Index of Orthopedics: Volume 1: Issue 1
- Associate Professor, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Resident, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Orthopaedic Surgeon, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Resident, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Assistant Professor, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
- Professor, Department of Orthopaedic Surgery, School of Medicine, University of Ioannina, Greece
The authors declare that there is no conflict of interest regarding the publication of this paper
Fibrodysplasia ossificans progressiva (FOP) consists a very rare condition in human. The diagnosis is not always easy and it needs a thorough examination of the patient clinically, radiologically as well as a detailed medical history. Unfortunately, there is no definitive treatment and its current management for is limited to the prevention of new flare- ups and ossifications, symptomatic management and maintenance of patient’s functionality. A possible misdiagnosis is not rare due to the low incidence of the disease but may have negative results on the patient. In the present study we present a case of FOP in 21 years old patient who was referred to our department after being operated twice in his right hip.
Fibrodysplasia ossificans progressiva (FOP), also known as Munchmeyer’s disease, is an extremely rare, 1 in 1 million, and severely disabling disease. It was first described in 1648 by Guy Patin as “stone man syndrome”[2,3]. Most cases appear as a result of both genetic and environmental influence. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. Genetic transmission of the disease is autosomal dominant inheritance. Recent studies reveal that nearly all cases are caused by the identical mutation in ACVR 1 (activin type 1 receptor) gene that causes a single amino acid substitution, in the bone morphogenetic protein (BMP) type 1 receptor ACVR 1. ACVR1 is present in skeletal muscles and cartilage and controls the growth and development of muscles and bone including ossification[4,5]. This mutation causes mild constitutive activation of BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation. As there is no known effective treatment for this syndrome, it has been reported that treatment of FOP may potentially be based on interfering mechanisms that block ACVR1[4,5]. There is no ethnic, racial, gender or geographic predisposition.
Myositis ossificans is characterized by congenital extraskeletal malformations and progressive heterotopic ossification. Its first manifestations are usually around the 5th year of life. Individuals with FOP appear normal at birth except for the characteristic brachy symphalangism of the great toes which are present in all classically affected individuals and can lead to early clinical diagnosis. This characteristic is present in 95% of patients with FOP. During the 1st decade of life, children develop painful and highly inflammatory soft tissue swelling/ lumps, also called flare- ups that transform soft tissues, through a process of endochondral
ossification, into an armament- like encasement of bone. This process starts without prior notice and without any injury or trauma soft tissues are transformed in cartilage and bone. Once it has already started, no medication can prevent it. Any type of trauma in patients with FOP may trigger an inflammation process which leads to the development of a calcified painful mass and eventually to complete ossification of muscular system. The procedure of the ossification is similar with the regeneration of a post-fracture bone. Cases that have been reported, symptoms are initiated at the first or second decade of patient’s life. The majority of patients with FOP are misdiagnosed early in life, due to the fact that the early diagnostic features are poorly recognized by the most clinicians. Ectopic ossification could be precipitated by a number of factors such as low- energy trauma to the muscles, intramuscular immunizations- mandibular blocks for dental work-blunt muscle trauma from bumps, biopsy of the lumps, careless venupunctures and viral diseases such as influenza[12–14]. Cardiac muscle and smooth muscle are not involved in the process of heterotopic ossification.
The clinical picture of FOP arises in cephalo-caudal pattern, starting in the dorsal, axial, cephalic and proximal areas, progressing to ventral, appendicular, caudal and distal tissues. Consequently, it begins in the cervical spine with stiffness of the neck as an early finding. Radiographic findings reveal large posterior elements, tall and narrow vertebral bodies and fusion of the facet joints between C2 and C7. Furthermore, the presence of osteochondromas has been reported in these patients. Patients with FOP may also suffer from developmental abnormalities of the temporomandibular joints, due to spontaneous in later stages of FOP or post-traumatic extra-articular ankylosis, with resultant malnutrition, severe weight loss and poor oral hygiene. In 50% of the cases, patients suffer conductive hearing loss due to middle ear ossification.
During the course of the disease, individuals may develop thoracic insufficiency syndrome (TIS) that can lead to life-threatening complications. This includes ankylosis of the costovertebral joints, ossification of intercostals muscles, paravertebral muscles, kyphoscoliosis or thoracic lordosis, leading to morphological complications, mobility limitations and eventually to cardiopulmonary impairment due to decreased lung expandability and Cor Pulmonale. Patients with this condition are at high risk of developing pneumonia and right-sided heart failure[17,18]. According to studies, the risk of cardiopulmonary complications is increased when an infection is associated. For this reason, all infections must be treated aggressively in patients with FOP.
As the condition progresses through the years, patients develop in axial regions subfascial nodules, highly inflammatory and painful, often mistaken for tumours. These types of flare- ups are usually found on posterior neck, paraspinal muscles of the back, limb girdles and the mastication muscles. Episodes of ossification with subsequent disability were characteristically erratic. In most cases, patients report long periods of apparent inactivity of disease which often lasts more than 4 years and might last for 13 years.
Moreover, additional skeletal deformities are short malformed thumbs, clinodactyly, short broad femoral neck and proximal medial tibial osteochondromas. Regarding the malformation of great toes, we recognize four subtypes: type I, is the most common, where each big toe is short, has a single phalanx deviated laterally at the metatarsophalangeal joint and lacks a skin crease. Continuing, in type II big toes are of normal length with progressive bony fusion with increase age. Type III big toes are clinically and radiologically normal in early childhood but become rigid in the 2nd decade due to osteophytic lipping. Finally, in type IV all toes show variable reduction defects accompanied by hand malformations.
Unfortunately, there is no treatment for this disease and the current medications offer only symptomatic and palliative management. Surgical removal of the heterotopic bone exacerbate explosive and new osseous bridge may be formed.
- 21-year-old male patient presented in our department (Department of Orthopaedic Surgery, University Hospital of Ioannina) with a 5-year history of right hip pain and stiffness. The patient has past medical history of severe pain and increasing stiffness in the hip. At the age of 16, the patient had an injury in his right hip after sports activity and he was referred to the local Orthopaedic Department. After the radiographic examination, heterotopic ossification was noted extending across the hip joints and in soft tissues around the femoral neck on radiograph. The patient was advised to be operated and surgery was required for excision of the heterotopic ossification by an orthopaedic specialist in another department. Six months after the operation, the restriction in movements persisted and the pain recurred. Eighteen months later, the hip movements were severely restricted causing inability squatting and sitting properly. The radiograph of the hip revealed the appearance of a new heterotopic ossification bridge, which was decided to be managed with hemiarthroplasty of the hip.
At the time of the first examination in our department, the patient had difficulty in moving his right shoulder, right hip and neck. At the time of evaluation, radiologic examination showed radiographic evidence of heterotopic ossification to be present at hip exactly on the same place that was excised (Figure 1). Radiographs of other anatomic areas were conducted and revealed the presence of heterotopic ossification in unexpected places such as the cervical spine and the right shoulder (Figures 2 & 3).
Regarding his family history, any similar cases were not observed. Nevertheless, patient’s father had passed away for unknown respiratory reason due to lack of primary medical assistance.
Our diagnosis was based on the characteristic findings evidenced in the physical and radiological examination. On physical examination, multiple, small, irregular, subfascial nodules were present. Some of them highly inflammatory and painful, whereas other painless and non-tender hard bony masses. These tumor-like swellings were found on the posterior aspect of the cervical spine, in the paraspinal muscles of the back, in the limb girdles and the mastication muscles8. In addition, alterations of mobility were found. The range of motion of the right hip was restricted leading to severe limitation of his daily activities, such as sitting properly on a chair and sit cross-legged. The right shoulder flexion and abduction movements were noticed to be restricted. The patient suffered also from scoliosis. The neck flexion and extension movements were found to be severely restricted. The plain radiographs of the upper limbs showed ossifications in the right shoulder. Lateral radiograph of cervical spine showed orthotopic fusion of the posterior elements of multiple subaxial vertebrae. Heterotopic ossification at the lumbar paravertebral region was also present.
Laboratory findings were unremarkable. Such clinical and radiological manifestations were associated with FOP. The clinical diagnosis of fibrodysplasia
ossificans progressive was based on the past medical history, clinical examination, that showed soft tissue swellings on the head – neck – upper back and alterations in mobility and radiological findings that revealed the presence of progressive widespread heterotopic ossification in the specific anatomic patterns[10,19,20]. The patient is currently under outpatient clinical supervision.
Fibrodysplasia ossificans progressiva is considered to be the most catastrophic disease seen in humans. There are approximately 800 cases reported of this rare genetic disorder worldwide. Although it is characterized by spontaneous de novo mutations in the majority of the cases, have also been described cases with an autosomal dominant pattern of inheritance[9,10].
A case report, in Paediatric Orthopaedic Department of Regional Hospital de Alta Especislidad del Bajio, Guanajuato Mexico, of a 11 years old female patient with FOP came with functional limitation of the knee joint, tilting of the pelvis, back pain and inability to walk. In radiologic examination, a femoro-tibial bone bridge was formed, maintaining knee flexion fixed at 90o. Patient underwent surgical management and release of bone bridge through bone resection osteotomy. At 4th postoperative week, in new X-ray study, the appearance of a new osseous bridge was noticed, without any new findings. At five- year follow-up, femoro-tibial bone bridge matured and was formed exactly on the same place that was excised. On the other hand, satisfactory results were reported after surgical excision of the heterotopic bone in combination with indomethacin and single fraction irradiation as a preventive measure after the operation.
FOP is commonly misdiagnosed, because of the very low incidence of the disease and due to failure to distinguish the rapidly developing soft tissue swellings which appear on the head- neck- upper back. Specifically, differential diagnosis of malformed great toes includes, isolated congenital malformation- brachydactyly-synostosis- symplalagism syndromes and juvenile bunions. Furthermore, differential diagnosis of the disease includes, aggressive juvenile fibromatosis- osteosarcoma-lymphaedema- desmoids tumors- soft tissue sarcoma and acquired ossification2-13.
The hallux valgus deformity and preosseous tumor-like swellings are critical early diagnostic findings of FOP, that all clinicians should be aware of, in order to avoid to exacerbate progression of the disease with dangerous and unnecessary procedures and achieve a better long-term management of patients with FOP. Our patient did not have congenital malformation of great toes (malformed hallux), but he had soft tissue lesions of the neck and upper back. Although, the orthopaedic surgeons that evaluated him were not aware of the possible association of tumor-like lesions with FOP.
Unfortunately, diagnostic errors occur up to 87% of cases and may cause severe iatrogenic harm, such as incisional and excisional biopsies that lead to permanent harm and catastrophic lifelong disability. Moreover, the mean time to reach diagnosis is 4.1 years.
The definitive diagnosis of FOP depends mainly on the clinical and radiological demonstration of the characteristic skeletal malformations. Moreover, the diagnosis of bilateral hallux valgus on ultrasound may the first prenatal evidence of the disease. Taking into consideration, the mutation of BMP type I receptor, prenatal testing is not indicated for general mutation screening, however it could be considered within a family in which a child has been diagnosed previously. Unnecessary and harmful diagnostic biopsies of the lumps should be avoided as they accelerate the emergence of new nodules which ends in the cascade of painful new flare- ups, progressive heterotopic ossification, and disability. CT and MRI examinations of early lesions have been described but are superfluous. Bone scan findings suggest normal modeling- remodeling of heterotopic ossification.
Laboratory findings show normal bone mineral metabolism, although during flare- ups there is a slight elevation of serum alkaline phosphatase activity and urinary basic fibroblast growth factor levels.
Current management for FOP is limited to the prevention of new flare- ups and ossifications, symptomatic management and maintenance of function. Effective medical symptomatic treatment is the application of high-dose steroids within 24-36 hours of the initial lesion. Conservative treatment with NSAIDS, COX2 inhibitors, leukotriene inhibitors and mast cells stabilizers have been used with no apparent positive results. Surgical removal of heterotopic bone by bone resection osteotomy, to mobilize joints, is generally counterproductive because additional HO develops at the operative site and is associated with a number of complications. Surgery may be indicated only with a focused indication such as to prevent spinal deformity through an arthrodesis.
Diminished pulmonary reverse due to fixation of the chest wall appears to be the predisposing factor to pneumonia in these patients. Therefore, preventive measures should be taken by application of pneumococcal and influenza immunization strictly subcutaneously.
There is no cure available for this disease and the current medications are still only symptomatic and palliative. Although, the pace of the disease is different from patient to patient and as many do not develop comorbidities, they usually have a long life expectancy. Unfortunately, in most cases patients are confined to wheelchair by the 3rd decade of life, and require lifelong assistance in performing activities of daily living. The median age of survival is approximately 45 years old, and death often results from cardiopulmonary complications of TIS and severe malnutrition.
The discovery of the responsible gene and the molecular mechanisms correcting the hyperfunctioning BMPs signaling pathways, revealed new long-term approaches to the treatment of the disease, necessitated additional studies of potential medical interventions and facilitates molecular diagnosis in clinical practice. Molecular analysis of DNA to detect the mutations of ACVR1 is important for patients with FOP to avoid misdiagnosis and prevent iatrogenic harm[9,26].
In conclusion, based on our experience with the described patient, it is our strong belief that the physician should suspect the possibility of FOP diagnosis in adolescents who are referred for stiff joint in combination with the radiological image of heterotopic ossification. These patients should be examined carefully both clinically and radiologically in all major joints as well as in the spine because misdiagnosis may lead to early operation which can provoke additional formation of HO.
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Figure 1: Presence of Heterotopic Ossification in the operated right hip
Figure 2: Presence of Heterotopic Ossification in the right shoulder
Figure 3: Presence of Heterotopic Ossification in the cervical spine.
Title: MD, PhD
First Name: Naoki
Last Name: Kondo
Affiliation: Division of Orthopedic Surgery, Niigata University Medical and Dental Sciences, Niigata, JAPAN.
Specialization: Orthopedic Surgery,
FOP is a rare disease so basically relevant to be published. Why is it worth reporting for the authors? Is the case too young age? You should mention about that.
If possible, I would like to observe (know) the histopathological findings for resected ectopic ossification or femoral head.
Range of motion of right hip; How was that? I think exact degree of each range of motion should be described.
You need exact each range of motion about the restricted side of shoulder joint.
3) You need exact data about scoliosis such as Cobb angle.
4) Exact range of motion of cervical region is also required.
5) Laboratory findings. What abut bone metabolism markers such as BAP, P1NP, TRACP-5b, and NTx, etc.? If possible, the authors should demonstrate.
You should point out or speculate the main findings to suspect FOP. You should mention that how long it took for the diagnosis of FOP in the present case.
Figure1; You should describe this X-ray. Hemiarthroplasty, why wirings were applied around proximal femur. I think that you also show AP- view of hip joint.
Figure2; Is it really right shoulder? I think left shoulder. Please check and modify if needed. You also should describe the exact location of heterotopic ossification.
Figure 3; Does this patient have cervical myelopathy? Also I think that subcutaneous of occipital area is also HO. Does this patient have swallowing disability?
Moderate revision is required.
PS: Readers are requested to not to use this article for your research purposes as this is still in pending status.