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PubMed1999

Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder that is characterized by progressive heterotopic ossification of soft tissues and congenital malformation of the great toes. Although previous case studies have reported hearing loss in individuals with FOP, there have been no large-scale studies regarding the nature or cause of the hearing loss. Here, we report the findings of a two-part study. In Part I, we report the findings of a postal survey regarding hearing loss that was sent to 102 individuals with FOP. In Part II, we report the findings of on-site hearing evaluations of eight individuals with FOP. The findings of both studies indicate that individuals with FOP are at risk for hearing loss and that the type of loss is predominantly conductive in nature, similar to that seen in individuals who have otosclerosis.

Adolescent↗

PubMed2001

Fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder of connective tissue. The condition is characterized by congenital malformation of the great toes and by progressive heterotopic ossification of the tendons, ligaments, fasciae, and striated muscles. Fibrodysplasia ossificans progressiva occurs sporadically and is transmitted as a dominant trait with variable expression and complete penetrance. Reproductive fitness is low. There are fewer than 150 known patients with the disorder in the United States. A point prevalence of one affected patient in every 2 million of population has been observed. There is no sexual, racial, or ethnic predilection. The disease presents in early life; its course is unavoidably progressive. Most patients are confined to a wheelchair by the third decade of life and often succumb to pulmonary complications in the 5th/6th decade of life. At present there is no effective prevention or treatment. 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. The FOP gene has recently been mapped to human chromosome 4q 27-31.

Adolescent↗

PubMed2000

Fibrodysplasia ossificans progressiva: case report.

Fibrodysplasia ossificans progressiva is a rare genetic disease characterized by widespread soft tissue ossification and congenital stigmata of the extremities. We report on a male child followed for ten years since the age of 3 years and 9 months, when the diagnosis was made. He was born with bilateral hypoplasic hallux valgus and ventricular septal defect, corrected by trans-sternal approach when 32 months old. Restriction of neck mobility followed and foci of ectopic ossification appeared. Four crises of disease exacerbation were treated with oral prednisone and/or other antiinflammatory drugs. Sodium etidronate 5 to 10 mg/kg/day was prescribed intermittently during about six years but was discontinued due to osteopenia. The disease course has been relentless, with severe movement restriction including the chest wall. A review showed few similar case reports in the Brazilian literature. We revisit the criteria for diagnosis and the essentials of management and treatment.

Adolescent↗

PubMed1995

Ultrastructural finding of vascular degeneration in fibrodysplasia ossificans progressiva (FOP).

The masseter and temporalis muscles were investigated ultrastructurally in 2 patients having fibrodysplasia ossificans progressiva (FOP). Results showed atrophy and necrosis of muscle fibres. Both cases contained cartilage which was calcified in the second case and was associated with degenerating chondrocytes. The blood vessels showed various changes, with haematoma formation and large fibrin deposits. Some of the fibrin deposits seen in the second case were surrounded with cartilage. This suggests that the cartilage probably forms as a reaction to an old haemorrhage. It is possible that the effect of the mutant gene found in FOP is on blood vessels rather than the normal regulatory mechanisms of the inducible osteogenic precursor cells. These degenerating blood vessels often result in haemorrhage and fibrin deposits; the fibrosis, cartilage or bone formation are probably secondary changes. Amianthoid fibres found in the tendon of the temporalis muscles of the second case, together with the other changes of fibrosis and cartilage formation, account for the severe restricted mouth opening suffered by these patients.

Adolescent↗

PubMed1996

Submandibular swelling in patients with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossifcans progressive (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of soft tissues. Although ankylosis of the temporomandibular joint occurs commonly in the late stages of the disease, only one well-documented case of submandibular heterotopic ossification in a patient who had FOP exists. Twelve (11 %) of our 107 patients who have FOP had submandibular heterotopic ossification that was mistaken initially in seven of the patients for mumps, angioneurotic edema, abscess, mononucleosis, or neoplasm. Two male patients and 40 female patients ranging in age from 6 to 47 years (mean, 21 years) were studied. Ten patients survived following assiduous precautionary measures. One patient who required emergency tracheostomy and ventilatory support also survived. Another patient died of inanition from chronic swallowing difficulty. An effective treatment program includes early identification of the submandibular flare-up, nutritional support, and glucocorticoid therapy. Submandibular swelling in patients who have FOP can be a medical emergency and requires intensive precautionary measures to avoid catastrophic clinical deterioration. These measures include avoidance of lesional manipulation, airway monitoring, and aspiration precautions. Submandibular swelling should be recognized as a variable feature of FOP.

Adolescent↗

PubMed2000

Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31.

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein-signaling pathway.

Chromosome Mapping↗

PubMed2004

Consideration of Rituximab for fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a severe, progressive disease of the musculoskeletal system. Muscles, tendons and other connective tissues ossify after minor trauma, and patients often become encased in a second immobile skeleton. There is no known cure or treatment for FOP. It has been found that lymphocytes from FOP patients elaborate excess levels of bone morphogenic protein-4 (BMP-4). Given this, it has been suggested that allogenic bone marrow transplantation (BMT) possibly could be a cure for FOP, and drawn attention to a previously unappreciated case of an FOP patient who had successful BMT for aplastic anemia with apparent short- and medium-term arresting of the FOP disease process. However, BMT has non-trivial associated morbidity and mortality. Here, it is noted that if B cells are found to be the lymphocytes responsible for excess BMP-4 production in FOP, use of Rituximab, a monoclonal anti-CD20 antibody which effectively targets B cells, could be a less permanent and less risky treatment alternative for FOP.

Antibodies, Monoclonal↗

PubMed1993

Differential diagnosis between fibrodysplasia ossificans progressiva and childhood dermatomyositis with calcinosis.

Both fibrodysplasia ossificans progressiva (FOP) and childhood dermatomyositis with calcinosis are rare diseases, and present with ossifying or calcifying processes. Six cases of FOP and one case of childhood dermatomyositis with calcinosis are studied. All six FOP patients had the typical digital anomalies and the characteristic ectopic bone formation starting from the trunk. Calcification in the case of childhood dermatomyositis occurred in the limbs. A carefully differentiated diagnosis between these two diseases is needed, because they share common clinical and radiologic features, but require different management. Delay in the diagnosis of FOP is common, although early recognition of FOP prevents a child from accidental or iatrogenic injury, which can precipitate ectopic ossification. Surgical removal of the ectopic bone or release of the contracture in three FOP patients was followed by rapid recurrence. Entrapment neuropathy and a mild myopathic pattern in two FOP patients, who underwent nerve conduction and electromyographic studies, were secondary to ectopic bone formation. One FOP patient received a computed tomography examination which showed basal ganglia calcification. No coexistence of FOP and childhood dermatomyositis with calcinosis was found.

Adolescent↗

PubMed2005

A new mutation of the noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family.

A new mutation of the Noggin gene in a French Fybrodysplasia ossificans progressiva (FOP) family: Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of the muscles. We previously located a FOP gene in the 17q21-22 region and described several mutations of the noggin (NOG) gene (located in 17q22) in four FOP patients, including the G91C mutation which is transmitted dominantly in a Spanish FOP family. We describe in the present study a new mutation of the NOG gene in a French FOP family. This new mutation is a guanine to adenine change at nucleotide 283 (283G --> A) of the NOG gene, and is transmitted in the family (in the heterozygote form) by the affected mother to her two affected children. At the peptide level this mutation (A95T) substitutes an Alanine residue by a Threonine at position 95 of the Noggin protein. The Alanine mutated residue is located just adjacent to the myristoylation site of the protein, where all the mutations we described until now are located.

Adenosine↗

PubMed2003

Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa-1: clues to a vascular origin of heterotopic ossification?

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable genetic disorder, which is characterized pathologically by sporadic episodes of explosive growth of mesenchymal cells in skeletal muscle followed by cellular differentiation to heterotopic bone through an endochondral process. This study examined the histological origin and differentiation state of stromal cells in early FOP lesions and investigated the association between the phenotype of these FOP cells and bone formation. Interestingly, FOP lesional stromal cells were found to display characteristics of the smooth muscle (SM) cell lineage and are therefore potentially of vascular origin. These cells co-express multiple SM lineage markers along with multiple proteins associated with bone formation including the obligate osteogenic transcription factor Runx2/Cbfa-1. It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway.

Biopsy↗

PubMed1999

Mobility challenges and solutions for fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive soft tissue ossification. Although signs may be present at birth, the first appearance of ectopic bone typically occurs in early childhood. The primary target is the axial musculature. Eventually ectopic bone also occurs in ligaments, fascia, aponeurosis, tendons, and joint capsules of the appendicular skeleton with a proximal to distal predilection. As the disease advances, mobility becomes restricted, and affected individuals are typically limited to bed or chair by their early 30s. This report describes a 30-year-old woman with advanced FOP. She had a fused spine and a fixed pelvis, with hips and knees locked in flexion and feet in plantarflexion. Her upper limb mobility was similarly restricted. She was not able to stand upright or sit independently. The modification of a commercially available power wheelchair that allowed the patient to maintain her employment as a preschool teacher and custom shoes are described. Creative physiatric intervention is essential to liberate human potential for people with FOP.

Activities of Daily Living↗

PubMed2001

Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva.

We report noggin mutations in three Spanish families with fibrodysplasia ossificans progressiva (FOP). The three propositi have typical FOP findings; in the first and third families the parents are unaffected, while in the second family the father is partially affected. DNA of the three propositi and their parents was screened by sequencing for mutations in the noggin gene (NOG). Sequencing indicated a G to C mutation at nucleotide 274 of the NOG gene in the first propositus, encoding for the G92R substitution at the peptide level; this first mutation is de novo, the corresponding change not being observed in parents. In the second propositus, a G to T mutation at nucleotide 271 encodes for the G91C substitution, transmitted in the corresponding family by the partially affected father. In the third propositus, sequencing indicated a G to A mutation at nucleotide 275, encoding for the G92E substitution; this third mutation is de novo. All three mutations, as well as the Delta42 deletion already reported, resulted in the alteration of the portion of the NOG gene at positions 265-282, encoding for the potential N-myristoylation site at residues 89-GGGGGA-94.

Binding Sites↗

PubMed2004

Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary connective tissue disease characterized by progressive postnatal heterotopic bone formation. Although the genetic defects of FOP are not known, several lines of evidence have suggested that bone morphogenetic protein-4 (BMP4) may be involved in the pathophysiology. Nevertheless BMP4-transgenic mice have previously failed to develop the disorder and there has been no good animal model of the disease. Here, we report that a unique transgenic mouse line that overexpresses BMP4 under control of the neuron-specific enolase (NSE) promoter develops a FOP-like phenotype. Mating of these animals with transgenic animals that overexpress the BMP inhibitor noggin prevents the disorder, confirming the role of BMP4 in the pathogenesis of the disease. Heterotopic bone formation in these animals appears to follow the classic endochondral ossification pathway. Sex-mismatched cell transplantation experiments indicate that multiple cell sources contribute to the heterotopic ossification. This remarkable animal model provides a unique opportunity to further study the role of the BMP signaling pathway in heterotopic ossification and to improve our understanding of the clinical aspects of FOP.

Animals↗

PubMed1982

The radiological spectrum of fibrodysplasia ossificans progressiva.

The radiographic manifestations of nine South African patients with fibrodysplasia ossificans progressiva (FOP) have been analysed in detail. In three of these individuals, a 10--15 year follow-up was available. The condition usually presents before the age of 5 years; in one infant, abnormal calcification was demonstrated at 9 months. The disorder is remorselessly progressive but the hands, diaphragm and viscera are spared. Ossification in ligaments at the site of their attachment to long bones produces a 'pseudo-exostosis' appearance. Tethering of the shafts of long bones and growth at the proximal metaphyses can result in dislocation of shoulder and hip joints. In the hip joint the sloping configuration of the acetabular roof is produced by normal growth at the proximal metaphyseal end of the tethered femur. Calcification in periarticular tissues, together with bony and fibrous ankylosis, contributed to joint fixation. A similar process of growth inhibition leads to disparity in size between the bodies of the cervical vertebrae and their posterior appendages. It is concluded that apart from the developmental abnormality in the great toes, the skeletal changes in FOP are the consequence of soft tissue ossification and that the condition is not a primary bone dysplasia.

Arthrography↗

PubMed1977

Studies on alkaline phosphatase activity cultured cells from a patient with fibrodysplasia ossificans progressiva.

The cytoplasm of tumor cells from a subdermal nodule in a patient with fibrodysplasia ossificans progressiva (FOP) exhibited intense enzymatic activity in cryostat sections processed for demonstration of alkaline phosphatase. Nuclear heterochromatin and nucleoli, particularly in the area of the dense component, also showed strong reactivity. Finely minced blocks from the lesion of the patient with FOP revealed lighter reactivity which, in the tumor cells, avoided membrane limited spaces and appeared to be confined to hyaloplasm. Extracellular spaces disclosed very little or no reactivity and specimens from the patient's uninvolved skin lacked staining. The tumor cells from the subdermal nodule did not exhibit increased acid phosphatase activity. Cells (L-FOP) derived from a subdermal nodule and grown by tissue culture techniques also synthesized large amounts of prostaglandin E-like material and alkaline phosphatase. The amounts of prostaglandin E-like material synthesized by these L-FOP cells was reduced by more than 31 per cent by the antiinflammatory drugs indomethacin and sodium meclofenmate. Also, the production of alkaline phosphatase by these L-FOP cells was reduced by more than 40 per cent by ethane-1-hydroxyl-1,1-diphosphonate. Addition of prostaglandin E to nonlesion cells did not result in increased alkaline phosphatase activity.

Alkaline Phosphatase↗

PubMedDate not supplied

Fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva, a rare genetic disabling disease characterized by heterotopic bone formation, is of special interest for general medicine since the bone morphogenetic proteins (especially BMP-4) involved in its pathogenesis are known to play a role in skeletal morphogenesis, and the gene antagonist to BMP-4 noggin might be useful in preventing lamellar bone formation. We present two cases with characteristic musculo-skeletal abnormalities and histopathological features (inflammatory infiltrates which destroyed muscle tissue replacing it by proliferating fibroblasts). In one patient due to high activity of fibroblasts, the histopathologic pattern appeared to be atypical and the lesion was recognized by a general pathologist as sarcoma. The other patient, due to the symmetrical induration of sternocleidomastoid muscles, was primarily recognized as scleredema. We stress the diagnostic importance of skeletal abnormalities (hallux valgus and others), and discuss differentiation from progressive osseous heteroplasia (POH) and congenital or acquired localized cutaneous and muscle ossifications which have a much better prognosis, as well as Albright's hereditary osteodystrophy, which differs by the presence of various systemic abnormalities. A study of FOP might provide an important clue to the genetic molecular mechanism of bone formation, development of heterotopic bone and a possible prevention by molecular manipulation with the gene responsible for bone morphogenetic proteins and their antagonists.

Adolescent↗

PubMed1998

Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a rare genetic disease characterized by heterotopic ossification in soft tissues. Severe disability results from progressive immobilization of the limbs, jaw, and chest wall. To determine whether cardiac function is altered in this disease, 25 patients ranging in age from 5 to 55 years (disease duration 1-51 years) were studied. History, physical examination, pulmonary functions, electrocardiography, and echocardiography were performed on each patient. Physical examination of the lungs and heart was unrevealing; no right sided ventricular gallops were heard, and no patient was found to have neck vein distention or peripheral edema. The patients had extremely limited chest expansion (1.9 +/- 0.8 inches), suggesting dependence on diaphragmatic breathing. Lung volumes were severely reduced (mean forced vital capacity 44% +/- 14% of predicted), but flow rates were relatively normal. All patients had normal capillary oxygen saturation. Echocardiography was technically difficult, but no abnormalities of left or right ventricular function were seen. Ten (40%) patients had electrocardiographic evidence of right ventricular dysfunction. Compared with patients without such evidence, these patients were older, had significantly longer disease duration, higher hemoglobin, and more impaired pulmonary function. The results of this study suggest that the presence of severely restrictive chest wall disease is associated with a high incidence of right ventricular abnormalities on electrocardiogram. Whether cor pulmonale will eventually occur remains to be determined.

Adolescent↗

PubMed2003

The spine in fibrodysplasia ossificans progressiva: a case report.

STUDY DESIGN: A case report of fibrodysplasia ossificans progressiva (FOP). OBJECTIVES: To report a very rare cause of back pain. SUMMARY OF BACKGROUND DATA: FOP is an autosomal dominant disorder with overexpression of bone morphogenetic protein 4 and negative HLA B27. Pathognomonic are congenital malformations of the big toes. METHODS: The authors report on a patient with FOP who presented with back pain at their outpatient clinic. RESULTS: On physical examination, several indurated masses were visible and palpable close to the left and right scapula and the thoracic spine. These were not tender or painful, nor warmed or inflamed. A significantly decreased range of motion of all levels of the spine and the shoulder were found. On the radiographs, segmentation defects of the cervical and lumbar spine as well as synostoses of the spinal processes were seen. The cervical vertebral bodies were small and unusually high. Heterotopic ossifications could be discerned in the lumbar postural muscles and the facet joints of the spine were ankylosed. Additionally to these findings, on the thoracic radiographs ossifications of the muscles of the shoulder girdle could be seen. The pathognomonic shortening of the first metatarsal bone and the proximal phalanx was bilaterally present. The surface shaded 3D-reconstruction of the computed tomography of the trunk showed multiple bulky and confluating ossifications of the shoulder girdle. The spinal processes of the thoracic spine were anklyosed by massive ossifications of the postural muscles. CONCLUSIONS: In FOP, diagnosis can be made by the typical clinical and radiological features.

Adolescent↗