The Histopathology of Fibrodysplasia Ossificans Progressiva

In order to better characterize the biological features of fibrodysplasia ossificans progressiva, we reviewed the histopathological specimens from eleven patients (twelve biopsies) who had a confirmed diagnosis of the disease. All of the biopsies had been performed in children, to exclude the diagnosis of a malignant lesion. In no instance was the diagnosis of fibrodysplasia ossificans progressiva considered before the biopsy. The results of a lesional biopsy in all eleven patients revealed normal endochondral osteogenesis at heterotopic sites. The results of biopsy of an early lesion in six children were misinterpreted as revealing a diagnosis of fibromatosis or sarcoma before the roentgenographic appearance of ossification. Immunohistochemical studies of sections of the earliest lesion demonstrated S-100 antigen positivity before the histological appearance of differentiated osteochondral tissue. The presence of congenital malformation of the great toes and of postnatal heterotopic endochondral osteogenesis strongly suggests that fibrodysplasia ossificans progressiva is a disorder of defective induction of endochondral osteogenesis. This study established the predominant histopathological findings associated with fibrodysplasia ossificans progressiva and can serve as a basis for postulation of a candidate gene in the pathogenesis of the disorder. A lesional biopsy is not needed to make the diagnosis; biopsy uniformly exacerbates the condition and should be avoided. Fibrodysplasia ossificans progressiva is an extremely rare disorder of connective-tissue differentiation that *No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were grants from the Hartford Foundation and the International Fibrodysplasia Ossificans Progressiva Association. tDepartment of Orthopaedic Surgery. Hospital of the University of Pennsylvania. Silverstein Two, 34(X) Spruce Street. Philadelphia, Pennsylvania 191()4. t1)epartment of Pathology. Jefferson University School of Mcdicine, Walnut Street. Philadelphia. Pennsylvania 19107. §Division of Human Genetics and Molecular Biology. Children s Hospital of Philadelphia. 34th and Civic Center Boulevard. Philadelphia. Pennsylvania 191(14. is characterized by congenital malformation of the great toes and by progressive hetenotopic ossification of the tendons, ligaments, fasciae, and skeletal muscle67’2’8’9 27.2 3O.3 .42 Hetenotopic ossification typically appears in the first decade of life, often beginning as painful, erythematous, subfascial nodules in the posterior portion of the neck and in the back77. Individual nodules may regress, or they may progress to form mature heterotopic bone. Progression of a lesion at any site appears to follow an atypical course. During the first few weeks (the early lesion), there is pain, erythema, swelling, warmth, and tenderness. After several weeks (the intermediate lesion), the swelling begins to subside. There is a decrease in the pain, enythema, and tenderness, but an increase in induration. After approximately twelve weeks (the late lesion), the swelling disappears, and the patient is left with a hard, non-tender lesion that is visible noentgenographically as a new area of ossification. Severe disability develops secondary to extra-articular ankylosis of the major dianthrodial joints924. Fibrodysplasia ossificans progressiva is presumably transmitted as an autosomal dominant defect67’7’8 62742, but affected individuals rarely reproduce35. The diagnosis can be made on the basis of congenital anomalies of the great toes and progressive ossification of soft tissue727. The pathogenesis of fibrodysplasia ossificans progressiva is unknown. Clinical tests have failed to demonstrate enzymatic or metabolic abnormalities, with the exception of mild, transient elevations in levels of serum alkaline phosphatase during new episodes of heterotopic ossification’4. There have been few histological studies of this disorder, and they have yielded inconsistent findings. Histological analyses of early lesions have shown a sequence of degeneration of skeletal muscle, dysplasia of fibrous tissue, and subsequent ossification, although the mechanisms of ossification have remained obscure’4’8 227. The ossification has previously been described as intramembranous on endochondral, or both5”’’4’92#{176}2728 3. However, many of these reports have included the cases of patients who had non-progressive and non-heritable forms of hetenotopic ossification. We undertook the current histopathological study in an attempt to clarify the process of ossification in this disease. Figs. 1-A and 1-B: Case 6. Photographs of a four-year-old girl who had characteristic findings of fibrodysp asia ossificans progressiva on the back. Fig. I -A: Posterior view showing multiple large soft-tissue nodules on the back and a fixed. flexed resting position of the neck. Fig. I-B: The nodules on the back are also seen on the lateral view. VOL. 75.A, NO. 2. FEBRUARY 1993 THE HISTOPATHOLOGY OF FIBRODYSPLASIA OSSIFICANS PROGRESSIVA 221 DATA ON iIIF E1.I vI N TABLE I PATIENTS FROM WII0M BIOPSY SPECIMENS OF THE LEsION WERE OBTAINED* Case Sex, Age at Biopsy (Yr.s ) Site of Biopsy Diagnosis after Biopsyt Age at Diagnosis (Yrs.) Diagnostic Criteria for FOPt Type of Ossification Congenital Progressive Malformation Heterotopic of Great Toes Ossification EndoIntrachondral membranous I F. 2 Back Sarcoma 4 + + + 2 F. 3 Back Sarcoma 4 + + + 3 F. 9 Leg Osteochondroma 12 + + + + 4 F. 4 Back FOP 4 + + + 5 6 M, 2 F. 2 Thigh Back Fibromatosis Sarcoma 3 4 + +