Fibrodysplasia Ossificans Progressiva
Summary
Clinical characteristics.
Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement due to ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome.
Diagnosis/testing.
The diagnosis of FOP is established in a proband with heterotopic ossification, hallux valgus malformations, and/or a heterozygous pathogenic variant in ACVR1 identified by molecular genetic testing.
Management.
Treatment of manifestations: Avoid intramuscular injections and arterial punctures. Fall prevention using household safety measures and ambulatory devices; use of protective headgear to reduce sequelae of falls; prompt medical attention after a fall with consideration of prophylactic corticosteroid use; management by a dietician for those with feeding difficulties; preventative dental care with precautions to avoid injury; orthodontic treatment with a practitioner with experience in FOP; consultation with an expert anesthetist with experience in FOP prior to elective anesthesia; use of singing, swimming, incentive spirometry; positive pressure ventilation when indicated for mechanical respiratory difficulties including thoracic insufficiency syndrome; anti-inflammatory medications for flare-ups; consider corticosteroids for flare-ups of the submandibular region or jaw, major joints, after significant soft-tissue trauma, and for prophylaxis prior to dental and surgical procedures. Conservative management for scoliosis. Consider bisphosphonates for corticosteroid-induced osteopenia; fractures should be managed by an expert in FOP; hearing aids and appliances for conductive hearing impairment; encourage hydration and avoidance of high protein and high salt intake to prevent renal stones; occupational therapy; warm water hydrotherapy for mobility difficulties; lower extremity elevation, DVT prophylaxis, and supportive stockings while avoiding traumatic compression for lymphedema. Psychological support.
Surveillance: Annual clinical evaluation including evaluation for scoliosis with orthopedist or geneticist familiar with FOP; annual nutrition evaluation and examination for jaw ankylosis; baseline pulmonary function assessment, sleep assessment, and echocardiogram before age ten years followed by annual clinical evaluation of respiratory status; annual evaluation for fracture risk; audiology assessment every 12 to 24 months; annual assessment for signs and symptoms of nephrocalcinosis, gastrointestinal complications, and skin integrity; dental examinations every six months; Doppler ultrasound if DVT is suspected.
Agents/circumstances to avoid: Avoid procedures that predispose to soft-tissue injury, including intramuscular injections such as vaccinations, arterial punctures, dental procedures, procedures related to anesthesia, biopsies, removal of heterotopic bone, and all nonemergent surgical procedures. Avoid contact sports, overstretching of soft tissues, muscle fatigue, and passive range of motion. Avoid falls. In individuals with thoracic insufficiency syndrome, avoid supplemental oxygen, which can suppress respiratory drive.
Genetic counseling.
FOP is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo ACVR1 pathogenic variant. Rarely, an individual diagnosed with FOP has an affected parent. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. Once the ACVR1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
There are no formal diagnostic criteria for fibrodysplasia ossificans progressiva (FOP).
Suggestive Findings
FOP should be suspected in individuals with the following clinical and radiographic findings.
Clinical findings
- Congenital hallux valgus deformity that is most often bilateral
- Progressive heterotopic ossification (extraosseous bone formation) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.
- Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature.
- Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications
Imaging findings (see Figure 1)
Figure 1.
Characteristic features of FOP. A photograph (A) and radiograph (B) of the feet in an affected boy age 15 years with classic FOP show short, malformed halluces with a single, dysplastic phalanx in each great toe. A photograph of his back (C) and a radiograph (more...)
- Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks' gestation [Maftei et al 2015].
- Radiographs of the halluces demonstrate short, malformed first metatarsals and a single dysplastic phalanx.
- Radiographs of affected areas demonstrate heterotopic ossification (extraosseous bone formation).
Note: Individuals with suspected FOP should avoid biopsy, elective surgery, and immunizations until diagnosis is confirmed [Kaplan et al 2019].
Establishing the Diagnosis
The diagnosis of FOP is established in a proband with hallux valgus malformations, heterotopic ossification, and/or a heterozygous pathogenic variant in ACVR1 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive features described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas individuals in whom the diagnosis of FOP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and radiographic findings suggest the diagnosis of FOP, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of ACVR1 to detect the most common pathogenic variant (c.617G>A; p.Arg206His) and other missense variants associated with FOP. Note: Since FOP occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplication is not indicated in individuals in whom a diagnosis of FOP is strongly suspected. Pathogenic loss of function variants in ACVR1 such as nonsense, frameshift, and splice-site variants have not been described.
- A skeletal dysplasia multigene panel that includes ACVR1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost, compared to comprehensive genomic testing, while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of FOP has not been considered, including in individuals with atypical phenotypic features and/or the absence of congenital hallux malformation, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be the best option. Exome sequencing is most commonly used; genome sequencing is an increasingly used alternative.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Fibrodysplasia Ossificans Progressiva
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ACVR1 | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
The pathogenic variant c.617G>A (p.Arg206His) has been identified in more than 97% of affected individuals. All additional pathogenic variants have been located in the glycine-serine(GS)-rich domain or the protein kinase domain [Shore et al 2006a, Zhang et al 2013].
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma, including intramuscular vaccinations [Pignolo et al 2016].
To date, more than 800 individuals with over 20 pathogenic variants in ACVR1 have been reported (overview in Kaplan et al [2019]). The following description of the phenotypic features associated with this condition is based on these reports and reports of classic FOP phenotype in individuals who did not have molecular genetic testing.
Table 2.
Select Features of Fibrodysplasia Ossificans Progressiva
| Feature | % of Persons with Feature 1 | Comment | |
|---|---|---|---|
| Bilateral congenital hallux valgus malformations | >97% |
| |
| Heterotopic ossification | ~100% |
| |
| Inflammatory soft-tissue swellings | ~100% | May be spontaneous or triggered by trauma | |
| Scalp nodules | ~40% |
| |
| Other skeletal manifestations | Osteochondromas | ~90% | Proximal medial tibia is most common site. |
| Cervical spine fusions | ~80% | Affecting C2 to C7 | |
| Short broad femoral neck | ~70% | ||
| Scoliosis | ~65% | May be rapidly progressive | |
| Thumb malformations | ~50% | ||
| Distal limb reduction defects | <3% | May be misdiagnosed as a brachydactyly syndrome | |
- 1.
Kaplan et al [2009], Piram et al [2011], Kaplan et al [2019]
- 2.
Shore & Kaplan [2008]
Hallux valgus malformation. Hallux valgus malformations are present from birth and may be identifiable on prenatal imaging [Maftei et al 2015]. The first metatarsal is short with a hallux valgus malformation and/or monophalangism with a single dysplastic phalanx (see Figure 1) [Towler et al 2020]. Additional hallux malformations can include a delta-shaped, dysplastic proximal phalanx. Hallux valgus malformations are most often bilateral but can be unilateral or absent in a minority of individuals with atypical FOP.
Heterotopic ossification
- Extraosseous bone formation (abnormal bone formation in soft connective tissues outside of the normal skeleton) may manifest as a palpable hard lump or mass. Onset of ossification in individuals with the most common pathogenic variant (c.617G>A; p.Arg206His) is age one to ten years, while onset of heterotopic ossification may be later in some individuals with atypical FOP.
- Heterotopic ossification can be spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from intramuscular vaccinations, falls, and surgical procedures. Painful, recurrent soft-tissue swelling may precede localized heterotopic ossification.
- Heterotopic ossification can occur at any location, typically affecting regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement due to ossification affecting joint mobility. Ossification of the jaw, head, and neck can affect swallowing and speaking.
- Heterotopic ossification occurring in the thoracic region, submandibular region, throat, or other locations near the airway may impact the airway or respiratory function. In addition, costovertebral involvement, ossification of intercostal muscles, paravertebral muscles, and aponeuroses, as well as progressive spinal deformity with kyphoscoliosis may lead to thoracic insufficiency syndrome, the predominant cause of mortality. Pneumonia, hypoxemia, hypercarbia, pulmonary hypertension, and right-sided heart failure may occur in individuals with thoracic insufficiency syndrome.
- Heterotopic ossification may be misdiagnosed as tumors or isolated osteochondromas such as those seen in hereditary multiple osteochondromas, especially if the hallux malformations are not recognized.
Soft-tissue swellings
- Soft-tissue swellings (flare-ups) may be spontaneous or follow an injury. They are characterized by painful swellings in soft connective tissue including skeletal muscles, tendons, ligaments, fascia, and aponeuroses. They may precede the development of localized heterotopic ossification.
- Scalp nodules occurring in neonates and infants have been described in 40% of individuals from a national disease registry [Piram et al 2011]. The nodules were large, firm, immobile, and tender, with rapid growth when they first appear. They generally regress spontaneously without treatment. The overlying skin was normal. Scalp nodules may be a localized manifestation of the soft-tissue swellings.
Additional skeletal malformations and manifestations variably seen:
- Variable thumb malformations may be present in some individuals, including hypoplasia and dysplastic phalanges.
- Limb reduction defects affecting the fingers may be seen in atypical FOP.
- Cervical spine fusions between C2 and C7 may be noted on cervical spine radiographs and may contribute to limitations in mobility as heterotopic ossification progresses. This occurs from intra-articular ankylosis of facet joints and early degenerative changes of the cervical spine.
- Scoliosis affects up to 65% of individuals, may be rapidly progressive due to paravertebral lesions, and may contribute to thoracic insufficiency syndrome.
- Pelvic radiographs may identify congenital short broad femoral necks, which rarely affect function.
- Developmental hip dysplasia is present in 60% of individuals with acute hip pain.
- Osteochondromas are reported in up to 90% of individuals, with the proximal medial tibia the most common location.
- Enchondromas, a benign tumor originating in cartilaginous tissue, have been described in several individuals [Tabas et al 1993, Rafati et al 2016]; the prevalence is unknown.
Fractures. Individuals with FOP are at increased risk for fractures of both normotropic and heterotopic bone due to the increased risk for falls, immobility, and corticosteroid-related osteopenia. Fractures in individuals with FOP usually heal with minimal heterotopic bone formation. Open reduction and internal fixation can lead to rapid onset of heterotopic ossification and is not recommended.
Hearing loss. Conductive hearing loss is present in 50% of individuals with FOP and may be slowly progressive. Onset is usually in childhood and may result from middle ear ossification. In some individuals, a sensorineural component may be present. Acute hearing loss is not usually associated with FOP and should prompt evaluation for other causes.
Renal stones. Individuals with FOP have a threefold increased risk of renal stones, which may be due to a combination of immobilization coupled with increased bone turnover. There has been no comprehensive study of stone composition in individuals with FOP.
Lymphedema may occur with flare-ups affecting the limbs. This may be acute, subacute, or chronic. In some individuals, underlying deep vein thrombosis may be present.
Genotype-Phenotype Correlations
The c.617G>A (p.Arg206His) pathogenic variant is associated with the classic FOP phenotype, including bilateral hallux valgus malformations and early-onset heterotopic ossification [Kaplan et al 2009].
Specific gain-of-function variants at amino acid residue 328 (p.Gly328Arg [c.982G>A and c.982G>C], p.Gly328Trp [c.982G>T], and p.Gly328Glu [c.983G>A]) have been associated with a characteristic phenotype that includes limb reduction defects, which may be misdiagnosed as an amniotic band defect or a brachydactyly syndrome, most commonly brachydactyly type B [Kaplan et al 2009].
Penetrance
The penetrance of gain-of-function variants in ACVR1 is estimated to be near complete; there are no reported individuals with nonpenetrance [Shore et al 2006b]. Among reported individuals with the most common pathogenic variant (c.617G>A; p.Arg206His), none are unaffected.
Prevalence
Based on studies in French [Baujat et al 2017] and British [Connor & Evans 1982] populations, the prevalence of FOP is estimated at one in one million (0.6-1.36 :1,000,000). Individuals with FOP have been reported in diverse ethnic populations, and no racial, ethnic, gender, or geographic predisposition has been identified.
Differential Diagnosis
The diagnosis of fibrodysplasia ossificans progressiva (FOP) is often missed, due in part to the rarity of the condition. Nearly 90% of individuals with FOP initially receive a misdiagnosis, with two thirds undergoing unnecessary and potentially dangerous procedures that lead to permanent harm and lifelong disability in as many as 50% [Kitterman et al 2005].
Disorders that may present with clinical features similar to those of FOP are summarized in Table 3.
Table 3.
Genes of Interest in the Differential Diagnosis of Fibrodysplasia Ossificans Progressiva
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/FOP | Distinguishing from FOP | |||
| EXT1 EXT2 | Hereditary multiple osteochondromas | AD | Multiple osteochondromas arising from growth plate in juxtaphyseal region of long bones or from surface of flat bones |
|
| GNAS | Progressive osseous heteroplasia (see Disorders of GNAS Inactivation) | AD 1 | Extensive bone formation (episodic & cumulative) w/in soft connective tissues |
|
| PTPN11 | Metachondromatosis (OMIM 156250) | AD | Osteochondromas & enchondromas |
|
| ROR2 | Brachydactyly type B1 (OMIM 113000) | AD | Distal limb (terminal) reduction-type defects w/brachydactyly | No heterotopic ossification |
AD = autosomal dominant; FOP = fibrodysplasia ossificans progressiva; MOI = mode of inheritance; POH = progressive osseous heteroplasia
- 1.
Disorders of GNAS inactivation are inherited in an autosomal dominant manner, with the specific phenotype determined by the parental origin of the defective allele.
Disorders to consider in individuals presenting with an isolated clinical feature characteristic of FOP [Kaplan et al 2008]:
- Hallux malformations may represent isolated congenital malformations (e.g., isolated brachydactyly) or juvenile bunions.
- Tumor-like swellings may be associated with sarcoma, desmoid tumor, aggressive juvenile fibromatosis, or lymphedema.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with fibrodysplasia ossificans progressiva (FOP), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Fibrodysplasia Ossificans Progressiva
| System/Concern | Evaluation | Comment |
|---|---|---|
| Overall | Clinical staging based on published criteria (see Table 5) | |
| Hallux malformations | Functional assessment w/orthopedist &/or physiotherapist | Rarely requires intervention |
| Heterotopic ossification | Clinical assessment of extent of heterotopic ossification & impact on function | Avoid elective medical, surgical, & dental procedures. |
| Thoracic insufficiency syndrome | Consider pulmonary & sleep studies | If clinical concern for mechanical respiratory insufficiency |
| Painful, recurrent soft-tissue swelling | History & physical exam for areas of soft-tissue swelling | |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Note: Further evaluation may be indicated for participation in clinical trials.
Table 5.
Clinical Staging of Fibrodysplasia Ossificans Progressiva
| Feature | Clinical Stage | ||||
|---|---|---|---|---|---|
| Early/Mild | Moderate | Late/Severe | Profound | End Stage | |
| History of flare-ups | None; or if present, limited to scalp, neck, or back | Mostly limited to axial regions & upper limbs | In any location | In any location | In any location |
| Body regions affected | Neck, back, upper limbs | Neck, back, chest, upper & lower limbs | Neck, back, chest, upper & lower limbs, jaw | Neck, back, chest, upper & lower limbs, jaw & distal limbs (wrists & ankles) | Ankyloses of most or all joints |
| Thoracic insufficiency (TI) | Limited chest expansion | Rigid chest wall, no chest expansion, diaphragmatic breathing | Symptomatic TI syndrome (pulmonary hypertension & right-sided heart failure) | SymptomaticTI syndrome (pulmonary hypertension & right-sided heart failure) | |
| Other complications | Pneumonia, pressure ulcers | Recurrent respiratory infections | |||
| ADLs | No or minimal assistance required due to mild joint limitations or physical delay in developmental milestones | Some assistance required | Assistance needed for most activities | ||