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Fibrodysplasia Ossificans Progressiva

FOP


Presentation

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
  • […] to the assessment of a chronic pelvic pain patient.[medconnection.ucsfhealth.org]
  • Neuropathic pain was reported by 13% of respondents. QOL inversely correlated with pain severity. 16 Despite usually worsening FOP, surgery is sometimes required.[ajmc.com]
  • For pain management, he was started on injection pamidronate 23 mg (1 mg/kg b.w./day) for 3 consecutive days, following which the patient had improvement in rest pain and tenderness had also decreased.[ijabmr.org]
  • 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]
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]
Soft Tissue Mass
  • Early diagnosis can prevent extensive heterotopic ossification and is possible with recognition of the classic clinical findings in the feet in association with rapidly evolving soft-tissue masses of the trunk and extremities.[ncbi.nlm.nih.gov]
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]
  • This leads to progressive immobility; patients are usually wheelchair-bound by the second decade of life and die of thoracic insufficiency by the fourth decade of life.[journals.sagepub.com]
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]
  • 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.[doi.org]
Trismus
  • However, there are very few reports of trismus due to fibrodysplasia ossificans progressiva (FOP) following third molar surgery.[ncbi.nlm.nih.gov]
Hearing Impairment
  • 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]
  • IMPAIRMENT IN FOP Hearing impairment is a common feature of FOP and occurs in approximately 50% of patients.[pubmedcentral.nih.gov]
  • In some patient hearing impairment are present. [1], [2] Due to rarity of the disease, the rate of misdiagnosis of the FOP is estimated at 80 percent or higher.[jotr.in]
  • 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[physio-pedia.com]
  • Both patients have mild cognitive impairment and conductive hearing impairment.[karger.com]
Alopecia
  • 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]
  • 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]
  • Complications Fibrodysplasia ossificans progressiva (FOP) is sometimes associated with alopecia and deafness.[emedicine.medscape.com]
  • Conductive deafness due to ossicular fusion (25%), mental retardation, alopecia, and cardiac conduction defects are other associations. [4] Radiological investigations help in clinching the diagnosis of MOP.[annalsofian.org]
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]
  • Initial symptoms include painful lumps, mostly in the neck, dorsal trunk, and proximal extremities; there is also stiffness in the adjoining joints, with erythema and mild fever. [4] The lumps decrease in size over a few weeks but joint mobility remains[annalsofian.org]
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]
Ankylosis
  • 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]
  • 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]
  • One year later, patient appeared with newly developed bilateral cervical swellings, CT and MRI revealed diffuse bilateral paravertebral and neck extensor musclesswelling with diffuse high T2 signal intensity on MRI ( Figures 1a, 2a and 2b ).[omicsonline.org]
  • swelling and inflammation (myositis) followed by more rapid ossification in the injured area.[icdlist.com]
Torticollis
  • 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]
  • 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]
  • 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]
Myopathy
  • .- ) muscular dystrophies and myopathies ( G71 - G72 ) myopathy in amyloidosis ( E85.- ) myopathy in polyarteritis nodosa ( M30.0 ) myopathy in rheumatoid arthritis ( M05.32 ) myopathy in scleroderma ( M34.- ) myopathy in Sjögren's syndrome ( M35.03 )[icd10data.com]
  • About Fibrodysplasia Ossificans Progressiva (FOP) FOP is a rare, severely disabling congenital myopathy characterized by heterotopic ossification (HO) of muscles, tendons, and ligaments.[prnewswire.com]
  • School of Medicine, established by Diane Weiss in memory of her parents NIH Research Grant renewed for 4 years FOP Research Lab collaborates with scientists from University of California-Berkeley, Oxford University and Association Francaise Contre Les Myopathies[ifopa.org]
  • NIH: National Library of Medicine Genetics (Medical Encyclopedia) [ Read More ] Muscle Disorders Also called: Myopathy Your muscles help you move and help your body work. Different types of muscles have different jobs.[icdlist.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.[academic.oup.com]
  • Neck stiffness is an early finding and can precede the appearance of HO at that site. Cervical spine abnormalities include large posterior elements, tall narrow vertebral bodies, and fusion of the facet joints between C2 and C7 [ 8 ].[ojrd.biomedcentral.com]
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.[doi.org]

Workup

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
  • Pulmonary function testing quantified the degree of restrictive lung disease caused by her profound scoliosis and intercostal muscle calcification.[ispub.com]

Treatment

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

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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".

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  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

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Last updated: 2019-07-11 19:59