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 Table of Contents  
CASE REPORT
Year : 2014  |  Volume : 7  |  Issue : 1  |  Page : 84-87

Fibrodysplasia ossificans progressiva: A case report


1 Department of Orthopedics, TMSS Medical College, Bogra, Bangladesh
2 Department of Medicine, Rafatullah Community Hospital, Bogra, Bangladesh
3 Department of Radiology and Imaging, Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh

Date of Web Publication6-Jun-2014

Correspondence Address:
Ahmed Al Mustaque
Department of Orthopedics, TMSS Medical College, Bogra
Bangladesh
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7341.134027

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  Abstract 

Fibrodysplasia ossificans progressiva (FOP) is an inherited disease in which progressive ossification of striated muscles leads to severe disability and there are associated characteristic congenital skeletal malformations. FOP used to be referred to as Stoneman's Syndrome. There are no ethnic, racial, or religious patterns. Also, there are no other known examples in medicine of one normal organ system turning into another. The case we report herein is a 23-year-old male patient with the clinical and radiologic characteristics of FOP. The importance of this case was that in spite of beginning early with the typical presentation of FOP for a long time and the fact that the patient consulted with tertiary care specialists, the diagnosis had been missed.
This indicates that the general physicians, radiologists and other specialists' awareness and knowledge of FOP are low.

Keywords: Heterotopic ossification, misdiagnosis, mutation


How to cite this article:
Mustaque AA, Montasir AA, Amin MB. Fibrodysplasia ossificans progressiva: A case report. J Orthop Traumatol Rehabil 2014;7:84-7

How to cite this URL:
Mustaque AA, Montasir AA, Amin MB. Fibrodysplasia ossificans progressiva: A case report. J Orthop Traumatol Rehabil [serial online] 2014 [cited 2019 May 26];7:84-7. Available from: http://www.jotr.in/text.asp?2014/7/1/84/134027


  Introduction Top


Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disorder. It is a rare disease, affecting about one out of two million people worldwide. [1] Seven hundred cases have been reported so far. Diagnosis of FOP can be made based on the patient's characteristic signs and symptoms of the disorder. [1]


  Case report Top


A 23-years-old male patient presented in the orthopedic OPD of TMSS medical college and Rafatullah Community Hospital with the complaints of rigidity of axial joints and right knee for the last 20 years. According to the statement of the patient's relative and also from the patient, he was reasonably alright up to 3 years of his age, and then he developed an abscess over his right shoulder. A village doctor offered surgical drainage but his father failed to collect the required amount of money. The village doctor gave several injections of unknown formulations to heal the abscess. The abscess eventually healed but from then his neck movement became gradually restricted. The patient developed painful swellings on his back as he grew up [Figure 1] and [Figure 2]. These swellings hardened over a period of few days and the patient later developed stiffness of spine by the time he became a young man. The patient was subjected to manipulations by physicians, physiotherapist and surgeons; he gradually developed stiffness of bilateral shoulders and the right knee [Figure 3]. The patient came from a rural, poor socioeconomic background. There is no history of consanguineous marriage between his parents. On examination, the patient had bony hard swellings in cervico-thoraco-lumbar spine, and both the knees. Movements of the spine were restricted in all directions. Restricted active and passive movements were observed. There were several hard swelling over his back. His hearing was normal. The CBC showed microcytic, hypochromic anemia with normal calcium, alkaline phosphatase and other metabolic parameters. Radiographs showed ossification of muscles in cervical, thoracic and lumber region [Figure 4],[Figure 5],[Figure 6]. There was also ossification around the knee and the shoulder [Figure 7] and [Figure 8]. The X-ray foot showed great toes with hallux valgus deformity [Figure 9].
Figure 1: Bony deformity of patient

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Figure 2: Scoliosis and bony exostosis in paravertebral region

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Figure 3: Bony exostosis around both knee joint

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Figure 4: Xray of cervical spine AP view shows— Heterotropic bone formation in para vertebral and subcutaneous structures (White arrow). Degenerative changes of cervical spine is also evident

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Figure 5: Xray of dorsal spine AP view— Scolisis is noted with convexity towards left. Orthotopic fusion of dorsal vertebra is seen. Psuedoexostoses with soft tissue ossification is evident (White arrow)

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Figure 6: Xray of pelvis AP view— Extensive ligamental and right paravertebral ossification is seen (White arrow). Intervertebral disc calcification is apparent. Right sided osseous bridge is evident between the ilium and sacrum (Black arrow)

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Figure 7: X ray of right shoulder joint oblique view— Diffuse soft tissue ossification (White arrow) overlying the right chest wall and axilla is evident

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Figure 8: X ray of right knee joint lateral view— Ectopic calcification seen extending posteriorly from to lower end of femur to upper end of tibia (White arrow). Fibula shows psuedoarthrosis in proximal end. Vascular calcification is also evident subcutaneously

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Figure 9: . X ray right foot AP view— Hallux valgus deformity is noted. Great toe shows early degenerative changes

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  Discussion Top


The first case of FOP may have been described by Guy Patin in 1692, but the first detailed description of FOP was given in 1740 by John Freke, a London surgeon. McKusick noted that the muscles were only secondarily affected, and adopted the term fibrodysplasia in 1972. [1],[2] Most cases of fibrodysplasia ossificans progressiva result from new mutations in the gene. FOP usually occurs in the people with no history of the disorder in their family, as in our case also. In a small number of cases, an affected person has inherited the mutation from one affected parent. [1] Researchers believe that a mutation in the ACVR1 gene may change the shape of the receptor under certain conditions and disrupt mechanisms that control the receptor's activity. [1] The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF beta superfamily. Bone morphogenetic proteins (BMPs) exhibits broad spectra of biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. BMPs are members of the transforming growth factor-β (TGF-β) family that bind to type II and type I serine-threonine kinase receptors, and transduce signals through Smad and non-Smad signaling pathways. Recent findings have revealed that BMP signaling is finely tuned by various mechanisms in both the positive and the negative fashion. Perturbations of BMP signaling pathways are linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. FOP is caused by a recurrent heterozygous activating mutation of Activin receptor type IA/Activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that occurs in all the classically affected individuals. [3] The ACVR1 gene provides instructions for producing a member of a protein family called bone morphogenetic protein type I receptors. It helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone (ossification) that occurs in the normal skeletal maturation from birth to young adulthood. The FOP mutation dysregulates BMP signaling and initiates the formation of a disabling second skeleton of heterotopic bone. This results in overgrowth of the bone and cartilage and fusion of joints, resulting in the signs and symptoms of FOP. This is known as progressive heterotopic ossification (HO) and it usually begins in the first decade of life. [1] In patient with FOP any injury and viral illnesses often precipitate new flare-ups leads to severe exacerbations of the disorder, resulting in ossification and joint ankylosis. [2],[4] HO progresses in characteristic anatomic and temporal patterns. Dorsal, axial, cranial, and proximal areas of the body tend to be involved first, with ventral, appendicular, caudal, and distal areas involved later. [2] In our patient it started in the cervical region later involved thoracic and lumber spine. HO eventually leads to ankylosis of all major joints of the axial and appendicular skeleton, restricting movement. [2] During the early childhood, those with FOP form painful fibrous nodules over the neck, back and shoulders. These nodules often develop after a child experiences some sort of trauma. [2] Episodes also can occur without any warning. [2] In most cases, the nodules transform into a bone. When the body starts to generate new bone, the patient usually experiences a painful flare-up. Tissue swelling, low grade fever, joint stiffness can occur. Flare-ups can last as long as six to eight weeks. Bony lesions in FOP have macroscopic features of modeling and remodeling similar to those found in the normotopic skeleton. People who have FOP experience different rates of new bone formation. In some the progress is rapid, while in others it is more gradual. 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. Misdiagnosis has led to unnecessary invasive procedures, such as biopsies. [2] Most common misdiagnoses for FOP are cancer, aggressive juvenile fibromatosis, also called desmoid tumors, and progressive osseous heteroplasia.

Despite advances in understanding the pathophysiology of FOP, there are no therapies with scientifically proven benefits for the prevention or treatment of FOP. Current approaches to FOP treatment are palliative and symptom-modifying. [4],[5] Chemical inhibitors to the pathogenic ALK2 receptors are considered possible medical agents for FOP. Another treatment strategy for FOP is using allele-specific RNA interference (ASP-RNAi), where modified small interfering RNAs (siRNAs) conferring allele-specific silencing against the disease-causing ALK2 mutants found in FOP. The siRNAs may become novel therapeutic agents for FOP. [6] Surgery is not an option for removing the excess bones because surgery often results in more bone formation. Prevention of soft-tissue injury and protection against the influenza virus remain a hallmark of FOP management because both soft-tissue injuries and influenza infections can provoke flare-ups of FOP. [5] Intramuscular injections can also provoke flare-ups and must be assiduously avoided. A brief course of high-dose corticosteroids begun within the first 24 h of a flare-up may help to reduce the intense lymphocytic infiltration and tissue edema seen in the early stages of the disease. [5] Mast cells, lymphocytes, and their associated inflammatory mediators may also be reduced with the use of mast-cell stabilizers, leukotriene inhibitors, nonsteroidal anti-inflammatory medications, and the COX-2 inhibitors. [5] Angiogenesis, a prominent histopathological feature of preosseous FOP lesions, thus becomes a potential target for the therapy. Angiogenesis may potentially be minimized with anti-angiogenic agents, such as nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, thalidomide. Etidronate has been studied in FOP because of its inhibitory effect on the bone mineralization and its potential to impair ossification at high dosages. [4],[5] The newer aminobisphosphonates do not possess this activity. [5] Reports have suggested that pamidronate may have beneficial effects either alone or with steroids for the treatment of acute flare-ups. [5] FOP is a genetic disease, and the ultimate treatment will likely involve a gene correction or a gene bypass approach in the cells and tissues involved in the disease process.

Fibrodysplasia ossificans progressive is a rare disease. Early recognition of this autosomal dominant disorder is important for genetic counseling and minimizing the trauma and painful flare ups.

 
  References Top

1.Frederick SK. Fibrodysplasia ossificans progressiva-An historical perspective. Clin Rev Bone Miner Metab 2005;3:179-81.  Back to cited text no. 1
    
2.Mayur K, Sidhartha N, Nagaraja HS. Fibrodysplasia ossificans progressiva in a four year old child. J Orthop Case Rep 2012;2:17-20.   Back to cited text no. 2
    
3.Takahashi M, Katagiri T, Furuya H, Hohjoh H. Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressive. Gene Ther 2012;19:781-5.   Back to cited text no. 3
    
4.Gosai MM, Hariyani HB. Case report- Fibrodysplasia ossificans progressiva. Natl J Med Res 2013;3:1.   Back to cited text no. 4
    
5.The medical management of Fibrodysplasia ossificans progressiva: Current treatment consideration, The International Clinical Consortium on Fibrodysplasia Ossificans Progressiva. Philadelphia, PA 19104 May 2011.  Back to cited text no. 5
    
6.Kaplan J, Kaplan FS, Shore EM. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Ther 2012;7:786-90.  Back to cited text no. 6
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]



 

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