Fibrodysplasia ossificans progressiva

INTRODUCTION — Fibrodysplasia ossificans progressiva (FOP; MIM #135100; also called myositis ossificans progressiva or "stone man disease") is a rare connective tissue disorder characterized by severe, progressive heterotopic ossification of soft tissues that spans joints and results in an ectopic skeleton [1]. It severely decreases mobility and causes significant disability with no effective treatment.

The clinical features and treatment of FOP will be reviewed here. Heterotopic ossification as a complication of surgery or trauma is discussed separately. (See "Complications of total hip arthroplasty", section on 'Heterotopic ossification' and "Surgical management of severe lower extremity injury", section on 'Heterotopic ossification' and "Surgical management of severe lower extremity injury".)

EPIDEMIOLOGY — The prevalence is approximately 1 in 2 million with no sex, racial, ethnic, or geographic predisposition [1]. There are no known risk factors.

PATHOGENESIS — FOP is caused by mutations in the ACVR1/ALK2 gene on chromosome 2q24, which encodes activin A receptor type I/activin-like kinase 2, a bone morphogenetic protein type I receptor [2]. Most cases are sporadic, but autosomal dominant germline transmission has been reported in a small number of cases.

CLINICAL FEATURES — Patients with FOP generally appear normal at birth except for bilateral malformation of the great toes, which are characteristically short and laterally deviated (hallux valgus); the first metatarsals are malformed and the first toes have an absent or fused interphalangeal joint [1] (picture 1).

Variable clinical features of FOP include short, malformed thumbs (in approximately 50 percent), clinodactyly, neck stiffness, and hearing loss (in approximately 50 percent) [3,4].

Sporadic, painful episodes of rapidly progressive soft tissue swelling ("flare-ups") typically begin during the first decade of life [4-7]. These usually present as nodules on the head or back and occur at a median age of 1.5 years, although 10 percent of patients present with nodules in the neonatal period [8]. The soft tissue swellings may resolve but more often transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into ribbons, sheets, or plates of heterotopic bone [9]. Flare-ups may be precipitated by soft tissue injury, intramuscular injection, surgical incisions, falls, muscular stretching, or viral illness [10]. They typically begin in the head, neck, and shoulders and progress from cranial to caudal, dorsal to ventral, axial to appendicular, and proximal to distal [4]. The diaphragm, tongue, extraocular muscles, cardiac muscles, and smooth muscles are spared.

FOP lesions go through predictable stages. Pain, erythema, tenderness, swelling, and warmth are present in the first few weeks. During the intermediate stage, induration increases but pain and erythema improve. During the late stage (after 12 weeks), the nodule hardens with radiographic ossification, but the swelling resolves [11]. In a survey of 44 patients with FOP, the average age of onset of heterotopic ossification was 5 years, restrictive ossification was present in 80 percent of patients by age 7, and 95 percent of patients had severely restricted motion in the upper extremity by age 15 [12].

The heterotopic bone eventually extends across joints, resulting in progressive and irreversible immobility, weight loss (secondary to ankylosis of the jaw), and thoracic insufficiency syndrome (image 1). Patients are dependent upon diaphragmatic breathing because the diaphragm is spared. Most patients die of respiratory depression or pneumonia. Starvation (related to ankylosis of the jaw) used to be a common cause of death, but modern feeding tubes have made starvation a less common cause of death. (See 'Prognosis' below.)

LABORATORY FEATURES — Biochemical studies (eg, serum alkaline phosphatase, parathyroid hormone level, renal function, urinary calcium, and phosphate) are usually normal [13]. Alkaline phosphatase is elevated in some patients during new episodes of heterotopic ossification formation [14].

RADIOGRAPHIC FINDINGS — Characteristic radiographic features of FOP include joint malformations, particularly of the great toe (eg, bilateral hallux valgus deformity, malformed first metatarsal, absent or fused interphalangeal joint), and soft tissue ossification [3]. Preosseous lesions and early heterotopic ossification are visible on bone scan, computed tomography, or magnetic resonance imaging before radiographs [13,15].

Variable radiographic features of FOP include proximal medial tibial osteochondromas (approximately 90 percent); orthotopic fusions of the posterior elements of the cervical spine (approximately 80 percent); broad, short femoral necks (approximately 50 percent); and malformations of the thumbs (approximately 50 percent) [1,3].

DIAGNOSIS — FOP is a clinical diagnosis that is confirmed with molecular genetics. FOP should be suspected in children with hallux valgus, progressive soft tissue swelling, and nodules on the head or back. Biopsy of the soft tissue lesions may precipitate a flare-up and should be avoided [10,16].

Definitive diagnosis requires genetic confirmation with specific molecular genetic studies that detect missense mutations or "in frame" deletions in the protein-encoding region of the ACVR1 gene [3,8,17]. Consultation with a clinical geneticist is recommended before genetic testing [16].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FOP includes other conditions associated with malformed great toes, soft tissue swelling, or heterotopic ossification. The combination of these three findings generally distinguishes FOP from these conditions.

●Other conditions with malformed great toes – Other conditions associated with malformed great toes include isolated congenital malformations, brachydactyly, synostosis and symphalangism syndromes (ie, fusion of bones and joints of the fingers or toes), and juvenile bunions [3,18]. In contrast to these conditions, children with FOP often have other skeletal malformations (eg, malformations of the thumb, cervical spine abnormalities, osteochondromas of the proximal medial tibia), rapidly progressive soft tissue swelling, and heterotopic ossification [3]. Juvenile bunions are not present in the neonatal period, whereas the hallux valgus deformity in FOP is present at birth.

●Other conditions with femoral or tibial osteochondromas – Distal femoral and proximal tibial osteochondromas also may occur in patients with hereditary multiple osteochondromas [19]. However, patients with hereditary multiple osteochondromas do not typically have malformed great toes or episodic flare-ups. (See "Nonmalignant bone lesions in children and adolescents", section on 'Osteochondroma and hereditary multiple osteochondromas'.)

●Other conditions with heterotopic ossification – Heterotopic ossification also may occur in children with progressive osseous heteroplasia (POH; MIM #166350), a rare genetic condition characterized by cutaneous ossification that progresses to involve subcutaneous and deep connective tissues [1]. POH is distinguished from FOP by the sites of ossification and lack of great toe malformation and "flare-ups." Although acquired heterotopic ossification also occurs at sites of trauma, it is rare in young children and not usually associated with great toe malformation or flare-ups.

●Other conditions with rapidly progressive soft tissue lesions – Rapidly progressive soft tissue lesions may raise concern for neoplasms and other tumors (eg, soft tissue sarcoma, osteosarcoma, aggressive juvenile fibromatosis [extra-abdominal desmoid tumors]) or lymphedema [3,19]. However, the sudden onset and rapid change in size and shape (often within hours) of soft tissue lesions associated with FOP is not characteristic of these conditions. Evaluation of the great toes and consideration of FOP should be considered before biopsy is performed. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical presentation' and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Clinical presentation' and "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy", section on 'Clinical presentation and diagnosis'.)

MANAGEMENT — Management of FOP is predominantly supportive and focuses on prevention of flare-ups, patient and family education and counseling, and improved quality of life. Several drugs are in clinical trials to determine if they are effective in decreasing heterotopic bone formation in patients with FOP: palovarotene, REGN 2477, and rapamycin. None is approved by the US Food and Drug Administration (FDA) or the European Medicines Agency, but palovarotene has been approved in Canada.

Children with FOP should be managed in consultation with an expert in FOP. Consensus guidelines from the International Clinical Council on FOP (ICC) and consultants for the medical management of FOP are available on the International Fibrodysplasia Ossificans Progressiva Association website [16].

Prevention of flare-ups

Avoid biopsies, surgery, and trauma — Biopsies and removal of lesions are contraindicated because they precipitate aggressive ossific reaction in the soft tissues. Similarly, correction of fixed deformities often leads to further ossification and loss of motion [4].

Attempts at resecting the ankylosis across the jaw have been unsuccessful and are not recommended [20,21]. Scoliosis is usually not addressed surgically because spinal fusion, especially posterior fusion, in younger patients generally results in worsening of the curve [22]. However, rapidly progressive lumbar curves in children younger than five years of age may warrant anterior, with or without posterior, surgical treatment to prevent progression [23].

FOP patients have increased anesthetic risks due to restrictive lung disease, fused cervical vertebrae, restricted oral access, and abnormal cardiac conduction. Considerations for general anesthesia in patients with FOP are provided in the ICC guidelines [16].

Prevention of falls — Falls may lead to injury and painful flare-ups. In a survey of 135 patients with FOP, 81 percent reported an injury related to a fall; two-thirds of falls led to painful flare-ups and one-half of falls led to permanent disability [24]. Strategies to prevent falls include limiting high-risk activities, installing handholds and other safety measures in living spaces, and the use of headgear [16].

Prevention of viral illnesses — Viral illnesses can cause flare-ups of FOP [25]. Strategies to prevent viral illness include frequent washing of the hands with soap and water or an alcohol-based hand sanitizer; not touching the eyes, nose, or mouth with hands unless the hands are washed; and limiting contact with people who are sick [16,26]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'.)

Immunizations

●Influenza vaccine – Influenza infections may trigger flare-ups of FOP [25]. The ICC suggests annual influenza vaccination for patients with FOP, with specific caveats [16]:

•The live attenuated influenza vaccine (LAIV) is not recommended because it may precipitate a flare-up.

•The inactivated influenza vaccine (IIV) should be administered according to a modified protocol in which it is administered subcutaneously rather than intramuscularly.

•Influenza vaccine should not be administered during a flare-up or within six to eight weeks of a flare-up.

•Influenza vaccine should not be administered near a joint or muscle group that has been affected by FOP.

Close contacts of patients with FOP also should receive annual influenza immunization. The ICC recommends that close contacts of patients with FOP receive IIV rather than LAIV [16].

●Other vaccines – Recommendations for other vaccines are individualized according to the potential benefits and harms for the particular vaccine in a particular patient. Factors to be considered include the risk of precipitating a flare-up, the risk of exposure to a vaccine-preventable disease, and the number of doses of vaccines received before the child was diagnosed with FOP. Detailed recommendations are provided in the ICC guidelines [16]. In general:

•Vaccines should not be administered during a flare-up or within six to eight weeks of a flare-up.

•Vaccines should not be administered near a joint or muscle group that has been affected by FOP.

•Diphtheria- or tetanus-toxoid containing vaccines (eg, the combination diphtheria, tetanus, and acellular pertussis vaccine) may cause flare-ups, heterotopic ossification, and permanent loss of joint motion [16,27]. They should be avoided in children with FOP unless indicated to prevent life-threatening illness [16].

Flare-ups also may be caused by vaccines that contain components of diphtheria and tetanus as protein conjugates (eg, Haemophilus influenzae type b [Hib] vaccine; meningococcal serogroups A, C, W, and Y vaccine; pneumococcal conjugate vaccine; combination Hib and meningococcal serogroup C vaccine). The safety of these vaccines for patients with FOP is uncertain.

•Intramuscular (IM) injections are contraindicated because they precipitate flare-ups.

Whether vaccines that are typically administered IM are effective when administered subcutaneously is uncertain. There is some evidence to effectiveness for hepatitis A and B vaccines when administered subcutaneously [28,29], but evidence for other vaccines that are typically administered IM (eg, human papillomavirus vaccine, meningococcal serogroup B vaccine) is lacking.

•Subcutaneous administration is routinely recommended for the following vaccines, which are generally considered safe for patients with FOP: measles, mumps, and rubella (MMR) vaccine; the varicella vaccine; the combination MMR and varicella vaccine; and inactivated poliovirus vaccine [16,30].

Glucocorticoid prophylaxis — A short course of glucocorticoids may be warranted to prevent flare-ups within 24 hours of severe soft tissue trauma or emergency, elective, major, or minor surgery (eg, appendectomy, dental surgery) [16]. The ICC suggests prednisone 1 to 2 mg/kg orally once or twice per day (maximum daily dose 100 mg) for three to four days [16]. Equivalent doses of other oral glucocorticoids may be administered. Although glucocorticoid prophylaxis has not been studied systematically in patients with FOP, inflammation plays in important role in the development of FOP flare-ups [31,32].

Symptomatic management of early lesions

Glucocorticoids — A short course of glucocorticoids may be warranted for the early symptomatic management of flare-ups affecting the jaw, submandibular area, or major joints (eg, hip); consultation with an expert in FOP is recommended for patients with submandibular flare-ups. When administered within the first 24 hours of a flare-up, a short course of glucocorticoids may reduce inflammation and tissue edema and prevent some symptoms. Glucocorticoids usually are not used in the symptomatic management of flare-ups of the neck or trunk because these flare-ups are typically prolonged and recurrent [33].

When glucocorticoids are used, the ICC suggests prednisone 1 to 2 mg/kg orally once or twice per day (maximum daily dose 100 mg) for three to four days [16]. Equivalent doses of other oral glucocorticoids may be administered.

After discontinuation of the glucocorticoid, or if glucocorticoids are not used, topical or systemic nonsteroidal anti-inflammatory medication (eg, ibuprofen) may be used for symptomatic management during the remainder of the flare-up. Local application of cool packs also may be helpful.

The use of glucocorticoids in the symptomatic management of FOP flare-ups is based upon the importance of inflammation in FOP flare-ups [31,32]. In a survey, 75 percent of 500 patients used short-term glucocorticoids for flare-ups of the limbs; among these, 31 percent reported that glucocorticoids always improved symptoms, and 55 percent reported that they occasionally did; 12 percent reported that they had complete resolution of a flare-up with glucocorticoids [9].

Ibuprofen — Use of ibuprofen (or other prostaglandin inhibitors) may prevent heterotopic ossification because inflammatory prostaglandins are thought to stimulate induction of heterotopic bone [34-36].

Palovarotene — Palovarotene is a selective retinoic acid receptor gamma agonist [37].

Indications — Palovarotene is available in the United States and Canada for the reduction of heterotopic ossification in females ≥8 years of age and males ≥10 years of age with FOP; it is available for chronic treatment with dose escalations for flare-ups/substantial trauma (chronic/flare-up regimen) or for treatment of flare-ups only.

The safety and potential efficacy of palovarotene were demonstrated in a randomized placebo-controlled trial in 40 patients with FOP experiencing a flare-up. This study revealed a promising but nonsignificant decrease in heterotopic ossification formation [38,39]. In a subsequent, multicenter, open-label, single-arm trial of the chronic/flare-up regimen, palovarotene reduced the mean annualized new heterotopic ossification volume by 60 percent among 97 participants (mean age 15 years) available for the 18-month visit compared with 101 untreated patients (mean age 17 years) from a natural history study [40].

Contraindications and precautions

●Contraindications

•Pregnancy – Including pregnant people, people who are breastfeeding, and those of childbearing potential.

Exceptions include meeting all conditions of pregnancy prevention or there is no risk of pregnancy due to physical limitations.

As with other retinoic acid derivatives, palovarotene is teratogenic.

•Known hypersensitivity to retinoids.

●Precautions

•Growing children with open growth plates – Palovarotene may cause premature closure of the physeal growth plates. In clinical trials, 24 percent of participants <18 years of age with open epiphyses had premature physeal closure.

Before initiation of palovarotene, growing children should undergo baseline evaluation of linear growth (plotting of height on standard growth curves), sexual maturity (picture 2A-C), and skeletal maturity (hand/wrist and knee radiographs). Reassessment of linear growth and radiographic evaluation of skeletal maturity is recommended every three months until patients reach skeletal maturity or final adult height.

•Hepatic and kidney impairment – Palovarotene has not been studied in patients with moderate or severe hepatic impairment or severely reduced glomerular filtration rate and is not recommended for these patients.

●Drug interactions

•CYP3A4 inhibitors and inducers – Palovarotene undergoes hepatic metabolism by cytochrome P450 3A4 (CYP3A4). Use with CYP3A4 inhibitors may increase toxicity and is not recommended; however, dose adjustments are available for use with moderate CYP3A4 inhibitors if concurrent use is unavoidable. Use with moderate or strong CYP3A4 inducers is not recommended due to potential for decreased efficacy. Lists of CYP3A4 inhibitors and inducers are provided in the table (table 1).

•Tetracyclines [41] – Cases of pseudotumor cerebri have been reported with concurrent use of tetracyclines and systemic retinoic acid derivatives. Palovarotene prescribing information recommends against coadministration [42].

•Other oral retinoids (including vitamin A) should be avoided due to risk for vitamin A toxicity.

Administration — Palovarotene should be taken with food and ideally at the same time each day. The capsules may be swallowed whole or the contents may be emptied onto a teaspoon of soft food (eg, applesauce, yogurt) and consumed immediately.

Among those who could be pregnant, a pregnancy test should be obtained before drug administration, within one week of initiation, and periodically during treatment.

●Chronic regimen

•Age ≥14 years – 5 mg orally once daily

•Age 8 to <14 years (females) or age 10 to <14 years (males):

-Weight 10 to <20 kg – 2.5 mg orally once daily

-Weight 20 to <40 kg – 3 mg orally once daily

-Weight 40 to <60 kg – 4 mg orally once daily

-Weight ≥60 kg – 5 mg orally once daily

●Flare-up regimen – Begin the flare-up regimen at the onset of the first flare-up symptom or as soon as possible after a substantial high-risk traumatic event likely to lead to a flare-up (eg, fall, substantial contusion, surgery). For patients who are receiving chronic palovarotene, the chronic regimen should be discontinued when the flare-up regimen is initiated and resumed when the flare-up regimen is completed.

•Age ≥14 years – 20 mg orally once daily for four weeks, followed by 10 mg orally once daily for eight weeks

•Age 8 to <14 years (females) or age 10 to <14 years (males)

-Weight 10 to <20 kg – 10 mg orally once daily for four weeks, followed by 5 mg orally once daily for eight weeks

-Weight 20 to <40 kg – 12.5 mg orally once daily for four weeks, followed by 6 mg orally once daily for eight weeks

-Weight 40 to <60 kg – 15 mg orally once daily for four weeks, followed by 7.5 mg orally once daily for eight weeks

-Weight ≥60 kg – 20 mg orally once daily for four weeks, followed by 10 mg orally once daily for eight weeks

●Adjustments to flare-up regimen

•Persistent symptoms – If symptoms persist, treatment with the lower dose (ie, that used for weeks 5 through 12) may be extended in four-week intervals. A maximum number of four-week intervals has not been established. We make this determination on a case-by-case basis and extend the treatment as the patient tolerates and the symptoms dictate.

•New or worsening flare-up – If the patient has a new flare-up at a different location or marked worsening of the original flare-up, the 12-week flare-up regimen should be restarted.

●Adverse effects – Adverse effects reported among >20 percent of clinical trial participants include dry skin (78 percent), dry lips (55 percent), alopecia (41 percent), pruritus (40 percent), erythema (32 percent), skin exfoliation (31 percent), and rash (30 percent) [43]. Other adverse effects include dry eyes, sensitivity to sunlight, hearing and vision impairment, mouth ulcers, paronychia, pancreatitis, and hypertriglyceridemia [33,37,44,45]. Refer to the drug interactions program or local prescribing information for dosage reductions for intolerable adverse reactions.

Other agents — As the molecular mechanisms of FOP become better known, other therapeutic agents have shown promise [46]:

●REGN-2477 – REGN-2477, an activin A antibody, has shown promising preclinical results and is in late clinical trials in the United States and Europe [NCT03188666] [47,48].

●Rapamycin – Rapamycin, an mTORC1 inhibitor that is a commonly used immunosuppressant, has shown mixed results [49,50] and is in late clinical trials in Japan [UMIN000028429] [46].

●Anti-interleukin agents – In a case report, anti-interleukin agents (anakinra and canakinumab) appeared to be helpful in decreasing the frequency of flare-ups [51], but anti-interleukin therapy remains investigational.

Preventive dental care — Preventive dental care is a crucial component of the management of FOP and should begin as soon as possible. Preventive dental care is discussed separately. (See "Preventive dental care and counseling for infants and young children".)

Consultation with a dental professional with expertise in FOP is recommended before any dental procedure [16]. Injections of local anesthetic for dental procedures should be avoided [52].

Hearing evaluation — Children with FOP are at increased risk for conductive hearing loss. They should undergo evaluation for hearing impairment with audiometry at least every other year [16]. (See "Hearing loss in children: Screening and evaluation", section on 'Formal audiology'.)

Respiratory health — Chest deformity and scoliosis in patients with FOP may decrease respiratory capacity. Respiratory health can be maintained in patients with FOP through active respiratory activity (eg, singing, incentive spirometry, peak flow whistles) [16].

PROGNOSIS — Most patients require a wheelchair by age 20 years [1]. Alternative feeding methods (eg, feeding tubes, gastrostomy tubes) have prolonged the life span of patients with ankylosis of the jaw. In a review of information from two large registries, the median lifespan was approximately 40 years; the most common causes of death were thoracic insufficiency (54 percent) and pneumonia (15 percent) [53].

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a rare connective tissue disorder caused by mutations in the ACVR1/ALK2 gene, which encodes a bone morphogenetic protein receptor. Most cases are sporadic. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical features – Characteristic clinical features include bilateral malformation of the great toes at birth (they are short and laterally deviated [ie, hallux valgus]) (picture 1); sporadic, painful episodes of rapidly progressive soft-tissue swelling ("flare-ups"); and heterotopic ossification that eventually spans joints, resulting in progressive and irreversible immobility, weight loss, and thoracic insufficiency syndrome. (See 'Clinical features' above.)

Flare-ups usually begin in the first decade of life, presenting as nodules on the head or back. They can be precipitated by soft tissue injury, intramuscular (IM) injection, surgical incision, falls, muscular stretching, or viral illness. (See 'Clinical features' above.)

●Diagnosis – FOP should be suspected in children with hallux valgus, progressive soft tissue swelling, and nodules on the head or back. Definitive diagnosis requires molecular genetic studies that detect missense mutations or "in frame" deletions in the protein-encoding region of the ACVR1 gene. Biopsy of soft tissue lesions may precipitate a flare-up and should be avoided. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of FOP includes other conditions associated with malformed great toes, soft tissue swelling, or heterotopic ossification. The combination of these three findings generally distinguishes FOP from these conditions. (See 'Differential diagnosis' above.)

●Management – Management is predominantly supportive and focuses on prevention of flare-ups, patient and family education and counseling, and improved quality of life. Palovarotene is a selective retinoic-acid receptor gamma agonist that inhibits heterotopic ossification and shows clinical promise. It is not widely available. (See 'Management' above.)

•Prevention of flare-ups

-Biopsies, surgery, and trauma should be avoided if possible. (See 'Avoid biopsies, surgery, and trauma' above.)

-Limiting activities with a high-risk of falls, installing handholds and other safety measures, and use of headgear may prevent falls or severe trauma from falls. (See 'Prevention of falls' above.)

-IM injection of vaccines is contraindicated. Additional immunization precautions are discussed above. (See 'Immunizations' above.)

•Use of palovarotene – Palovarotene is a selective retinoic-acid receptor gamma agonist that inhibits heterotopic ossification. It is available for the reduction of heterotopic ossification in females ≥8 years of age and males ≥10 years of age with FOP.

•Preventive health maintenance

-Preventive dental care is discussed separately. (See "Preventive dental care and counseling for infants and young children".)

-Children with FOP should undergo evaluation for hearing impairment with audiometry at least every other year. (See 'Hearing evaluation' above.)

-Respiratory health can be maintained through active respiratory activity (eg, singing, incentive spirometry, peak flow whistles). (See 'Respiratory health' above.)