Fibrodysplasia ossificans progressiva

ARTICLE

Auteur(s) : Maria BLASZCZYK, Slavomir MAJEWSKI*, Ligia BRZEZINSKA-WCISLO, Stefania JABLONSKA

Department of Dermatology and Venerology, Warsaw School of Medicine, 02-008 Warsaw, Koszykowa 82a str., Poland. 
*Silezian Academy of Medicine, Katowice, Poland

Article accepted on 14/2/2003

Fibrodysplasia ossificans progressiva (FOP) is a very rare, genetic, severely disabling disease. A characteristic feature is aggressive fibroblast proliferation and extensive inflammatory infiltrates in the subcutaneous tissue, tendons, ligaments, fascias and muscles, leading to heterotopic bone formation. 
This rare disease raised an enormous interest since it is believed that understanding of the genetic mechanism of mature bone formation may be a clue both to the regeneration of bones and the prevention of heterotopic ossification [1-3]. 
The majority of cases are sporadic, occur mainly in Caucasians [4-5], are autosomal dominant with complete penetration but variable expressivity of the gene [6, 7]. The disease is characterized by recurrent painful episodes of soft tissue swelling leading to heterotopic mineralization and true bone tissue formation (ossification) [5]. Characteristic of the disease is a variety of congenital skeletal abnormalities of the hands and feet, especially hallux valgus deformity, sometimes with microdactyly, synostosis and hypoplasia of phalanges. These anomalies, if present at birth, facilitate the diagnosis of FOP, even before the onset of the first symptoms of soft tissue swelling, preceding clinical and radiological signs of ossification [2].
In most cases swelling of soft tissues starts in the first decade of life, not infrequently after a mild trauma. Within weeks or months, painful and tender indurations (present as subcutaneous tumors) become gradually ossified and transform into heterotopic bone tissue. Most frequently involved are the paraspinal muscles of the back and of the limb girdles, although all muscles, aponeuroses, fascias, tendons and ligaments could be affected by calcification and ossification [8]. The progressive course of FOP with variable periods of the disease quiescence leads to several complications, including torticollis (involvement of sternocleidomastoid muscles), with contractures of muscles and deformity of the neck and thorax, scoliosis and joint immobilization due to periarticular ossification. Soft tissue swelling may be accompanied by fever, mistakenly suggestive of infectious origin. In some patients with FOP, deafness, alopecia and secondary amenorrhea were reported [2]. 

We describe two typical cases of FOP, one of them misdiagnosed as osteosarcoma (a not infrequent histological error), and the second categorized initially as scleredema Buschke. We discuss the course and therapeutic modalities which proved to be of some benefit in our patients.

Case 1

A girl, presently 18-year-old, has been under our care since the age of 12 years.
Her parents are healthy, non related. She had one brother 17-year-old, healthy. At the age of 4 yrs she developed, allegedly not after trauma, a soft tissue swelling followed by impairment of movement. At the age of 11 yrs, after trauma, in the scapular area a painful and rubbery-soft tissue tumor appeared, which was excised. Histologic diagnosis by an experienced general pathologist was sarcomatous myxofibroma. She was treated with 6 courses of cytostatics, however the condition deteriorated due to steadily developing new heterotopic ossifications.
On the trunk and extremities, and especially in the scapular area, there were widespread tender subcutaneous indurations. A hard tumor progressively developed resulting in thorax deformity and torticollis (Fig. 1). She had typical hallux valgus since birth (Fig. 2).
The histologic examination showed a pronounced proliferation of fibroblasts replacing muscle fibres in several areas (Fig. 3). Focally fibroblasts showed some abnormal morphology, however with no sarcomatous atypia. Mononuclear infiltrates were moderate within muscle, and abundant in the subcutaneous connective tissue.
Laboratory tests: X-ray examination, bone scintigraphy and densitometry disclosed heterotopic bone formation within soft tissue, primarily with no evident changes in the skeletal system. Of the abnormal findings there were only increased serum levels of phosphates (6.0 mEq/1) and alkaline phosphatase (889 IU), and increased Ca/P ratio. Other blood tests (serology, biochemistry, immunology), parathyroid study and all other function tests were normal.

Treatment

Prednisone in moderate doses and antibiotics were ineffective. Interferon gamma (800 000 – 1 000 000 U, 3 times a week, for six months) produced softening of the skin and regression of subcutaneous indurations, with no effect on the heterotopic bone formation. For 26 months she was treated p.o. with biphosphonate (Benefos 400 mg/day), which induced a remarkable decrease in alkaline phosphatase and slight decrease in the rate of new heterotopic bone formation, however the old osseous changes remained, with partial immobilization of the knees, hips and shoulder girdles. The surgery of the hip and a knee was unsuccessful. The general condition remained satisfactory, however the patient was partly immobilized.

Case 2

A 16-year-old girl was admitted to our Department with a preliminary diagnosis of scleredema Buschke. At the age of 12 years she developed symmetrical hardening of subcutaneous tissues along the sternocleidomostoid muscles (Fig. 4). She was treated with antibiotics and corticosteroids, with no effect. At the time we saw her, 6 months after the onset of the disease, the main clinical finding was immobility of the neck due to symmetrical stony-hard sternocleidomastoid induration, later developed hardening of the thorax and shoulder-girdle and stony-hard tumors as in case 1. Her general condition was satisfactory, and the movements of lower extremities and hips were preserved. X-rays disclosed calcification and ossification of affected muscles. Densitometry and calcium-phosphate metabolism, as all other metabolic studies were normal, except for slightly elevated serum level of Vit. D3. There were no neurological, myological and vascular abnormalities.

Histologic examination showed slight dermal fibrosis and pronounced proliferation of fibroblasts accompanied by inflammatory infiltrates in the subcutaneous tissue and muscles, with focal destruction of muscle fibers and fagocytosis. The indurations progressively spread on the arms and upper trunk resulting in limitations of the movements of shoulder girdles, knees and hips.

The girl was treated with prednisone (up to 50 mg daily) and gamma interferon (1 × 10⁶ 3 times weekly, for 3 months), which resulted in regression of the subcutaneous indurations but had no effect on the calcification and bone formation. The application of biphosphonate (Benefos 800 – 400 mg daily, for several months) did not prevent development of new bone formation, however it decreased the rate of appearance of new indurations. The surgery had no beneficial effect on the motion. The general condition did not deteriorate during a 10-year long observation, however the immobilization slowly progressed.

Comment

Our cases had all the characteristic features of FOP with typical pronounced fibroblast proliferation [1, 9] and skeletal abnormalities. This is a basic difference from progressive osseous heteroplasia (POH), also characterized by heterotopic bone formation but involving mainly the dermis. Similarly to FOP, POH is congenital or starts in infancy but, in contrast to FOP, there are no dysmorphic features and the prognosis is usually better [10, 11]. FOP should also be differentiated from Albright’s hereditary osteodystrophy (AHO), i.e. X-linked or autosomal dominant disorder with distinctive cutaneous, endocrinologic, developmental and orthopedic symptoms [12], reported to be due to mutation in the gene encoding the stimulatory G protein of adenylate cyclase. “Platelike osteoma cutis” (POC) differs by the localized character of ossification in the dermis, developing congenitally or in infancy, with no dysmorphic features [13, 14]. Secondary cutaneous ossifications of the skin and subcutaneous tissue, most often post-traumatic, are often referred to as circumscribed or local myositis ossificans [15]. The name is confusing since FOP is sometimes reported under the name of myositis ossificans. However like in FOP, the histologic pattern might also mimic malignant tumor in this localized disease, and such cases were reported as malignant pseudotumors of the soft tissues with ossification [16]. Among all the disorders of ossification, FOP has the poorest prognosis, and patients frequently die in third-fifth decade due to chest wall involvement and pulmonary complications secondary to restricted ventilation [17].
The pathogenesis of FOP is unknown, and although the genetic search is advanced the gene is not yet characterized and the cause of the disease not revealed. The FOP gene was believed to be BMP-4 (bone morphogenetic protein) of TGFβ family [18], overproduced in lymphocytes and lesional skin of the patients. This putative gene was found by some investigators linked to markers mapped to chromosome 4q 27-32 [19, 20], by the others on chromosome 17q22 [21] at the location of the gene of noggin, a powerful antagonist of BMP-4. However further studies failed to detect mutations both in the BMP-4 gene and in the noggin coding region [22, 23]. Inflammatory infiltrates and angiogenesis appear also to play a role in excessive fibroblastic proliferation, and trauma might be an evoking factor [24]. Thus the genetics of FOP appear to be more complex and heterogenous, and a mutation of BMP-4 itself may not be responsible for the disease, but for some factors interacting with the BPM-4 pathway [23], possibly a gene encoding inhibitor of BMP-4, however different from nogging.
No established treatment for FOP is available, and corticosteroids, i.v infusions of EDTA, binders of dietary calcium, seem to be only marginally effective. In our case 1 we initially used IFN gamma, which is known to decrease proliferation and metabolism of fibroblasts. In FOP, a decrease of fibroblast activity leads to inhibition of their invasion into the muscle tissue. Administration of INF gamma for 6 months resulted in regression or decrease of subcutaneous indurations, and this supports an important role of fibroblasts in the pathogenesis of early stages of the disease. However, this treatment had only slight or moderate effect on bone formation. The use for almost 3 years of biphosphonate was found to produce improvement of mobility, normalization of deranged calcium/phosphate metabolism and a decrease in alkaline phosphatase levels. Most importantly, the bone formation process became considerably slower and less pronounced, and the general condition of the patients remained satisfactory with a slower rate of progressing disability.n

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