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|LETTER TO EDITOR
|Year : 2016 | Volume
| Issue : 2 | Page : 354-356
A case of fibrodysplasia ossificans progressiva: 20 years of follow-up
Kumar Abhishek1, Sanjeev Jain2, Rajesh Khadgawat1
1 Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pediatrics, JLN Medical College, Ajmer, Rajasthan, India
|Date of Web Publication||3-Mar-2016|
Department of Endocrinology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Abhishek K, Jain S, Khadgawat R. A case of fibrodysplasia ossificans progressiva: 20 years of follow-up. Neurol India 2016;64:354-6
Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling disorder of connective tissues characterized by progressive heterotopic calcification. We reported a case of a 5-year-old girl diagnosed with this rare disease in 1995 in Neurology India. Here, we are reporting a 20-year follow-up of the same case.
This girl initially had a firm non-tender swelling over the scapular region followed by a firm, hard bony swelling over the right sternocleidomastoid muscle. Subsequently, she developed multiple swellings over the neck, spine, shoulder, and pelvic girdle leading to progressive restriction of movements. Skiagrams showed calcifications in the soft tissues that were detected with routine radiological investigations. Biopsy from one of the swellings revealed fibroblastic proliferation of connective tissue surrounding the muscle bundles. She was treated with steroids for a brief period to halt the progression of the disease but without any success.
The girl, now a 23-year-old female, reported to one of the authors for follow-up. She continued to have soft tissue calcifications with the progressive restriction of limb movements and became bed ridden from July 2014. During this period, she had an episode of fever, possibly viral, subsequent to which she noticed a rapid increase in the calcifications at multiple sites especially around the chest, resulting in restriction of chest wall movement (thoracic insufficiency syndrome). Around the age of 23 years, she developed restriction in mouth opening, thereby causing difficulty in eating and resulting in a marked weight loss (she fed herself with a straw/self-designed spoon). From the last few months, calcification around the pelvic and shoulder girdle caused almost complete restriction of movement. This, along with the marked restriction of movements of the spine, resulted in a fixed posture where she could not lie down or sit [Figure 1] and [Figure 2]. She developed multiple hard nodules, owing to subcutaneous calcification, that were clearly visible on inspection [Figure 3]. She was the youngest of four siblings (a product of non-consanguineous marriage) without any other member being affected by the disease. She achieved menarche at the expected age and was having regular menstrual periods. Tests for higher mental functions, hearing, and vision were normal. Routine investigations including renal/liver/thyroid functions were within normal range for age as were serum parathyroid hormone and serum 25-hydroxy vitamin D levels.
|Figure 1: Clinical picture showing the usual sitting posture of the patient on bed (with permission of family and patient)|
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|Figure 2: Chest X-rays of the patient showing multiple soft tissue calcifications (white arrows)|
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|Figure 3: Clinical photograph of the elbow of the patient showing multiple soft tissue calcifications (black arrows)|
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Fibrodysplasia ossificans progressiva is an autosomal dominant genetic disorder characterized by heterotopic calcification that limits movements. It is a rare disorder and is believed to occur in approximately 1 in 2 million people worldwide without any ethnic, racial or geographic predisposition. Early in the life, there are no features of FOP except for congenital malformation of the great toes that is present in many patients. As the patients grow old, they experience sporadic episodes of soft tissue swelling that may regress but usually turn into heterotopic bone in the muscles, tendons, ligaments, and fascia. Progressive accumulation of this heterotopic calcification leads to ankylosis of multiple joints and progressive immobility. Immobility is cumulative, and most patients are wheelchair-bound by the end of the second decade of life. Heterotopic ossifications usually follow specific anatomic patterns. They begin in the dorsal, proximal, axial, and cranial regions of the body (neck, shoulders, back) and progress into ventral, caudal, and distal regions (trunk and limbs). Ossification does not involve smooth muscles, cardiac muscles, diaphragm, tongue, and extra-ocular muscles. The median lifespan for these patients is approximately 40 years and has not changed much in last two decades. The cause of death is usually respiratory infection in the setting of thoracic insufficiency syndrome.
Our patient was in the third decade of her life, and had become wheelchair bound. The development of jaw ankylosis and thoracic insufficiency syndrome was adversely affecting her prognosis.
Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) Type I receptor, has been identified in all sporadic and familial cases of FOP. Mutated ACVR1/ALK2 receptor leads to destabilization of the glycine-serine activation domain, suggesting overactive bone morphogenetic protein signaling pathway as the underlying cause of the ectopic chondrogenesis, osteogenesis, and joint fusions seen in FOP.
No disease-modifying therapy has emerged in the last 20 years. Our patient has received nonsteroidal anti-inflammatory drugs and steroids during flare-ups. She has also been advised a trial of mast cell inhibitors and aminobisphosphonates with her consent at the discretion of treating physician during the flare-ups. Physiotherapy and surgery were not of great help in improving mobility as they induced flare-ups and ended up further compromising her mobility.
The discovery of the causative gene along with emerging insights into the pathophysiology of ACVR1/ALK2-mediated heterotopic ossification suggests at least four possible approaches to the treatment and/or prevention of FOP. These approaches include blocking activity of the mutant FOP receptor, diverting the responding mesenchymal stem cells to a soft tissue fate, inhibiting inflammatory and neuro-inflammatory triggers of FOP flare-ups, and altering the inductive and/or conducive microenvironments that promote the formation of FOP. Palovarotene, a highly selective retinoic acid receptor gamma agonist, is currently under research in phase 2 clinical trial to prevent heterotopic ossification during and following a flare-up in subjects with FOP.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 2009;30:379-90.
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A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 2006;38:525-7.
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[Figure 1], [Figure 2], [Figure 3]