A Severely Disabling Disorder: Fibrodysplasia Ossificans Progressiva

Clin Rheumatol (2001) 20:273–275 ß 2001 Clinical Rheumatology

Clinical Rheumatology

Case Report A Severely Disabling Disorder: Fibrodysplasia Ossificans Progressiva H. Kocyigit1, N. Hizli1, A. Memis2, D. Sabah2 and A. Memis1 1˙

Izmir Atatu¨rk Training Hospital; 2Ege School of Medicine, I˙zmir, Turkey

Abstract: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare hereditary disorder characterised by progressive heterotopic ossification of the soft tissues. The resulting progressive immobilisation of the limbs, jaw and chest wall generally leads to severe disability. We present an 18-year-old girl with advanced FOP. She had three operative interventions to excise her ectopic bones but all resulted in failure. Treatment strategies for this disorder should include the avoidance of exacerbating factors.

Ossification around the hips may prevent ambulation. Nutrition may be impaired owing to severe involvement of the muscles of mastication. Baldness and deafness are occasional features. This disorder was first described more than 300 years ago; more than 600 cases have been reported worldwide [1,2], and at present there is no effective prevention or treatment for this catastrophic disease. We present an 18-year-old white girl with advanced FOP.

Keywords: Disease progression; Myositis ossificans; Ossification, heterotopic

Case Report

Introduction Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disorder of connective tissue characterised by congenital malformation of the great toes and by progressive postnatal heterotopic ossification of muscle, tendon, ligament and fascia. Typically, heterotopic ossification appears within the first decade of life and manifests as painful subcutaneous lumps, followed 4–6 months later by radiological evidence of ossification. Progressive episodes of heterotopic ossification result in bony masses. The main sites for these lesions are over the spine, the shoulder joints and the jaw, but they can also occur elsewhere. Gradually, these bone masses immobilise the major joints of the axial and appendicular skeleton, ultimately restricting mobility [1,2]. Involvement of the spine generally leads to complete fusion, mimicking ankylosing spondylitis [3]. Correspondence and offprint requests to: Dr Hikmet Kocyigit, 1408 Sokak No:2/4, Alsancak, 35220 Izmir, Turkey. Tel: +.90.542.5923515; Fax: +.90.232.4616586; E-mail: [email protected]

The patient’s history began at the age of 6 years, when she developed a painful subcutaneous lump in the dorsal paraspinal region. At the age of 7 she had undergone an operation to excise this undiagnosed lump. Within 4 months a new mass appeared at the operation site. She seemed to have a period of disease quiescence between ages 8 and 15. However, between ages 15 and 17 several painful, tender and rubbery masses also appeared at various sites. As these masses ossified, they immobilised her joints. During this period she had two more operations to restore the decreased range of motion in her jaw and right elbow, but only temporary benefit had been gained. As her disease progressed she became dependent and required maximum assistance for nearly all activities of daily living. She complained of a moderate hearing loss and alopecia. She had regular menstrual cycles with hypomenorrhoea. Family history was negative for fibrodysplasia ossificans progressiva. On musculoskeletal examination her entire spine was fused, with bilateral atrophy of the paraspinal muscles. She had a right-sided C-shaped thoracolumbar scoliosis. Both shoulders and the right elbow were fixed. The right mid-arm was firm and non-tender. There was a moderate restriction of the movement of the left elbow and right wrist. Her gait was slow and effortful. She was unable to

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sit because her hips could only flex to 15º on the right and 55º on the left. She had also severe limitation in knee and ankle mobility. The range of motion of the other joints in the upper and lower extremities was normal. Chest expansion and jaw movement were extremely limited. Bilateral malformed big toes were observed. Her intelligence and the physical examinations related to the other systems were normal. Her laboratory tests, including CBC, ESR, chemistries, liver transaminases, electrolytes, urinalysis, rheumatoid factor, CRP, ANA and anti-dsDNA, were all within normal limits. HLA-B27 was negative. The 24-h urine calcium, phosphorus, sodium, potassium and chloride values were also normal. An AP chest radiograph revealed mature ossification of the overlying soft tissues, both on the lateral chest wall and on the axillary region bilaterally (Fig. 1). A lateral view of the cervical spine revealed ossification of the ligamentum nuchae and interspinous ligaments between the occiput and the upper back. Radiography of the right elbow showed an ectopic bone formation extending from the volar side of the humerus to the forearm proximally (Fig. 2). A pelvis radiograph showed the soft tissue ossification in linear formation, particularly on the right side (Fig. 3). On radiography of the feet

H. Kocyigit et al.

Fig. 3. AP pelvic radiograph showing the ossification of the soft tissues in linear formation.

Fig. 4. Radiograph of the feet reveals the bipartite-shaped proximal phalanx of the great toe and hallux valgus.

Fig. 1. Chest radiograph demonstrating mature ossification of the overlying soft tissues on the lateral chest wall and axillary region.

the proximal phalanx of the great toe was seen to be bipartite in shape, owing to malformation, along with hallux valgus bilaterally (Fig. 4). Bone scintigraphy revealed multiple foci of increased uptake around the maxilla, left parasternal regions, multiple ribs anteriorly and posteriorly, lumbar spine, bilateral sacroiliac joints, right elbow, right femur, knees and ankles. A cranial CT scan demonstrated ossifications and calcifications in the muscles of mastication and the surrounding soft tissues. Audiography revealed a moderate mixed-type hearing loss of which the conductive component was dominant. We used no medications because she seemed to be in a period of disease quiescence for the last 8 months. Only customised shoes with heel lifts were prescribed to aid her ambulation. A regular follow-up was recommended.

Discussion Fig. 2. Radiograph of the right elbow shows an ectopic bone extending from humerus to forearm.

Fibrodysplasia ossificans progressiva is an extremely rare hereditary disorder that is transmitted as an autosomal dominant [4], occurring in 1 in 2 million

Fibrodysplasia Ossificans Progressiva

persons [2]. The FOP gene [5] was localised to a small region on the long arm of chromosome 4. The diagnosis of FOP is clinical. Despite the unique clinical features, afflicted patients are frequently misdiagnosed in childhood. The mean delay to reaching the correct diagnosis after the onset of ectopic ossification was found to be about 3 years (range 0–14 years) in different series [2,6]. Some of the early symptoms of this disorder may be joint stiffness and arthritis-like pain. Therefore, rheumatologists should be vigilant for FOP in patients who present with similar symptoms. The case described here showed the characteristic clinical and radiographic features of the disorder and was consistent with the previous reports. One of the important clues to the diagnosis is the presence of malformation of the big toe, which occurs in more than 95 % of cases of FOP. It has also been reported that mild forms of the disease exist, and normal great toes were encountered one such mild case [7]. Connor and Evans [6] described four subtypes of malformation of the big toes. As our patient had short big toes, each possessing two phalanges, her findings were mostly consistent with the features of type II toe malformations described by these authors. There is no established treatment for this disorder. Corticosteroids, non-steroidal anti-inflammatory agents, etidronate, warfarin, radiotherapy and surgery have been used, but none were effective [1,2,8]. Recent studies have demonstrated the expression of bone morphogenetic protein 4 (BMP 4) in immortalised lymphoblastoid cells from patients with FOP [9,10]. Moreover, histologic examination of early preosseous fibroproliferative FOP lesions demonstrated highly vascular areas. Kaplan et al. [11] reported that the levels of basic fibroblast growth factor, an extremely potent angiogenic peptide, were variably elevated in the urine of patients with FOP during times of disease flare-ups. On the basis of these data, new therapeutic approaches attract some attention. There are currently several investigational medicines under development, including an antiangiogenic agent and a BMP inhibitor (noggin), but they are not yet in human use (Frederick S. Kaplan, personal communication, 2000). In general, physical therapy is not recommended for patients who have FOP, as stretching of the soft tissues around a joint can lead to a painful flare-up. Joints should never be passively stretched. Active range-ofmotion exercises should be encouraged if the movements are comfortable. Many available adaptations or modifications, such as shoes, canes and wheelchairs, can be prescribed for a disabled patient with FOP to achieve functional independence in the home and community. Briefly, primary therapy for this debilitating disease has been supportive care.

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Although the lifespan of patients with FOP appears to be reduced, most of them may reach adult life. Ectopic ossification can be precipitated by a number of factors, such as biopsy, intramuscular injections, dental therapy, any prolonged pressure on the body (i.e. tight clothing), aggresive physical therapy, falls and injuries. In particular, exacerbation of bone formation in response to surgery and other tissue trauma is common and has been reported [6,12,13]. Therefore, the clinician should be aware of not only the clinical symptoms but also the exacerbating factors of this disorder.

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Received for publication 7 July 2000 Accepted in revised form 20 October 2000