This disease presents at birth typically with infants having deformed big toes and/or thumbs, or lumps on their toes or fingers. Sometimes a joint may simple be missing. Overgrowths of the rib cage result in decreased expansion and growth of lungs resulting in respiratory compromise. The disease progresses from above downwards (proximal-to-distal fashion) and the child suffering from FOP may have difficulty in opening the mouth and eating due to involvement of the facial and neck muscles and maxillofacial bones. Painful, rubbery indurations in the soft tissues occur sporadically, usually as a result of, and at the site of trauma.

Because FOP is such a rare disease, it can be confused with cancer. Some characteristic features of this disease include deformity of the big toes and/or thumbs; the characteristic hallux valgus deformity, torticollis and a thorax deformity.

Fibrodysplasia ossificans progressiva is sometime associated with alopecia and deafness [7]. Neurologic symptoms are also common in these patients.

• Pain

  Medications also are available to help relieve symptoms of FOP, such as pain and inflammation. [ucsfbenioffchildrens.org]

  Painful swelling of muscles (myositis) leading to ossification began at a mean age of 4.6 years (range, 0-16 years) initially in the neck and upper spine (in 25 subjects) and later around the hips, other major joints, and jaw. [ncbi.nlm.nih.gov]

  At the upper end, pain occurred every day in 45.3% of patients; at the other end of the continuum, 28.2% reported pain 1 to 9 days a month.29 IMPACT ON QUALITY OF LIFE Of those reporting pain, 74% took pain medication; 17% used a prescription narcotic [ajmc.com]

  A constellation of deformities such as torticollis, painful spine, and painful and marked limitation of the weight bearing zones were confusing with variable age of onset. [bone-abstracts.org]

• Soft Tissue Swelling

  To our knowledge, diffuse soft tissue swelling of the scalp as a preosseous lesion of FOP and associated MRI findings have not yet been reported. [ncbi.nlm.nih.gov]

  tissue swelling (flare-ups) that result in abnormal bone formation in muscles, tendons, and ligaments. [clinicaltrials.ucsf.edu]

  FOP is commonly misdiagnosed as there is failure to link the rapidly developing soft tissue swellings that appear on the head, neck and upper back with the malformed big toes. [fopaustralia.org]

• Wheelchair Bound

  Fibrodysplasia ossificans progressiva (FOP) is a rare condition of ectopic calcification leading to increasing disability throughout life, with most patients being wheelchair bound by the age of 30. [ncbi.nlm.nih.gov]

  Our patient was in the third decade of her life, and had become wheelchair bound. [neurologyindia.com]

  Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome. [orpha.net]

• Soft Tissue Mass

  Fibrodysplasia ossificans progressiva (FOP) is an exceedingly rare genetic disorder of connective tissue characterized by extensive and irreversible heterotopic ossification of soft-tissue masses that develop in response to inflammation or trauma. [ncbi.nlm.nih.gov]

• Weakness

  Overview A very rare progressive disorder involving calcification of muscles, tendons and ligaments Symptoms - Myositis ossificans progressiva * Muscle weakness * Rigid muscles * Tendon weakness * Rigid tendons * Calcium deposits in muscles * Movement [checkorphan.org]

  Muscle disorders can cause weakness, pain or even paralysis. [icdlist.com]

  Flare-ups may involve a combination of swelling (from mild to severe, or “tumor-like”), redness, warmth, pain and weakness, or limited use of muscles/joints. [clementiapharma.com]

  […] risk - i.e. sports player with trauma to thigh / large haematoma Minimise haemorrhage & inflammation - ice & elevation - active ROM / avoid passive ROM - 3/52 course of NSAIDS Resection Indication - large mass of bone - significant pain, stiffness & weakness [boneschool.com]

• Trismus

  However, there are very few reports of trismus due to fibrodysplasia ossificans progressiva (FOP) following third molar surgery. [ncbi.nlm.nih.gov]

  Severe trismus and contraindicated exodontia in a patient with fibrodysplasia ossificans progressiva: case report. British Journal of Oral and Maxillofacial Surgery. 2018; 56(5):427-9. Wang Z, Wang X, Liu B, Hou Y. [ijp.mums.ac.ir]

• Hearing Impairment

  impairment Deafness Hearing defect [ more ] 0000365 Respiratory insufficiency Respiratory impairment 0002093 5%-29% of people have these symptoms Anemia Low number of red blood cells or hemoglobin 0001903 Failure to thrive Faltering weight Weight faltering [rarediseases.info.nih.gov]

  Maximizing pulmonary function and minimizing respiratory complications may be beneficial for these people.[3] Restrictive pulmonary diseases (i.e. pneumonia)[5] Auditory System Middle ear ossifications[5] Hearing impairments[5] Hearing loss occurs in [physio-pedia.com]

  Both patients have mild cognitive impairment and conductive hearing impairment. [karger.com]

  Hearing loss is often conductive, possibly due to middle ear ossification; in some patients, the hearing impairment is neurologic [10]. Hearing aids are often helpful [10]. [clinmedjournals.org]

  About half of people with FOP experience hearing impairment. Poor blood flow can lead to pooling of the blood in the arms or legs, causing visible swelling. A person with FOP can eventually become completely immobilized. [healthline.com]

• Ankylosis

  These often progress and form mature bone tissue with resulting ankylosis of the major joints. [bjanaesthesia.org.uk]

  This study presents a case of FOP with temporomandibular joint ankylosis. An eight-year-old boy with the chief complaint of reduced mouth opening and clinical and radiological features of FOP. [ijp.mums.ac.ir]

  As the condition progresses, HO leads to joint ankylosis, breathing difficulties, and mouth-opening restriction, and it can shorten the patient's lifespan. [ncbi.nlm.nih.gov]

• Muscle Swelling

  Swelling of the soft parts is rare and can be the initial manifestation. We report three patients where initial swelling preceded the ossification. [ncbi.nlm.nih.gov]

  Trauma, such as a fall, invasive medical procedure, or viral illness, may trigger muscle swelling and inflammation episodes. These flareups can last several days to months and often result in permanent bone growth in the injured area. [health.com]

  Any trauma to the muscles of an individual with fibrodysplasia ossificans progressiva, such as a fall or invasive medical procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification in the injured [ghr.nlm.nih.gov]

  […] procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification in the injured area. [icdlist.com]

• Torticollis

  A constellation of deformities such as torticollis, painful spine, and painful and marked limitation of the weight bearing zones were confusing with variable age of onset. [bone-abstracts.org]

  Some characteristic features of this disease include deformity of the big toes and/or thumbs; the characteristic hallux valgus deformity, torticollis and a thorax deformity. [symptoma.com]

  The child progressively developed torticollis toward right side and stiffening over the nape of neck and inability to flex the neck even to a mid-flexion range with painful movements. [aihbonline.com]

  He had kyphoscoliosis, torticollis, rigid abdomen, and multiple muscle contractures. He also had short great toes. [annalsofian.org]

• Bony Swelling

  He re-presented at the age of nine with neck swelling, stiffness, pain and numerous bony swellings over the occiput, the posterior neck, parascapular and thoraco-lumbar paraspinal regions. ( Figures 1A and 1B ) Further examination revealed bilateral big [ncbi.nlm.nih.gov]

• Joint Stiffness

  Tissue swelling, joint stiffness and serious discomfort can occur. Some may have a low-grade fever. Flare-ups can last as long as six to eight weeks. The disease then progresses along the trunk and limbs of the body. [ucsfbenioffchildrens.org]

  FOP causes difficulty of movement, joint stiffness, and can lead to difficulties with eating and breathing. [rarediseasereview.org]

  The functional changes happen due to the joint stiffness as the ribbons of heterotopic ossification cross the joints, commonly shoulders, hips, and knees. [omicsonline.org]

  Critical Essential Core Tested Community Questions (7) Sorry, this question is for PEAK Premium Subscribers only Sorry, this question is for PEAK Premium Subscribers only (OBQ13.52) A 26-year-old man presents with generalized back and joint stiffness [orthobullets.com]

• Alopecia

  Mental retardation, alopecia, and cardiac conduction defects are other associations. [4] This case had short great toes, no mental retardation or conductive deafness. Radiological investigations are characteristic in myositis ossificans progressive. [ijcasereportsandimages.com]

  Fibrodysplasia ossificans progressiva is sometime associated with alopecia and deafness. Neurologic symptoms are also common in these patients. Workup consists of a detailed history and physical examination. [symptoma.com]

  Complications Fibrodysplasia ossificans progressiva (FOP) is sometimes associated with alopecia and deafness. [emedicine.medscape.com]

  […] parts of the body become ossified, more specific symptoms can include: Trouble eating that may lead to nutritional deficiencies or malnutrition Difficulty speaking Dental problems Difficulty breathing Respiratory infections Hearing impairment Hair loss (alopecia [verywellhealth.com]

• Erythema

  The clinical symptoms include pain and inflammation of the soft tissue, sometimes associated with fever and cutaneous erythema, joint symptoms--pain, stiffness most frequently concerning the scapular and pelvic girdle, bone malformations--short hallux [ncbi.nlm.nih.gov]

  Approximately 50% of patients in the Connor and Evans study reported pain associated with flare-ups, and 25% noted overlying erythema. 10 The results of a survey study of patients with FOP by Pignolo et al indicated that swelling occurred in 93.1% of [ajmc.com]

  CASE A nine-year-old girl presented the initial symptoms of FOP with tender and painful masses on the anterior abdominal wall accompanied by warm overlying skin and erythema. [scielo.br]

  There was no increased warmth or erythema of the overlying skin (Fig. 1). The cervical spine had severely limited range of motion in all directions. The thoracic and lumbar spines were scoliotic (Fig. 1) with limited flexion and extension. [journals.lww.com]

• Sparse Hair

  Two of 3 patients have sparse hair that grows very slowly, and the eyebrows are sparse or missing. The sparse hair and eyebrows became more prominent in the second decade of life. All 3 patients show mild cognitive impairment. [karger.com]

  hair and eyebrows, and neuroimaging abnormalities especially involving the pontine region [6]. [mdpi.com]

• Neck Swelling

  He re-presented at the age of nine with neck swelling, stiffness, pain and numerous bony swellings over the occiput, the posterior neck, parascapular and thoraco-lumbar paraspinal regions. ( Figures 1A and 1B ) Further examination revealed bilateral big [ncbi.nlm.nih.gov]

• Neck Stiffness

  We observed two Chinese patients who suffered from progressive pain and ankylosis of major joints with congenital bilateral hallus valgus malformation, neck stiffness, and several posttraumatic ossified lesions on the head and dorsum. [ncbi.nlm.nih.gov]

  Past medical history revealed congenital bilateral hallus valgo deformation, neck stiffness and several post-traumatic ossified lesions on the head (temporal and occipital region) and dorsum. [bjanaesthesia.org.uk]

  stiffness, due to cervical spine anomalies, is an early presentation. [joacp.org]

• Headache

  Prevalence of recurrent severe headaches (HA) (26 %) was similar to that in the general population, but prevalence in females with FOP (36 %) was almost fourfold greater than in males. [ncbi.nlm.nih.gov]

  Patient and observation In October 2013, a 12-year-old girl was referred to the paediatric clinic of KCMC with fever, weakness and headache for seven days, which was diagnosed as malaria and treated accordingly. [panafrican-med-journal.com]

• Myoclonus

  Three patients with FOP (1.8 %) reported myoclonus, a prevalence much greater than reported in the general population (P < 0.001). Our worldwide survey indicates that neurological symptoms are common in FOP. [ncbi.nlm.nih.gov]

Workup consists of a detailed history and physical examination.

Laboratory tests

• Complete blood count
• Serum alkaline phosphatase levels 
• Parathyroid hormone (PTH) levels 

Biopsies should not be performed as they may exacerbate the condition.

Imaging 

• CT scan is the best imaging modality. It may show heterotopic ossification of pterygoid muscles and retrognathia in older patients [8]. 
• MRI may be conduced to see the extent of soft tissue involvement
• Bone scintigraphy

Test results 

Diagnosis is mainly through physical findings such as the hallux valgus, big toe or thumb deformity, torticollis, etc. A high serum alkaline phosphatase may also indicate FOP.

• Soft Tissue Calcification

  Multiple heterotopic soft tissue calcifications, severe scoliosis and typical anomalies of toes and thumbs on the radiographs were pathognomonic for fibrodysplasia ossificans progressiva. [ncbi.nlm.nih.gov]

  She continued to have soft tissue calcifications with the progressive restriction of limb movements and became bed ridden from July 2014. [neurologyindia.com]

  Bilateral exuberant soft tissue calcifications were present on the radiographic exams, and the patient also presented with bilateral short-length hallux valgus. [casereports.bmj.com]

• Muscle Calcification

  While the literature does not contain reports of any patients experiencing laryngeal muscle calcification, the literature does recommend avoiding tracheostomy to prevent airway obstruction secondary to traumatic calcification. [ispub.com]

Currently, there is no cure or treatment for FOP. Effective therapies for FOP and possibly other common conditions of HO (heterotopic ossification), may potentially be based on future interventions that block ACVR1/ALK2 signalling [9]. Rituximab has been used [10].

Prognosis for fibrodysplasia ossificans progressiva is poor because of the involvement of thoracic muscles and restrictive lung disease [5]. The median lifespan is approximately 40 years of age [1]. Most patients remain severely debilitated in the course of their life and ultimately die of complications caused by this disease.

Complications

Patients should be protected from surgical procedures, including biopsies if possible, to avoid harming them [6]. FOP, for reasons unknown, occurs in sites where trauma has occurred. So patients suffering from this condition need to take special care in avoiding unnecessary surgical procedures and/or tests. Common complications of this disease include restrictive lung disease, respiratory compromise, cardiac failure, and one or more of these complications are usually the cause in death in FOP.

FOP is a rare, disabling genetic disease of progressive heterotopic endochondral ossification enabled by missense mutations that promiscuously and provisionally activate ACVR1/ALK2, a bone morphogenetic protein type 1 receptor, in all affected individuals [2]. The FOP gene has recently been mapped to human chromosome 4q 27-31 [3]. It is an idiopathic condition as the cause or precipitating factor(s) of these mutation are heretofore unknown.

Incidence

It is an extremely rare disease with an estimated prevalence of only 1 case per 1.64 million in the United Kingdom. The exact incidence of FOP in the United States is unknown.

Age

It starts in infancy and persists for life. It is also known to have in utero involvement.

Sex

It occurs equally in both sexes, however some studies show that it is slightly more common in females.

Race

There is no ethnic, racial, gender or geographic predilection to FOP [1].

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by symmetrical congenital malformations of the blastemal anlage of hands and feet and by progressive heterotopic chondrogenesis and ossification of the soft connective tissues [4].

The recent discovery of overproduction of bone morphogenetic protein-4 in lesional cells and lymphocytic cells of affected patients provides a clue to both the underlying pathophysiology and potential therapy [3].

This overactivation of the gene encoding the bone forming receptor leads to deposition of extracellular matrix in different nonskeletal sites of the body. This results in ossification of ligaments, tendons and muscles and ultimately the patient's body starts "turning into stone".

Fibrodysplasia ossificans progressiva, unfortunately, has no prevention. It is a heritable genetic disorder which can only be diagnosed during the intrauterine period or after birth.

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites [1]. It results in conversion of soft tissues into hard bone and slow but complete destruction of the normal musculature and structure of the body.

Definition

Fibrodysplasia ossificans progressiva is an extremely rare disease of the connective tissue in which bone starts to form in all parts of the body including muscles, ligaments, tendons, etc.

Cause

It occurs due to a genetic mutation in the bone forming receptor gene which results in abnormal overproduction of bone.

Symptoms

Initial symptoms include deformities or lumps in the big toes and/or thumbs leading to a characteristic 'hallux valgus' deformity. Slowly the muscles of the chest become involved which affects the respiratory and cardiac musculature. The patients become physically debilitated and often survive up to only 35 to 45 years of age.

Treatment

This disease has no known cure. It can be managed with some medications but no known drug is known to suitably treat this disease.

1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia Ossificans Progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011 Dec 1;6:80. 
2. Kaplan FS, Lounev VY, Wang H, Pignolo RJ, Shore EM. Fibrodysplasia Ossificans Progressiva: a blueprint for metamorphosis. Ann N Y Acad Sci. 2011 Nov;1237:5-10 
3. Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia Ossificans Progressiva. Paediatr Radiol. 2001 May;31(5):307-14. 
4. Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia Ossificans Progressiva: a clue from the fly? Calcif Tissue Int. 1990 Aug;47(2):117-25. 
5. 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. Mar 2010;92(3):686-91
6. Muthu V, Khaire NS, Varma S. Fibrodysplasia Ossificans Progressiva-primum non nocere. Clin Rheumatol. Apr 2014;33(4):591-2
7. Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with Fibrodysplasia Ossificans Progressiva. Am J Audiol. June 1999;8(1):29-33.
8. Carvalho DR, Farage L, Martins BJ, Speck-Martins CE. Craniofacial findings in Fibrodysplasia Ossificans Progressiva: Computerized tomography evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Apr 2011;111(4):499-502.
9. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia Ossificans Progressiva. Best Prac Res Clin Rheumatol. 2008 Mar;22(1):191-205
10. Altschuler EL. Consideration of Rituximab for Fibrodysplasia Ossificans Progressiva. Med Hypotheses. 2004;63(3):407-8