictive respiratory failure, and the OSCAR schedule recommends avoiding vaccinations in children and discussing them case by case in adults [4]. Experience with COVID-19 comes from the IFOPA registry (Kou 2022: 326 patients from 69 countries; 15 vaccinated under anti-inflammatory cover, 1 flare-up), from a 45-year-old woman with ossification 3 months after infection (Grgurevic 2021) and from the case of Brance 2022 already mentioned [4]. For contaminated wounds, the ICC recommends human tetanus immunoglobulin and advises against intramuscular or subcutaneous tetanus vaccine unless necessary [11]. GeneReviews considers respiratory vaccines (influenza and pneumococcus) particularly important and allows the subcutaneous route when the benefit outweighs the risk, at least 6–8 weeks after recovery from a flare-up [1]. The inclusion of the 23-valent polysaccharide vaccine in group 1 of the PNDS predates the French revision of the pneumococcal strategy: the HAS recommendation validated on 23 July 2026 discontinued PPV23, PCV13 and PCV15 at all ages and provides for PCV20 in at-risk children and adolescents and PCV21 as preferred in at-risk adults aged 18 to 64 and in all adults aged 65 or over, as a single dose [41]. Both are vaccines conjugated with the carrier protein CRM197, a non-toxic mutant of diphtheria toxin, like the Prevenar 13® of group 4, and the European SmPCs indicate exclusively the intramuscular route [42, 43]. In the USA, the CDC retains PPSV23 to complete the schedule after PCV15 in adults and as an alternative to PCV20 in at-risk children aged 2 to 18 [44, 45].

7.4. Treatment of flare-ups

The choice of treatment depends on the location of the flare-up, and this rule is common to the PNDS and the ICC. For flare-ups of the limbs and limb roots (shoulders, hips), the jaw and the submandibular and submental regions, early high-dose, short-course corticosteroid therapy is used, started within the first 24 hours, because it acts on the initial phase of inflammatory infiltration of muscle; for flare-ups of the posterior neck, thorax and dorsolumbar region, non-steroidal anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase 2 (COX-2) inhibitors are used, and corticosteroids are not recommended, because these flare-ups are frequent, particularly in paediatrics, appear to respond less and would expose patients to the complications of repeated corticosteroid therapy, dependence and rebound [4, 11]. There is no proof that corticosteroids prevent secondary ossification [4].

The doses of the class I NSAIDs appear in the detailed 2024 ICC version: ibuprofen, in children 4–10 mg/kg orally every 6 hours as needed and in adults 200–800 mg every 6 hours as needed, with food; indometacin, in children 2–4 mg/kg/day or 150–200 mg/day (whichever is lower) in 3 doses, and in adults 50 mg 3 times daily or 75 mg modified-release twice daily; celecoxib (Celebrex®), 100–200 mg twice daily for maintenance, not exceeding during flare-ups 250 mg/m² or 6 mg/kg twice daily (whichever is lower, rounded to the nearest multiple of 100 mg) or 600 mg/day for more than 16 months, contraindicated in sulfonamide allergy and aspirin-sensitive asthma [27]. The adverse effects to monitor are gastrointestinal bleeding and deterioration of kidney function [27]. The PNDS insists on gastroprotection above the age of 10 with any prolonged NSAID use, on the risk of ulcer, gastritis and even peritonitis, on the possible confusion between an abdominal flare-up, the pain of abdominal ossification and gastrointestinal perforation, and on stopping NSAIDs in the event of proven or suspected infection [4]. The ICC found no evidence that chronic use of NSAIDs or COX-2 inhibitors prevents or improves flare-ups [11]. The adverse effects of corticosteroids listed by the ICC include acne, adrenal suppression, avascular necrosis of the hip, cataracts, chronic dependence, Cushing syndrome, diabetes, glaucoma, growth retardation, hypertension, immunosuppression, osteoporosis, peptic ulcer, bruising, sleep and mood disturbances and weight gain; in endemic regions, antiparasitic precautions may be needed [11, 27]. The ICC recommends that the patient keep prednisone at home (“pill-in-pocket” strategy) to start treatment within 24 hours [11].

During and after the flare-up, gentle active mobilisation should be resumed as soon as possible, under analgesia, to limit ankylosis; the reference doctor should be informed, and the start and end dates of the flare-up recorded in the follow-up notebook [4]. Analgesic measures include ice, paracetamol, ibuprofen and tramadol, and the ICC discusses non-pharmacological alternatives (balneotherapy, biofeedback, relaxation, massage, self-hypnosis, cognitive behavioural therapy, acupressure) and medicinal cannabis [4]. In children, tramadol is contraindicated below the age of 12 and, below the age of 18, after tonsillectomy or adenoidectomy, according to the FDA [46]; the French SmPC for the oral drops allows it from the age of 3, at the usual dose of 1 mg/kg per dose, 3 to 4 times daily, with a maximum of 2 mg/kg and of 100 mg per dose [47].

7.5. Prophylaxis after trauma and before procedures

7.6. Anaesthesia and surgery

General anaesthesia is performed only when absolutely necessary, after a pre-anaesthetic consultation by a multidisciplinary team familiar with the risks of FOP [4]. Cervical fusions, mandibular limitation, a sensitive airway and the risk of an obstructive cervical flare-up justify awake fibreoptic nasotracheal intubation by an experienced anaesthetist as the first choice; forced mouth opening should be avoided, and an otorhinolaryngologist should be present in theatre for emergency tracheotomy [1, 4, 11]. Emergency tracheotomy in a patient with anterior cervical ossifications may require a dental or other drill to create the airway [11]. Surgery is never used to remove heterotopic bone: in the Chinese registry, 22 of 25 excisions were followed by recurrence or new lesions [11, 34]. Fractures heal well with conservative treatment (closed immobilisation with splints and orthoses and a brief course of prednisone); open reduction with internal fixation may trigger rapid ossification and is contraindicated unless discussed with a specialist [1, 11]. A 12-year-old Chinese boy with a femoral shaft fracture, who years earlier had ossified the forearm after osteosynthesis at the age of 5, was treated with closed reduction under general anaesthesia and a hip spica cast, with no flare-ups at 4 and 12 weeks [48].

7.7. Dental care

Oral health should be maintained from early childhood to prevent TMJ ankylosis and infections of dental origin [4]. Mandibular anaesthetic blocks (inferior alveolar nerve, truncal blocks) are an absolute contraindication, because they cause ossification of the pterygoid muscles and TMJ ankylosis; para-apical, intraligamentary and intrapulpal anaesthesia are possible and recommended, in deciduous and permanent teeth, and, if local anaesthesia is not possible, general anaesthesia with the precautions described is considered [4, 11]. The mouth should not be stretched during treatment; with sufficient opening, normal instruments are used, and with an ankylosed TMJ special instruments and brushes, generally limited to the buccal surfaces [4]. In the presence of orofacial swelling or pain, the ICC recommends a full dental examination with radiography and pulp vitality testing; without a dental origin, a flare-up should be presumed and the flare-up dose of prednisone started, and, if examination is not possible, an antibiotic and prednisone should be combined until a diagnosis is made [11]. Routine orthodontics has not been reported as a cause of flare-ups [11].

7.8. Emergency

The ICC has published a list of recommendations for first responders and emergency departments, which the ICC medical guidelines summarise [11]. Avoid all intramuscular injections unless life-saving and central venous access unless life-saving; peripheral access is permitted with the finest needle and a brief tourniquet. Pad bony prominences. Do not manipulate the cervical spine, which is often ankylosed, and immobilise the neck in any head injury; cranial CT is mandatory in any head injury, even without loss of consciousness. Do not passively manipulate the jaw. In facial oedema, consider a drug reaction and cavernous sinus thrombosis, with a brief course of antihistamine to exclude allergy. In severe acute oedema of a limb, exclude deep vein thrombosis by Doppler and treat conservatively (analgesia, elevation, lymphatic drainage); fasciotomy worsens the flare-up and must be avoided, and, if suspicion of compartment syndrome is high, consider mannitol. In nausea and vomiting with an ankylosed jaw, cover empirically for aspiration pneumonia. In choking, the Heimlich manoeuvre only if there is no abdominal heterotopic bone. Chest compressions are probably futile in the adult with a rigid chest. For secretions, use bronchodilators, mucolytics, guaifenesin, mechanical insufflation-exsufflation and intravenous hydration, and never oxygen without monitoring. Always ask whether the patient is taking part in a clinical trial [11].

The PNDS paediatric emergency sheet adds that a trivial infection should be treated promptly with an antibiotic (amoxicillin and clavulanic acid) to prevent superinfection, that respiratory difficulty requires admission to respiratory medicine or intensive care with a pressure relaxer or Cough Assist and non-traumatic chest physiotherapy, that antitussive syrups, benzodiazepines, mucolytics and morphine derivatives are contraindicated in that context, and that oxygen alone does not treat acute restrictive respiratory failure and may worsen hypercapnia, and may be combined with non-invasive ventilation [4]. The French emergency card is issued only by the reference doctor of the OSCAR filière centre and contains contact details, treatments, allergies and emergency recommendations [4].

7.9. Treatment of complications and supportive care

Respiratory. Restrictive respiratory failure has symptomatic treatment. Singing, swimming, daily breathing exercises and incentive spirometry are encouraged; in advanced forms, thoracic hyperinflation with a pressure relaxer is used to improve chest compliance, without demonstrated objective benefit [4, 11]. Passive respiratory rehabilitation is proscribed [4]. In severe restrictive failure, polysomnography or polygraphy with pulse oximetry (SpO2) and transcutaneous capnography (PtcCO2) detects alveolar hypoventilation; nocturnal non-invasive ventilation (NIV), with a soft mask, is proposed in that situation and in chronic hypercapnia documented on blood gases [4, 11]. Continuous positive airway pressure in sleep apnoea and nocturnal hypoxaemia is under evaluation, and tracheotomy is exceptional, because of its complications and because it opens no therapeutic prospect [4]. In acute decompensation, low-flow oxygen therapy is used only with close monitoring, because unmonitored oxygen may cause severe hypercapnia by suppressing the hypoxic drive [1, 4, 11]. Prevention of respiratory infections includes vaccination of household contacts and subcutaneous vaccination of the patient when indicated (section 7.3) [11].

Thromboembolism and limb oedema. The PNDS recommends low-dose aspirin in bedridden adults with prolonged immobilisation, and the ICC one low-dose aspirin daily with food as prophylaxis of deep vein thrombosis, if indicated [4, 11]. Thromboses, generally venous, are treated with oral warfarin or intravenous heparin [4]. Acute or chronic oedema and lymphoedema are treated with cold, elevation, topical NSAIDs, gentle massage, analgesics (tramadol, morphine), NSAIDs and corticosteroids of undemonstrated efficacy, and an empirical antibiotic if skin infection is suspected; compression stockings are poorly tolerated, and the ICC allows fitted stockings in chronic lymphoedema, without traumatic compression, and lymphoedema therapy [1, 4, 11]. The PNDS states that worsening may lead to compartment syndrome «pouvant nécessiter une fasciotomie», and the supporting document describes a 40-year-old woman in whom fasciotomy was followed by massive ossification with ankylosis of the knee and hip; the ICC 2025 considers that fasciotomy worsens the flare-up and must be avoided, recommending mannitol if suspicion is high [4, 11].

Normotopic bone. Patients with frequent flare-ups who receive repeated corticosteroids should be assessed for osteopenia; intravenous bisphosphonates may be used to prevent corticosteroid-induced bone loss, and osteoporosis of the native skeleton is treated according to the usual protocols; dentists should be informed of previous bisphosphonate use [1, 11]. Bone mineralisation in adults is assessed by densitometry (DXA) or lateral radiography of the dorsolumbar spine [4].

Kidney. Prevention of urolithiasis rests on 1.5–2 L of water per day, avoidance of high-protein and high-salt diets and of a low-fibre diet, treatment of urinary tract infections and maintenance of calcium at the recommended daily intake for age and sex [1, 4, 11].

Nutrition, calcium and vitamin D. The risk of nutritional and vitamin deficiencies (digestive disturbances, anorexia due to mandibular ankylosis and nausea) justifies referral to a dietitian; involuntary weight loss of more than 5% in 6–12 months should be corrected [4, 27]. The PNDS recommends 500 mg of elemental calcium as a supplement to a calcium-rich diet, up to 1000 mg/day in total, and sufficient vitamin D to keep 25-hydroxyvitamin D above 20–30 ng/mL (50–75 nmol/L); the PNDS and the ICC write “ng/dl”, a unit incompatible with these values [4, 27]. The 2024 ICC version recommends the 2011 Institute of Medicine recommended daily allowance (1000 mg of elemental calcium in adults aged 18 to 50, obtained mainly from the diet, with supplements limited to 600 mg/day because of the risk of urolithiasis, and 600 units of vitamin D3 per day), with measurement of 25-hydroxyvitamin D and replacement if necessary, also to prevent hypocalcaemia after intravenous bisphosphonates [27]. The Amsterdam study suggests guiding nutrition by measured energy expenditure and body composition, because the usual formula overestimates requirements [32]. The French adult schedule includes an antacid when there is significant trunk deformity [4].

Skin. Pressure ulcers are prevented by positioning and padding and treated with a wound care team; intertrigo, pressure sores, eczema and ulcerations over ossifications are treated symptomatically [4, 11].

Hearing. Conductive hearing loss is corrected with hearing aids; aids are often necessary and tympanostomy tubes do not alter the course [1, 4, 13].

Spine. Scoliosis is managed conservatively, avoiding traditional surgery; rapid progression should be assessed by an expert [1, 11].

Chronic pain and mental health. The approach is multimodal, distinguishing neuropathic and nociceptive pain, treating depression and correcting poorly fitted chairs, footwear and aids; chronic headaches justify a neurology referral [11]. Psychological support should be offered at any age and reinforced at key moments (disclosure of the diagnosis, starting school and the 2nd cycle, use of a wheelchair, loss of autonomy, active flare-ups, transition to adult services, life as a couple, parenthood and working life), with attention to the fatigue and stress of parents and siblings; family therapy is recommended by the ICC [4, 11].

7.10. Rehabilitation, occupational therapy and adaptation

Physiotherapy is gentle and by active mobilisation, from the age of 5, and is not contraindicated during flare-ups: it works on joint range in the region of the flare-up to reduce secondary ankylosis, may be preceded by analgesics and gentle massage and never forces movement [4]. Stretching and forced passive mobilisation are proscribed, and the ICC considers passive mobilisation strictly prohibited; active self-stretching within sensitive but not painful ranges is recommended, and parents should encourage active movement in play [4, 11]. Balneotherapy and hydrotherapy in warm water relieve pain and stiffness, and cryotherapy is recommended during flare-ups [1, 4, 11]. Periodic occupational therapy guides positioning and technical aids: a wheelchair adapted to the deformities, adapted cutlery, non-slip mats, shoehorns, sock aids, zip hooks, shower seat, long-handled brush and raised toilet seat, as well as grab bars, wide doors and human assistance [4, 11]. School requires an individualised education programme and support staff [11].

7.11. Palovarotene (Sohonos®)

Mechanism. Palovarotene is a selective retinoic acid receptor gamma (RARγ) agonist that reduces downstream BMP signalling and inhibits ectopic chondrogenesis, the cartilaginous phase that precedes endochondral ossification [1, 11]. In the United States it is available as 1 mg, 1.5 mg, 5 mg and 10 mg capsules [20].

Clinical development. In the placebo-controlled phase 2 trial (NCT02190747), described in the PNDS supporting document, one cohort of 8 patients over 15 years received 10 mg/day for 2 weeks and then 5 mg/day for 4 weeks, and another of 24 patients over 6 years received 5 mg/day for 2 weeks and then 2.5 mg/day for 4 weeks; the high dose started at the onset of the flare-up for 6 weeks was associated with less new ossification, without a statistically significant difference [4]. The phase 3 MOVE trial (NCT03312634) was a single-arm study in patients aged 4 years or more, with 5 mg/day chronically and, during flare-ups, 20 mg/day for 4 weeks and 10 mg/day for at least 8 weeks, with weight-adjusted doses in skeletally immature patients, compared with an external control from the natural history study (NCT02322255) [49]. The interim analyses at 12 months met the futility criteria and dosing was suspended, but the monitoring committee recommended continuation; in the post hoc analyses at 18 months (97 treated patients versus 101 from the natural history study), the Bayesian model without transformation gave a 99.4% probability of any reduction (65.4% with transformation), the mean annualised volume of new ossification was 60% lower and the weighted linear mixed model showed a 54% reduction (nominal p 0.039) [49]. According to the FDA label, the annualised volume of new ossification on low-dose whole-body CT (excluding the head, blinded reading) was 9.4 cm³/year versus 20.3 cm³/year, a difference of −10.9 cm³/year (95% CI −21.2 to −0.6), in patients with a mean age of 15.1 years versus 17.8 [20]. In the exploratory month 48 analysis, the volume was numerically 46.4% lower, without statistical significance (nominal p 0.0585), and the proportions of patients with new ossification and of affected regions were similar [50].

Safety. All MOVE patients had adverse events, 97.0% at least one typical retinoid event and 29.3% at least one serious event; premature physeal closure or epiphyseal disturbance occurred in 21 of 57 (36.8%) patients under 14 years, and there was a decrease in vertebral density, mineral content and strength with an increased risk of vertebral fracture [49]. At month 48 follow-up, 24 of 80 patients under 18 years (30.0%), all under 14 years, had premature physeal closure, and the risk of new asymptomatic vertebral deformities increased [50]. In the label safety set (164 patients, 139 in the indicated population; mean exposure 79 weeks on the chronic regimen and 35 on the flare-up regimen; mean age 19 years, 8–61), mucocutaneous effects affected 98%, serious reactions 15% (the most frequent being premature physeal closure), discontinuation 8% and dose reductions due to mucocutaneous effects 37% on the flare-up regimen versus 4% on the chronic regimen; premature physeal closure occurred in 27% of patients under 18 at inclusion (31% of those aged 8/10–14 years and none aged 14 or over) [20]. Effects with a frequency ≥10% include dry skin (61% chronic / 57% flare-up), dry lips (47%/38%), arthralgia (36%/31%), pruritus (34%/48%), pain in extremities (29%/28%), rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral oedema and fatigue; alanine aminotransferase increased in 7.0% on the flare-up regimen and 1% on the chronic regimen, and hypertriglyceridaemia in 2% and 4%, without pancreatitis in FOP [20].

FDA label. The approved indication is the reduction in the volume of new heterotopic ossification in adults and paediatric patients aged 8 years and older (female) and 10 years and older (male) with FOP, ages from which about 80% of skeletal maturation has been reached [1, 20]. The boxed warning refers to embryo-fetal toxicity and premature epiphyseal closure in growing paediatric patients [20]. The drug is taken with food, at the same time each day; the capsule may be opened over a teaspoon of soft food (apple purée, low-fat yoghurt, warm porridge) to be taken within 1 hour; grapefruit and pomelo should be avoided; a missed dose is taken if less than 6 hours have elapsed [20]. The flare-up regimen starts at the first symptom or in the face of a high-risk traumatic event (surgery, intramuscular immunisation, mandibular block, muscle fatigue, blunt trauma, falls, influenza-like viral illness), replaces the daily dose and is completed over 12 weeks even if the flare-up resolves earlier; if the region worsens or a new flare-up appears, the 20 mg (or equivalent) regimen is restarted for 12 weeks; if it does not resolve, the week 5–12 dose is extended in 4-week periods; a new flare-up after resuming the chronic dose restarts the regimen [11, 20].

The GeneReviews table gives the third weight class as 30–59.9 kg, overlapping with the previous one; the FDA label defines it as 40–59.9 kg [1, 20]. Lower-strength capsules do not replace a 10 mg capsule, because 4 × 2.5 mg and 2 × 5 mg give maximum concentrations 31% and 17% higher [20]. For adverse reactions, the dose is reduced through the label steps (20→15→12.5→10→7.5→5 mg; 6→4 mg; 5→2.5 mg; 4→2 mg; 3→1.5 mg; 2.5→1 mg) [20]. Strong CYP3A4 inhibitors (ketoconazole doubles the maximum concentration and triples the area under the curve) and moderate or strong inducers (rifampicin reduces the maximum concentration by 19% and the area under the curve by 11%) should be avoided; moderate inhibitors as well, and, if unavoidable, the dose is halved (≥60 kg or ≥14 years: 2.5 mg chronic, 10 mg and 5 mg during flare-ups; 40–59.9 kg: 2 mg, 7.5 mg and 4 mg; 20–39.9 kg: 1.5 mg, 6 mg and 3 mg; 10–19.9 kg: 1 mg, 5 mg and 2.5 mg) [20]. The ICC warns that tetracyclines (minocycline, doxycycline) combined with palovarotene or other retinoids may cause intracranial hypertension (pseudotumour cerebri) [28]. No adjustment is necessary in mild to moderate renal impairment or in mild hepatic impairment; it is not recommended in moderate or severe hepatic impairment [20].

The contraindications are pregnancy and hypersensitivity to retinoids. A negative pregnancy test in the week before starting and periodically, effective contraception from 1 month before until 1 month after treatment, a pregnancy test 1 month after stopping, no blood donation during treatment and the following week, and no breastfeeding during treatment and for at least 1 month afterwards are required; in the United States there is a mandatory educational programme for prescribers [11, 20]. Monitoring includes, in growing children, baseline assessment of skeletal maturity (hand and wrist and knee radiographs), growth charts and pubertal stage, repeated every 6–12 months until skeletal maturity or final height; periodic radiological assessment of the spine (vertebral fractures from T4 to L4); monitoring of mucocutaneous effects, with emollients, sunscreen, lip balm and artificial tears, and of photosensitivity; monitoring for depression, anxiety, mood changes and suicidal ideation, whose baseline prevalence is high in FOP; and information about night blindness, which makes night driving dangerous [11, 20].

Regulatory status. Canada issued the notice of compliance on 21/01/2022 (priority review; Ipsen) and the medicine has been marketed since 20/06/2022 [21]. The FDA approved it on 16/08/2023 (new molecular entity), with efficacy supplements on 13/03/2025 and labelling supplements on 18/09/2026 [20]. The ICC also reports authorisation in the United Arab Emirates, Australia and Russia [11]. In the European Union, the Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion on 26/01/2023, confirmed after re-examination on 25/05/2023, and authorisation was refused on 17/07/2023; the reasons were that the conclusion of efficacy rested on an unjustified post hoc analysis after the prespecified objectives had not been met, the limited long-term data (107 treated versus 114 untreated in the main study), the risk of premature physeal closure that could not be mitigated by the proposed measures and quality issues with the active substance; the refusal had no consequences for patients in trials or in compassionate use [22]. The medicine has no authorisation in Portugal and no ANVISA registration, and the PNDS anticipates that it will not be marketed in France [4, 22, 51].

7.12. Garetosmab (Pasatru®)

Mechanism. Garetosmab is a fully human IgG4 monoclonal antibody that binds activin A and prevents activation of the mutant ACVR1 receptor, inhibiting activin signalling [23]. It targets the ligand, not the receptor, which avoids the paradoxical activation by dimerisation observed with anti-ACVR1 antibodies in animal models [6].

Phase 2 LUMINA-1 trial. In LUMINA-1 (NCT03188666), 44 adults (median 27 years) were randomised to garetosmab 10 mg/kg IV every 4 weeks (n = 20) or placebo (n = 24) for 28 weeks, followed by 28 open-label weeks (n = 43) [52, 53]. The primary endpoint of the first period (total lesion activity on PET-CT) was not met (p = 0.0741); the endpoint of the second period, prospectively changed to the number of new lesions, showed that no patient in the placebo group who switched to garetosmab developed new lesions (0% versus 40.9% in the first period; p = 0.0027) [52]. All patients had at least one adverse event in the first period (epistaxis, madarosis, skin abscesses), and there were 5 deaths (5 of 44; 11.4%) in the open-label period, considered unlikely to be related, without causality being excluded [52]. The PNDS, written before the phase 3 trial, describes promising preliminary results that required further study [4].

Phase 3 OPTIMA trial. OPTIMA (NCT05394116) randomised 63 adults (≥18 years; mean age 26.6 years, standard deviation, SD, 6.8; 60% women; 95% with R206H; mean baseline CAJIS 13) at 18 centres in 16 countries or regions, in a 1:1:1 ratio, to placebo (n = 21), garetosmab 3 mg/kg (n = 19) or 10 mg/kg (n = 23) IV monthly, stratified by baseline CAJIS and previous participation in LUMINA-1; enrolment took place between 21/11/2022 and 04/07/2024 and 62 patients completed 56 weeks [23, 54]. The primary endpoint was the number of new heterotopic ossification lesions at week 56 on low-dose whole-body CT: 19 lesions in 5 of 21 patients in the placebo group (24%), 1 lesion in 1 of 19 (5%) with 3 mg/kg (rate ratio 0.06; 95% CI 0.00–0.73; p = 0.027) and 2 lesions in 2 of 23 (9%) with 10 mg/kg (rate ratio 0.10; 95% CI 0.01–0.76; p = 0.026), reductions of 94% and 90% [23, 54]. Clinician-assessed flare-ups numbered 66 in the placebo group, 53 with 3 mg/kg (ratio 0.85; 95% CI 0.26–2.73) and 9 with 10 mg/kg (ratio 0.12; 95% CI 0.03–0.42); patient-reported flare-ups did not differ significantly; the mean volume of new ossification was 10.5 cm³ with placebo versus 0.02 and 0.01 cm³ with garetosmab (difference −10.4 cm³; 95% CI −27.5 to −0.3), not significant by the prespecified Wilcoxon test [23]. Adverse events of special interest occurred in 1 of 21 (5%) patients in the placebo group, none with 3 mg/kg and 4 of 23 (17%) with 10 mg/kg, all treatment-related; there were no deaths; the trial was funded by the sponsor [54].

FDA label. The FDA approved garetosmab on 19/08/2026, after priority review, with orphan drug and Fast Track designation, to reduce the formation of new heterotopic ossification lesions and clinician-assessed flare-ups in adults with FOP [23, 24]. The dose is 10 mg/kg IV over 60 minutes every 4 weeks, reducible to 3 mg/kg every 4 weeks if 10 mg/kg is not tolerated; a missed dose is given as soon as possible, rescheduling subsequent doses every 4 weeks from that date; the vial contains 300 mg/5 mL (60 mg/mL), diluted in 50–100 mL of 5% dextrose (0.9–25 mg/mL) with a pump and a 0.2–5 µm filter [23]. The IFOPA mentions the possibility of home administration when appropriate [24]. The drug is contraindicated in pregnancy: absence of pregnancy should be confirmed before starting and effective contraception used during treatment and for 6 months after the last dose, and breastfeeding is not recommended over the same period; in cynomolgus monkeys, exposures equivalent to human exposures caused postnatal malformations (neurological and testicular), neurobehavioural deficits and infant mortality, and the drug may impair male fertility [23]. Safety and efficacy have not been established in paediatrics, and data above 65 years are insufficient [23]. In the trial, the effects with a frequency ≥10% and higher than placebo (placebo / 10 mg/kg / 3 mg/kg) were abscess (10% / 35% / 11%), acne (10% / 30% / 16%), increased hair growth (0 / 26% / 42%), madarosis (19% / 26% / 16%), oral ulcers (5% / 26% / 5%), epistaxis (24% / 17% / 53%), folliculitis (10% / 9% / 16%), paronychia (0 / 4% / 11%) and rash (0 / 4% / 26%), with one cellulitis on 10 mg/kg; the label warns of skin and soft tissue infections that required treatment or hospitalisation and of spontaneous epistaxis, including one severe case requiring packing and a haemostatic agent, the patient being advised to seek help if it lasts more than 20 minutes [23].

Status outside the United States. The EMA accepted the application in the 1st quarter of 2026 and the assessment was ongoing in August 2026; garetosmab has orphan designation in the European Union (EU), the United States and Japan [24]. The EMA medicines database had no entry for garetosmab on 6 November 2026, and ANVISA has no registration [51]. A paediatric phase 3 trial (OPTIMA-2, NCT07559513; 18 patients aged 4 to <18 years in the United States and 2 to <18 years elsewhere; primary endpoints of safety and serum concentrations) was registered and not yet recruiting, with a planned start in February 2027; the Japanese phase 3 trial (NCT04577820) was withdrawn without patients [53].

7.13. Comparative regulatory overview

7.14. Off-label drugs (ICC class II)

The ICC considers that off-label drugs have no evidence of efficacy and should be considered only when three criteria are met simultaneously: severe and intractable flare-ups or unusually severe or rapid progression; standard therapies exhausted; and safe use (no contraindications, infection, immunocompromise or interactions) in accordance with the drug's authorised age [28]. The ICC does not recommend them as prevention and points out that their use may exclude the patient from clinical trials; anakinra, canakinumab, tofacitinib and imatinib have reports of benefit mainly in flare-ups and pain, whereas minocycline, momelotinib and pacritinib have activity only in animal models, and the functional benefit and benefit on ossification, long-term safety, the effect of withdrawal and paediatric safety remain unknown [28]. All the doses below are extrapolations from case series or from other indications, acknowledged by the ICC.

The PNDS included imatinib in class 2 and colchicine among the antileukotrienes, a classification that ICC 2025 does not retain [4, 11]; colchicine is not a leukotriene antagonist, but an inhibitor of tubulin polymerisation that reduces neutrophil migration and inflammasome activation, and the only antileukotriene used in FOP is montelukast [11]. A 2025 report described empirical use of intermittent ruxolitinib for 6 weeks at the onset of flare-ups in an adolescent girl with three severe corticosteroid-refractory flare-ups of the lower limbs in one year, followed by flare-up-free intervals of 5, 12 and 36 months and stable CAJIS for 5 years; this is an isolated case [55]. According to the ICC and GeneReviews, there is no current role for chronic use of anti-angiogenic agents, calcium chelators, colchicine, fluoroquinolones, propranolol, mineralisation inhibitors, peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonists and tumour necrosis factor alpha (TNF-α) inhibitors, and chemotherapy and radiotherapy are contraindicated [1, 11]. Oral matrix metalloproteinase 9 (MMP-9) inhibitors had no human data at the time of the guideline [11]. Smith's mentions the use of ascorbic acid with propranolol for flare-up prophylaxis, particularly after falls, in a Brazilian series (Palhares 2019); the ICC and GeneReviews attribute no role to it [1, 11, 13].

7.15. Clinical trials

The trials do not allow indirect comparisons: MOVE used an external control and a volume endpoint, OPTIMA a randomised control and a lesion-count endpoint, and the populations differ (children from 4 years in MOVE, adults only in OPTIMA) [49, 54]. The relative reductions in OPTIMA should be read together with the absolute rates: in the placebo group, 19 lesions were concentrated in 5 of 21 patients, and 16 patients had none in 56 weeks [23]. The natural variability of the disease hampers individual interpretation, and the 2026 ICC editorial points out that about 75% of drugs fail in phase 2, that several FOP trials have been stopped for futility or serious adverse events and that trials are not proven treatments [56].

7.16. Developments in the last twelve months

7.17. Allele-specific silencing and nucleic acid therapies

Nucleic acid therapies are at the preclinical stage in FOP. The strategy described in the sources is selective silencing of the mutant allele by gapmer antisense oligonucleotides: short oligonucleotides with a central deoxyribonucleic acid (DNA) region which, on hybridising with the target messenger ribonucleic acid (RNA), allows cleavage by ribonuclease H1, flanked by modified nucleotides (locked nucleic acids, LNA, or 2'-O-methoxyethyl, MOE) that increase affinity and stability [58]. Anwar and colleagues designed gapmers targeting the ACVR1 c.617G>A transcript with a single 2'-O-methyl modification at position 2 of the central region, which, together with the mismatch with the normal sequence, restricts cleavage of the normal transcript and preserves that of the mutant one [58]. The logic suits a heterozygous gain-of-function disease, because reducing only the mutant allele would preserve normal ALK2 function. In patient fibroblasts with the endogenous variant and in C2C12 cells with R206H constructs, the modified gapmers preferentially suppressed mutant RNA and protein and reduced osteogenic differentiation (alkaline phosphatase, alizarin red staining, osteogenic markers); in normal mice, the modification was associated with higher levels in skeletal muscle and tendon and lower markers of hepatic and renal stress [58]. This is proof of concept: there are no efficacy data in animal models of the disease or in humans, and tissue delivery, duration of effect, in vivo selectivity and long-term toxicity remain to be established. No gene therapy or gene editing trial in FOP is registered in the sources consulted.

7.18. Agents and procedures to avoid

7.19. Pregnancy, lactation and contraception

Pregnancy is possible, but maternal and fetal risks are serious, and the guidelines recommend that it should never occur without consideration and planning, that unwanted pregnancies and any pregnancy during clinical trials be avoided, and that care take place in a high-risk pregnancy centre with independent genetic counselling [1, 11]. The risks described by the PNDS are deterioration of respiratory function, miscarriage and preterm delivery, thromboembolism and flare-ups during pregnancy, whose treatment is limited by the toxicity of corticosteroids and NSAIDs; vaginal delivery is difficult because of pelvic and spinal malformations, and general anaesthesia is problematic [4]. Fertility is unknown and pregnancy uncommon [1]. In a retrospective series from Atlanta (February 2011 to July 2021; 3 women with classic FOP, in addition to 5 deliveries described earlier in the literature), all had severe restrictive lung disease and all had preterm deliveries by caesarean section after awake fibreoptic nasotracheal intubation, with an otorhinolaryngologist in theatre and perioperative glucocorticoids; post-partum haemorrhages were 2800 mL, 2000 mL and 1031 mL, due to difficult haemostasis at hysterotomy (classical vertical incision, calcifications of the myometrium, omentum and rectus abdominis); two had severe post-partum pre-eclampsia (magnesium sulphate as a single loading dose to avoid repeated venepunctures) and two fetal growth restriction; the newborns were 25 weeks (750 g), 34 weeks (1610 g) and 34 weeks (1810 g); two of the mothers were sisters with FOP inherited from their father, and the son of one of them had classic FOP; all had post-partum pressure ulcers [59]. Palovarotene and garetosmab are contraindicated in pregnancy, with effective contraception until 1 month and 6 months after the last dose, respectively, and breastfeeding is not recommended during these periods [20, 23]. Gynaecology follow-up begins at puberty, addressing menarche, relationships and contraception [4].

7.20. Children and transition

In children, prolonged NSAIDs are accompanied by gastroprotection above the age of 10, gentle physiotherapy begins at 5 years, respiratory function tests from 5 years, and vaccination, dental care and school require individual plans (in France, the individualised care plan) [4]. Palovarotene is not approved below 8 years in girls and 10 years in boys and, in skeletally immature children, requires monitoring of growth and skeletal maturation every 6–12 months; garetosmab has no paediatric data [20, 23]. The transition to adult services takes place at 17–18 years in three stages: re-explanation of the diagnosis and of the care pathway and assessments by the paediatric team; a joint consultation, in person or by telemedicine, with the adult lead; and a transition consultation at the expert centre, preceded by a full work-up at 18 years (section 11) [4].

7.21. Convergences and divergences between sources

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

FOP is autosomal dominant, with complete or near-complete penetrance and variable expressivity; most cases (about 90%) result from a de novo variant, with an effect of advanced paternal age, and inherited cases are rare [1, 4, 13]. The risks depend on the family scenario:

Germline mosaicism was presumed in a family with two affected Native American half-sisters, daughters of the same unaffected mother and different fathers (Janoff 1996) [1, 5]. Paternal mosaicism was suggested in a mildly affected father (minimal ossification, no great toe malformation) of a daughter with the classic form, in whom the variant was not detected in blood (Shore 2006b) [1]. Documented vertical transmission shows the variability: in a three-generation family, a man with only great toe malformation walked with a stick until the 8th decade, whereas his daughter developed mandibular ankylosis after extraction of a wisdom tooth at the age of 22 [5].

8.2. Testing of relatives

The PNDS recommends sampling the child and both parents at the time of molecular diagnosis [4]. GeneReviews recommends molecular testing of the parents after an apparent de novo case and testing of young asymptomatic siblings, whose early identification avoids iatrogenic harm (intramuscular injections, biopsies, surgery); in adults from a family with the classic form, testing is unnecessary if examination is normal, and in families with an atypical form it is recommended [1]. Testing of minors is justified here by the direct preventive benefit.

8.3. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The PNDS recommends that plans for parenthood in a person with FOP be supported by an expert genetics team and a level 3 maternity unit, addressing counselling, the feasibility and course of pregnancy, early prenatal diagnosis (non-invasive when the carrier is the father), the mode of delivery and postnatal organisation [4]. The ICC adds independent genetic counselling [11].

8.4. Content of counselling

Disclosure should be progressive, cautious and clear, and address the variability of the disease, genetic counselling, the importance of preventive measures, conventional and innovative treatments and the existence of experts and patient associations [4]. It should include therapeutic education from day one: prevention of trauma and injections, management of a flare-up, prednisone available at home and an emergency card [4, 11]. Pregnancy in a woman with FOP carries serious risks (section 7.19), and counselling should address them with the woman and her partner before conception [11, 59].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each study measures

The highest estimates come from the methods with the best ascertainment (capture-recapture in national databases), and the difference from older estimates of 1 per 2 million is attributed to this ascertainment, not to real variation [7, 13, 14]. The values are prevalences of diagnosed and known patients; a disease with late diagnosis and early mortality tends to be underestimated. There is no racial, ethnic, sex or geographical predisposition, and the recurrent variant arises de novo in all populations, with no founder effect [1, 4, 6]. The Chinese registry confirms the distribution across 23 provinces and the diagnostic delay (>3 years in 34.5% and >10 years in 9.7%) [34]. The 2000–2024 case review included patients from 57 countries, 47.0% from the Asia-Pacific region [35]. The sources consulted contain no prevalence estimates for Portugal or Brazil; the Brazilian series of Palhares 2019 is cited by Smith's in relation to flare-up prophylaxis, and the OPTIMA trial included centres from 16 countries or regions [13, 54].

9.2. Socioeconomic impact

In the 2026 French case-control study, of the 70 patients with a social security number, 50% were women, with a mean age of 25.3 years (SD 15.7), and comorbidities, consultations, hospitalisations and use of medical devices were significantly greater than in the 769 controls [15]. In a Swiss hospital cohort from 2012 to 2021 with six rare bone diseases, including FOP, in-hospital mortality was 2.26 times and admission to intensive care 3.08 times higher than in matched controls, but the data are aggregated and not specific to FOP [60].

9.3. Special populations

Children concentrate the flare-ups (8–15 years in the natural history study) and the risks of palovarotene to the physes, and are the group in which iatrogenic prevention has the greatest impact [4, 49]. Women of childbearing age require reproductive planning and contraception with the targeted drugs [20, 23]. Adults with advanced stages depend on respiratory, skin and nutritional care, and patients with an ankylosed jaw need their own feeding and emergency plans [4, 11].

9.4. Organisation of care in France

The PNDS organises follow-up between the reference and competence centres for constitutional bone diseases (CRMR MOC; coordinating centre at Necker-Enfants malades Hospital, Paris, and constituent sites at Cochin, Lariboisière, Lyon and Montpellier, with regional competence centres) and the general practitioner, within the OSCAR filière [4]. FOP is not on the list of the 30 long-term conditions (ALD), but may be recognised as an “off-list” ALD, being a serious, progressive or disabling condition with foreseeable continuous care for more than 6 months [4]. Children have an individualised care plan (PAI; circular no. 2003-135), from nursery to secondary school, renewed annually, which sets out prescriptions, the emergency protocol, timetables and adaptations of physical education and outings; disability-related rights are granted by the departmental houses for persons with disabilities (MDPH; law no. 2005-102, of 11/02/2005) [4]. The IFOPA international registry collects data twice a year, but in France entry of medical data was not authorised [4].

9.5. European networks and patient associations

The relevant European reference network is ERN BOND (rare bone diseases), which hosts the European FOP Consortium [4, 29]. The International Clinical Council on FOP publishes and updates the international recommendations (www.iccfop.org) [4, 11]. Patient associations include the IFOPA (founded in 1988 by Jeannie Peeper, with the international registry at fopregistry.org; www.ifopa.org), FOP France (founded in 2012 in Nantes; www.fopfrance.fr), EURORDIS (more than 1000 associations in 74 countries) and Tin Soldiers (South Africa, 2020, aimed at children with undiagnosed musculoskeletal diseases) [1, 4]. Orphanet publishes an emergency sheet for FOP [4].

10. Illustrative Clinical Case

De Brasi and colleagues described, in 2021, two Italian children with classic FOP and an initially difficult diagnosis [30]. The second patient was a 3-year-old boy, born at term to non-consanguineous parents, who sustained an accidental head injury. A few days later, the parents noticed an increase in head circumference and then a soft, painful mass in the eyelid region. The initial hypothesis was urticaria and angioedema due to an insect bite, treated with oral cetirizine and betamethasone, without improvement. On admission, he had painful facial lesions and macrocephaly (occipitofrontal circumference 54 cm, above the 95th centile). Tests, including tumour markers (carcinoembryonic antigen, alpha-fetoprotein), autoimmunity and infection screening, were normal, except for a C-reactive protein of 52.76 mg/L (normal 0–5 mg/L); cardiology, neurology, onco-haematology, otorhinolaryngology and ophthalmology assessments showed no abnormalities [30].

Brain CT showed oedema of the pericranial soft tissues around the calvarium, prominent vessels, small heterotopic calcifications in the lentiform nuclei, bilateral thickening of the optic nerves and pontine dysmorphism with bulging of the dorsal surface (Figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC8391109/figure/genes-12-01187-f004/) [30]. He continued cetirizine and betamethasone, with progressive reduction of the oedema. Weeks later a small soft left cervical mass appeared, which extended to the scapular region, with pain and limitation of neck movement; Doppler ultrasound showed thickening of all the posterior cervical and dorsal muscles, with heterogeneous echogenicity, no alteration of the fibrillar structure and markedly increased vascularity [30]. Brain MRI showed pontine dysmorphism with fusion of the facial colliculi and bulging into the 4th ventricle, thickened inferior cerebellar peduncles, squared frontal horns, mild ectasia of the Virchow-Robin spaces and T2 and FLAIR (fluid-attenuated inversion recovery) hyperintensity of the dentate nuclei and adjacent white matter (Figure 5: https://pmc.ncbi.nlm.nih.gov/articles/PMC8391109/figure/genes-12-01187-f005/), and cervicothoracic MRI showed diffuse hyperintensity and contrast enhancement along the muscles and fascial planes of the neck and chest wall (Figure 6: https://pmc.ncbi.nlm.nih.gov/articles/PMC8391109/figure/genes-12-01187-f006/) [30]. The craniofacial oedema progressively descended to the neck and formed a hard laterocervical swelling that extended to the subscapular region [30].

It was at the genetics clinic that the proximally implanted great toe, shorter than the 2nd toe and in bilateral valgus, was observed and the hypothesis of FOP raised. Analysis of peripheral blood DNA identified the heterozygous de novo variant NM_001111067.4:c.617G>A p.(Arg206His) (the article writes “c.617A>G”, an inversion of the notation), confirming the diagnosis at 3 years [8, 30]. The brainstem lesions, hamartoma-like and identical to those described by Severino 2016, had no clinical expression up to publication [5, 30].

The first patient in the same article illustrates iatrogenic harm. At age 2, after the first-year vaccines and the measles, mumps and rubella vaccine at 15 months, she developed a hard right cervical and scapular swelling after minor trauma, and then bilateral dorsal swellings; she had bilateral hallux valgus, two frontal café-au-lait spots and a lumbar angioma. MRI showed hyperintensity with enhancement in the latissimus dorsi, teres major, posterolateral cervical muscles, subscapularis and infraspinatus, foot radiography showed mild hallux valgus, triphalangism and an accessory distal epiphyseal nucleus, and CT showed no ossification. With suspected pyomyositis or myofibromatosis, a fine-needle biopsy was performed, which showed proliferation of fibroblastic and myofibroblastic spindle cells with mitoses without atypia; only afterwards was the hypothesis of FOP raised, confirmed by the de novo c.617G>A variant at 2.5 years [30].

Both patients were referred to the Italian reference centre for FOP, where sporadic flare-ups were treated with brief low-dose corticosteroid boluses and with corticosteroids for flare-ups and significant joint pain, in accordance with the ICC recommendations [30]. The boy's case teaches three lessons: head injury may trigger a pericranial flare-up presenting as macrocephaly and eyelid oedema; corticosteroid therapy instituted for another diagnostic hypothesis coincided with regression of the oedema; and the diagnosis depended on examination of the feet. The girl's case shows the biopsy that the guidelines seek to avoid [11, 30]. The management described in the report (low-dose corticosteroid boluses) does not coincide with the 2 mg/kg/day dose of the guidelines, and should not be taken as a protocol [4, 11].

11. Prognosis and Long-Term Follow-Up

11.1. Survival and causes of death

The reference estimate comes from Kaplan 2010, based on two registries that included more than 90% of known patients: over 33 years, 60 deaths were recorded (30 men and 30 women), with a median age at death of 40 years (3–77) and a known cause in 48 (80%); the median survival estimated from 371 living and 60 deceased patients was 56 years (95% CI 51–60) [25]. The main causes were cardiorespiratory failure due to thoracic insufficiency syndrome (54%; median age 42 years) and pneumonia (15%; median age 40 years) [25]. An older estimate gave a mean life expectancy of 45 years (Kaplan 2008, according to the PNDS supporting document), and Smith's indicates a mean of 40 years, with death in the 5th and 6th decades, mainly from restrictive lung disease and infections [4, 13]. In the United States, between 2017 and 2023 (250 people from the IFOPA database and registry), the age-adjusted mortality rate was 34.6 deaths per 1000 person-years (95% CI 22.5–51.7), versus 7.2–8.9 in the general population; the median age at death was 50.5 years (95% CI 46.5–57.5), versus 80.5, and the restricted mean life-years lost was 32.3 years (95% CI 26.8–37.8), versus 8.1 [26]. These figures describe the disease with symptomatic treatment; there are as yet no survival data on targeted drugs.

11.2. Functional prognosis and staging

Most patients are wheelchair-bound in the 3rd decade and need help from one and then two people with daily activities [4, 11]. No individual prognostic factors have been identified, and variability is great, with slow and rapid forms at any age of onset [4]. The clinical staging of Pignolo and Kaplan (2018), adopted by GeneReviews and the PNDS, organises follow-up:

CAJIS (Kaplan 2017, developed with 144 patients) assesses 15 sites (neck, jaw, thoracolumbar region and, bilaterally, shoulders, elbows, wrists, hips, knees and ankles) with 0 points (normal or limitation <10%), 1 point (10–90%) or 2 points (>90% or ankylosis), for a total of 0 to 30; it correlates with age, daily activities and walking and increased on average by 1 point every 2 years in the natural history study [4, 61]. The FOP-specific physical function questionnaire (PFQ; 24–26 questions scored from 1, unable, to 5, no difficulty) correlates moderately with CAJIS and with the volume of ossification and is used mainly in trials [4].

11.3. Organisation of follow-up

The PNDS recommends an assessment at an expert centre after confirmation of the diagnosis and at the pivotal ages of 5, 10 and 15 years, at transition, at 25 years and then every 5 years, with intermediate follow-up shared between the general practitioner and the specialist at the nearest reference centre, at least annually in children and annually in adults, in person or by teleconsultation; in adults, specialised work-ups should not be more than 3 years apart [4]. GeneReviews proposes a clinical review at least annually by an experienced orthopaedic surgeon or geneticist [1].

11.4. Surveillance table

11.5. Transition to adult services

Transition takes place at 17–18 years, preceded by a full work-up at 18 years, and proceeds in three stages: re-explanation by the paediatric team, a joint consultation with the adult lead and a transition consultation at the expert centre; in adults, follow-up is then coordinated by a rheumatologist or rehabilitation physician, together with the general practitioner [4].

12. Summary and Final Considerations

Fibrodysplasia ossificans progressiva is an ultra-rare autosomal dominant disorder, with a prevalence of about 1 per million in the estimates with the best ascertainment, caused in about 97% of patients by the same de novo ACVR1 variant, c.617G>A p.(Arg206His). The variant confers on the ALK2 receptor hypersensitivity and responsiveness to activin A, and the clinical result is the episodic transformation of muscles, tendons and ligaments into endochondral bone, accumulated over a lifetime until generalised ankylosis and thoracic insufficiency syndrome, with an estimated median survival of 56 years and a median age at death of 50.5 years in a recent North American cohort.

The diagnosis is clinical and depends on a sign present at birth: the short great toe in valgus. Recognising it before the first flare-up, or at the first swelling, avoids the biopsies, excisions and injections that, in published series, caused permanent loss of mobility in half of patients. Confirmation is by testing for c.617G>A and sequencing of ACVR1, without the need for tissue, and atypical forms require exome or genome sequencing.

Treatment continues to rest on prevention of trauma and invasive procedures, early treatment of flare-ups according to location (short-course high-dose corticosteroid for the limbs and submandibular region, non-steroidal anti-inflammatory drugs for the trunk), strict anaesthetic, dental and vaccination precautions and respiratory, nutritional and rehabilitation support, organised by expert centres in liaison with the general practitioner. The 2024 French PNDS and the 2025 ICC guidelines agree on these principles and differ on maximum doses, intravenous protocols and the management of compartment syndrome.

Two targeted drugs have been authorised in the United States: palovarotene, with a reduction in the volume of new ossification estimated by external comparison and a risk of premature physeal closure of about 30% in children, refused in the European Union; and garetosmab, which in OPTIMA reduced the number of new lesions in adults by 90–94%, at the cost of skin infections and epistaxis. Neither is authorised in the European Union, Portugal or Brazil. ALK2 inhibitors have had mixed results, with FALKON stopped for futility, and allele-specific silencing therapies remain preclinical.

13. References

1. Akesson LS, Savarirayan R. Fibrodysplasia ossificans progressiva. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2020 Jun 11 [updated 2024 May 23]. PMID: 32525643. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558090/
2. Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164–1209. doi:10.1002/ajmg.a.63132. PMID: 36779427
3. Orphanet. Fibrodysplasia ossificans progressiva (ORPHA:337) [Internet]. Paris: INSERM; 2026 [accessed 2026 Nov 2]. Available from: https://www.orpha.net/en/disease/detail/337
4. Haute Autorité de Santé; Centre de Référence des Maladies Osseuses Constitutionnelles (coord. Baujat G, Funck-Brentano T). Protocole National de Diagnostic et de Soins (PNDS): Fibrodysplasie ossifiante progressive (FOP). Texte, synthèse à destination du médecin traitant et argumentaire. Saint-Denis La Plaine: HAS; janvier 2024 (publié en ligne le 22 avril 2024). Available from: https://www.has-sante.fr/jcms/p_3503200
5. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 135100 (Fibrodysplasia ossificans progressiva; FOP). Available from: https://www.omim.org/entry/135100
6. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 102576 (Activin A receptor, type I; ACVR1). Available from: https://www.omim.org/entry/102576
7. GeneGuidance. Gene ACVR1: identifiers, clinical curation, ClinGen actionability, linked condition (OMIM 135100/ORPHA:337) and listed references [local database]. Extraction of 26 Sep 2026, accessed 2 Nov 2026.
8. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61–68. doi:10.1002/humu.23348. Consulted at https://rest.variantvalidator.org on 2 November 2026.
9. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–527. doi:10.1038/ng1783
10. Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379–390. doi:10.1002/humu.20868
11. Kaplan FS, Al Mukaddam M, Baujat G, Hidalgo Bravo A, Brown M, Cali A, et al. Medical guidelines for fibrodysplasia ossificans progressiva. JBMR Plus. 2025;9(11):ziaf150. doi:10.1093/jbmrpl/ziaf150
12. National Center for Biotechnology Information. ClinVar; VCV000018309: NM_001111067.4(ACVR1):c.617G>A (p.Arg206His). Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/18309/
13. Jones KL, Jones MC, del Campo M. Fibrodysplasia ossificans progressiva syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 688–691.
14. Baujat G, Choquet R, Bouée S, Jeanbat V, Courouve L, Ruel A, 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. 2017;12(1):123. doi:10.1186/s13023-017-0674-5
15. Baujat G, Bouée S, Solanke O, Croskery K, Kirion J, Cormier-Daire V, et al. The socioeconomic impacts of fibrodysplasia ossificans progressiva: evidence from a retrospective case-control study in France. JBMR Plus. 2026;10:ziag125. doi:10.1093/jbmrpl/ziag125
16. 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. 2021;16(1):350. doi:10.1186/s13023-021-01983-2
17. Piram M, Le Merrer M, Bughin V, De Prost Y, Fraitag S, Bodemer C. Scalp nodules as a presenting sign of fibrodysplasia ossificans progressiva: a register-based study. J Am Acad Dermatol. 2011;64(1):97–101. doi:10.1016/j.jaad.2010.04.025
18. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650–656. doi:10.1002/jbmr.2728
19. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Fibrodysplasia ossificans progressiva (MIM 135100). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 737–740.
20. Ipsen Biopharmaceuticals. SOHONOS (palovarotene) capsules, for oral use. Prescribing information. NDA 215559; initial U.S. approval 2023 (revised 9/2026). DailyMed setid 67dce406-7cc4-4d66-92de-ad18b6df0625. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=67dce406-7cc4-4d66-92de-ad18b6df0625
21. Health Canada. Drug Product Database and Notice of Compliance database: SOHONOS (palovarotene), Ipsen Biopharmaceuticals Canada Inc. Available from: https://health-products.canada.ca/dpd-bdpp/
22. European Medicines Agency. Sohonos (palovarotene): refusal of the marketing authorisation. EMA/CHMP; opinion 26 January 2023, re-examination 25 May 2023. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/sohonos Status reconfirmed in the EMA medicines database on 6 Nov 2026.
23. Regeneron Pharmaceuticals. PASATRU (garetosmab-grts) injection, for intravenous use. Prescribing information. BLA 761508; approved 19 August 2026. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761508
24. International Fibrodysplasia Ossificans Progressiva Association. U.S. FDA approves Regeneron Pharmaceuticals' garetosmab as a treatment for FOP. 19 August 2026. Available from: https://www.ifopa.org/us-fda-approves-regeneron-pharmaceuticals-garetosmab-treatment-fop
25. 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. 2010;92(3):686–691. doi:10.2106/JBJS.I.00705
26. Breskin A, Popoola VO, Davis M, Kile S, Souttou A, Rhee S, Knox C. Measures of mortality among people living with fibrodysplasia ossificans progressiva in the United States, 2017-2023. JBMR Plus. 2026;10:ziag154. doi:10.1093/jbmrpl/ziag154
27. International Clinical Council on FOP (Kaplan FS, Al Mukaddam M, Baujat G, et al.). The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. Updated July 2024. Available from: https://www.iccfop.org/s/ICCFOP_Guidelines_July2024.pdf
28. International Clinical Council on FOP. Updated statement regarding off label medications for the management of FOP. 30 May 2024. Available from: https://www.iccfop.org/s/20240530-ICC-Off-Label-Statement-Update.pdf
29. European Reference Network on Rare Bone Diseases (ERN BOND). Available from: https://ernbond.eu/
30. De Brasi D, Orlando F, Gaeta V, De Liso M, Acquaviva F, Martemucci L, et al. Fibrodysplasia ossificans progressiva: a challenging diagnosis. Genes (Basel). 2021;12(8):1187. doi:10.3390/genes12081187
31. Pignolo RJ, Kaplan FS. Clinical staging of fibrodysplasia ossificans progressiva (FOP). Bone. 2018;109:111–114. doi:10.1016/j.bone.2017.09.014
32. Rosenberg NM, Obdam LEM, Lubbers SP, Spapens Y, de Vries-Verweij ECE, Micha D, et al. Body composition and energy expenditure of patients with fibrodysplasia ossificans progressiva. Bone. 2026;212:118038. doi:10.1016/j.bone.2026.118038
33. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116(5):e654–e661. doi:10.1542/peds.2005-0469
34. Cui L, Ouyang Q, Guo J, Cai W, Pang Q, Chi Y, et al. The diagnostic journey of fibrodysplasia ossificans progressiva: evidence from a national cohort of 114 patients. Front Endocrinol (Lausanne). 2026;17:1941326. doi:10.3389/fendo.2026.1941326
35. Scott C, Al Mukaddam M, Davis M, De Cunto CL, Hsiao EC, Pignolo RJ, et al. Identifying global trends from case reports of fibrodysplasia ossificans progressiva: a scoping review. Ther Adv Musculoskelet Dis. 2025;17:1759720X251407060. doi:10.1177/1759720X251407060
36. Firth HV, Hurst JA. Lumps and bumps. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 222–223.
37. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Progressive osseous heteroplasia (MIM 166350). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 725–727.
38. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Multiple cartilaginous exostoses (MIM 133700, 133701, 600209). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 728–731.
39. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Brachydactyly B (MIM 113000). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 455–456.
40. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Multiple synostoses syndrome (MIM 186500, 186570, 610017, 612961). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 889–892.
41. Haute Autorité de Santé. Révision de la stratégie de vaccination contre les infections invasives à pneumocoques: place des vaccins à haute valence Prevenar 20 chez les nourrissons, les enfants et les adultes et Capvaxive chez les adultes. Vaccination recommendation validated on 23 July 2026 (decision no. 2026.0154/DC/SESPEV). [https://has-sante.fr/jcms/p_3601959/fr/](https://has-sante.fr/jcms/p_3601959/fr/). Accessed 7 Nov 2026.
42. Pfizer Europe MA EEIG. Prevenar 20 (pneumococcal polysaccharide conjugate vaccine, 20-valent, adsorbed): summary of product characteristics. EPAR, product information; first authorisation 14 Feb 2022. Amsterdam: European Medicines Agency [accessed 7 Nov 2026]. Available from: https://www.ema.europa.eu/en/documents/product-information/prevenar-20-epar-product-information_en.pdf
43. Merck Sharp & Dohme B.V. Capvaxive (pneumococcal polysaccharide conjugate vaccine, 21-valent): summary of product characteristics. EPAR, product information; first authorisation 24 Mar 2025. Amsterdam: European Medicines Agency [accessed 7 Nov 2026]. Available from: https://www.ema.europa.eu/en/documents/product-information/capvaxive-epar-product-information_en.pdf
44. Centers for Disease Control and Prevention. Pneumococcal vaccine recommendations [Internet]. Atlanta (GA): CDC; 2026 Feb 25 [accessed 2026 Nov 7]. Available from: https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/index.html
45. Centers for Disease Control and Prevention. Summary of risk-based pneumococcal vaccination recommendations [Internet]. Atlanta (GA): CDC; 2026 May 8 [accessed 2026 Nov 7]. Available from: https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/risk-indications.html
46. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. 2017 Apr 20 [accessed 7 Nov 2026, archived copy]. Available from: https://web.archive.org/web/2023/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-restricts-use-prescription-codeine-pain-and-cough-medicines-and
47. Agence nationale de sécurité du médicament et des produits de santé (ANSM). CONTRAMAL 100 mg/ml, solution buvable en gouttes (chlorhydrate de tramadol): résumé des caractéristiques du produit. Base de données publique des médicaments, CIS 60477650; mise à jour le 30/10/2025 [accessed 2026 Nov 7]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/60477650/extrait
48. Liu B, Lv X, Wang Y, Zhao C, Zhao J. Recurrent trauma and non-operative management of femoral fracture in fibrodysplasia ossificans progressiva: a pediatric case report. Front Pediatr. 2026;14:1777066. doi:10.3389/fped.2026.1777066
49. Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, et al. Reduction of new heterotopic ossification (HO) in the open-label, phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2023;38(3):381–394. doi:10.1002/jbmr.4762
50. Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Cheung AM, et al. Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial. JBMR Plus. 2026;10:ziag141. doi:10.1093/jbmrpl/ziag141
51. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos: medicamentos registados no Brasil [Internet]. Brasília: ANVISA; accessed 6 Nov 2026 (search for palovarotene and garetosmab with no records). Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
52. Di Rocco M, Forleo-Neto E, Pignolo RJ, Keen R, Orcel P, Funck-Brentano T, et al. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med. 2023;29(10):2615–2624. doi:10.1038/s41591-023-02561-8
53. ClinicalTrials.gov. Interventional studies in fibrodysplasia ossificans progressiva (NCT03188666, NCT05394116, NCT07559513, NCT05039515, NCT05090891, NCT04307953, NCT06508021, NCT03312634). U.S. National Library of Medicine; accessed 2 November 2026. Available from: https://clinicaltrials.gov/
54. Papa R, Rhee S, Delai P, Zhang K, Balcázar IB, Rethanavelu K, et al. Efficacy and safety of garetosmab, an activin A-blocking antibody, in fibrodysplasia ossificans progressiva (OPTIMA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2026;408:1583–1592. doi:10.1016/S0140-6736(26)01599-0
55. Chen RL, Yang TH, Wang YH, Shaw JJ, Chen LY. Intermittent and short-term empirical ruxolitinib regimen for steroid-refractory flareups of fibrodysplasia ossificans progressiva. Pharmacol Res Perspect. 2025;13:e70193. doi:10.1002/prp2.70193
56. Kaplan FS, Al Mukaddam M, Bachiller J, Baujat G, et al.; International Clinical Council on FOP. The twilight zone: between disappointment and hope in clinical trials for FOP [editorial]. 2026. Available from: https://www.iccfop.org/s/ICC-EDITORIAL-CLIN-TRIALS-FOP2026.pdf
57. Wang H, Toutounchi S, Pignolo RJ, Cheng X, Parker CD, Liu Q, et al. BCX9250 is a potent small-molecule inhibitor of activin A receptor type 1 (ACVR1/ALK2) for fibrodysplasia ossificans progressiva. JBMR Plus. 2026;10:ziag145. doi:10.1093/jbmrpl/ziag145
58. Anwar S, Hay S, Moriyama H, Mir F, Maruyama R, Yokota T. Single-base 2'OMe-modified LNA and MOE gapmers selectively silence ACVR1 R206H in fibrodysplasia ossificans progressiva. Mol Ther Nucleic Acids. 2026;37:102937. doi:10.1016/j.omtn.2026.102937
59. Forrest AD, Vuncannon DM, Ellis JE, et al. Fibrodysplasia ossificans progressiva and pregnancy: a case series and review of the literature. Case Rep Obstet Gynecol. 2022;2022:9857766. doi:10.1155/2022/9857766
60. Gaechter P, Meier C, Christ E, Ebrahimi F, Kutz A, Szinnai G. Adverse health outcomes across the life course in individuals with six rare bone diseases: a 10-year population-based cohort study. Eur J Endocrinol. 2026;195:518–528. doi:10.1093/ejendo/lvag171. PMID: 42689548
61. Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale (CAJIS) for fibrodysplasia ossificans progressiva (FOP). Bone. 2017;101:123–128. doi:10.1016/j.bone.2017.04.015