FOP, a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described a woman who "turned to wood," its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has recently been made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of endochondral osteogenesis programme, and the remarkable "clues from the fly" reported by Kaplan et al. in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.

Forty-four patients who had FOP responded by mail to a questionnaire regarding the age at the onset of heterotopic ossification at fifteen commonly involved anatomical sites. The average age of the patients when they responded to the questionnaire was twenty-seven years (range, three to sixty-nine years). The average age at onset of ossification was five years (range, birth to twenty-five years). The most common sites of early heterotopic ossification were the neck, spine, and shoulder girdle. By the age of fifteen years, forty-two (more than 95%) of the patients had severely restricted mobiÄ ty of the upper limbs. In these patients, heterotopic ossification proceeded in a direction that was axial to appendicular, cranial to caudal, and proximal to distal; this pattern appeared typical for FOP.

This article presents a brief review of how FOP affects the body.

Thirty-four patients with FOP are described. Progression of disability was erratic in all, but severe restriction of movement of the shoulder and spine was usual by the age of 10 years; the hips were usually involved by the age of 20 years, and most patients were confined to a chair by the age of 30 years. Exacerbating factors included trauma to the muscles, biopsy of the lumps, operations to excise the ectopic bone, intramuscular injections, careless venepuncture and dental therapy. Progression of disability did not appear to be influenced by any form of medical treatment and therefore management of the patients must concentrate on the avoidance of exacerbating factors.

A family with five persons affected with fibrodysplasia ossificans progressiva (myositis ossificans progressiva) in three generations are described. This is the first well documented three generation family with this condition and provides further evidence for autosomal dominant inheritance. A wide range of phenotypic severity is apparent, from disabling ectopic bone formation and premature death to an asymptomatic adult with characteristic big toe malformation.

Isolated cases of traumatic and pathologic fractures have been reported in the normotopic skeleton of patients with FOP. Now reported are two children with FOP who sustained traumatic fractures of heterotopic bone around the elbows. In both children the fractures healed uneventfully with normal appearing callus. These two extremely rare cases suggest that the biological response to fractures in the heterotopic skeleton appears indistinguishable from that in the normotopic skeleton in patients with FOP.

This article presents a brief review of all forms of heterotopic ossification.

Twelve of 107 patients who have FOP (11%) experienced submandibular (under the jaw/chin area) heterotopic ossification which was mistaken initially in seven of our patients for mumps, angioneurotic edema, abscess, mononucleosis, or neoplasm. An effective treatment program included early identification of submandibular flare-up, avoidance of lesional manipulation, nutritional support, glucocorticosteroid therapy, and measures to avoid airway obstruction. Submandibular swelling is a medical emergency requiring intensive precautionary measures in order to avoid potentially catastrophic clinical complications.

(A similar article was published in Bone and Min. Research.. 9 (Suppl 1), S428, 1994.)

Three unusually mild cases of FOP in an 80 year old man, a 44 year old woman, and a seventeen year old woman are described. The man, whose daughter had classic features of FOP, lacked malformation of the great toes and experienced unusually slow progression of the disease. Both women displayed late onset of heterotopic ossification. The older woman also displayed an unusually slow progression of the disease. All three patients remained ambulatory at the time of examination. Recognition of a mild form of FOP will influence diagnosis, counseling, and research in this rare condition.

Classic features of FOP are observed in 2 native American half-sisters from the same unaffected mother and different unaffected fathers. This is the first report of FOP in siblings from different pregnancies whose parents were unaffected. The findings in this family suggest the occurrence of mate rnal gonadal mosaicism in FOP and provide important new data for genetic counseling in this disease.

This editorial, accompanied by abstracts from the Second International Symposium on FOP, which was held in Philadelphia, PA on October 29-31, 1995, discusses the rare condition of FOP and provides information about ongoing research.

In order to better characterize the biological features of FOP, biopsies from eleven patients were reviewed. The results of biopsy in an early lesion in six children were misinterpreted as revealing a diagnosis of fibromatosis or sarcoma before the appearance of ossification. This study established the predominant histopathological findings associated with FOP 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 worsens the condition and should be avoided.

Genetic transmission of FOP from an affected father to each of his three children is examined. Although an autosomal-dominant genetic transmission has long been suspected, the findings in the family reported on here provide confirmation for such inheritance and a basis for the diagnosis and counseling of patients who have this disease.

Two new cases of severe progressive osseous heteroplasia, as well as the findings at the most recent follow-up of three patients whose cases were reported previously are examined. POH's features justify its consideration as a distinct developmental disorder of heterotopic ossification.

To characterize the radiographic and scintographic features of modeling and remodeling in the heterotopic skeleton of patients who have FOP, radiographs from 47 patients and radionuclide bone scans from 12 of those patients, all of whom had a confirmed diagnosis of the disease, were reviewed. A wide range of normal bone modeling and remodeling features was seen in the heterotopic skeleton of all but the youngest two (age, 1 year) of the 47 patients.

Heterotopic ossification is characterized by the formation of normal bone at ectopic soft tissue locations. Two rare heritable and developmental forms of heterotopic ossification, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, provide valuable clinical and pathogenetic insights into heterotopic ossification in humans. A fundamental understanding of the developmental and molecular pathology of these disorders may lead to more effective strategies for preventing and treating heterotopic ossification in humans.

Twenty-five patients with FOP ranging in age from 5 to 55 tears were studied at an international symposium devoted to the disorder. History, physical examination, pulmonary functions, electrocardiography, and echocardiography were performed on each patient. Physical examination of the lungs and heart was unrevealing. The patients had extremely limited chest expansion, suggesting dependence on diaphragmatic breathing. The lung volumes were extremely reduced, but flow rates were relatively normal. Patients uniformly displayed normal capillary oxygen saturation. Echocardiography was technically difficult, but no abnormalities of left or right ventrical function were seen. Ten patients has electrocardiographic evidence of right ventricular dysfunction. These patients were older, had significantly longer duration since FOP diagnosis, higher hemoglobin, and more impaired pulmonary function.

In patients who have FOP, routine childhood diphtheria-tetanus-pertussis (DTP) immunizations administered by intramuscular injection pose a significant risk of permanent heterotopic ossification at the site of injection while measles-mumps rubella immunizations administered by subcutaneous injection pose no significant risk. Intramuscular injections should be avoided, if possible, once a diagnosis of FOP has been established.

FOP is a rare, inherited disorder with progressive ossification of the connective tissue of muscles and ligaments in association with characteristic skeletal abnormalities. The disease is characterized by a progressively debilitating course involving the respiratory system, the musculoskeletal system and the spinal column. Its systemic manifestations create a challenging situation for anesthetic, medical, and surgical management. We were unable to find any previous description in the literature of general anesthesia with tracheal intubation and the use of muscle relaxants having been administered to a patient with FOP.

Spontaneous ossification of the temporomandibular joint (jaw) occurs late in the course of FOP but has been reported following dental procedures or oral trauma at any age. A postal survey of the sixty patient-members of the International FOP Association was conducted in order to determine the relationship of dental procedures to subsequent ossification and ankylosis (fusing) of the jaw. Injections of local anesthetic injection during dental procedures were found to pose serious and immediate risk for inciting heterotopic ossification and subsequent fusion of the temporomandibular joints in patients who have FOP.

Limb swelling has been noted in people with FOP, yet little is known about this complication of FOP. To determine the prevalence, natural history, and pathogenesis of limb swelling in this condition, the authors reviewed detailed medical records on 74 patients who had a documented history of FOP. Acute swelling of the limbs occurred in association with flare-ups of FOP in nearly all cases. Acute swelling in the upper limbs was focal and more nodular in contrast to acute swelling in the lower limbs, which was more diffuse. Acute swelling in the upper limbs occurred in all 74 patients, while acute swelling in the lower limbs occurred in 47 of the 74 patients (64%).The intense angiogenesis and edema seen on histopathologic evaluation of pre-osseous FOP lesions may play a role in the pathogenesis of limb swelling.

This article provides a case report of a four year old girl with FOP who was admitted to The Children's Hospital of Philadelphia for dental work. The article addresses the management of difficult dental problems where assiduous precautions are needed to prevent untimely heterotopic ossification of the jaw. Guidelines for anesthetic management are included.

FOP is a rare congenital disorder characterized by diffuse ossification of extraskeletal connective tissue. The classical features and progression of the disease are described and three cases are presented which fall into the general pattern of FOP clinically and radiologically. A contstant feature seen was the slight metaphyseal flaring with spiking at the edges of the metaphyses, compatible with minor alteration in bone morphology during growth. These changes cannot be seen after epiphyseal fusion. The major abnormalities persist into adult life.

A child with MOP was treated for 8 years with EHDP 30-40 mg/kg per day. Latterly he complained of severe, progressive bone and joint pain which made standing and walking almost impossible. A radiographic skeletal survey showed diffuse ricket-like lesions. Withdrawal of EHDP therapy produced substantial improvement in his general condition as well as in the radiographic appearance of the bones. Multiple exostoses were observed in this case and particularly those around the knees presented a peculiar morphology. This supports the theory that exostoses originate from a defect of metaphyseal modelling.

Using data from a survey of 44 patients who have FOP, age- and joint-specific risks of new joint involvement were estimated. Regions in which the risk of heterotopic ossification appears to remain constant with age include the neck, spine, shoulders, elbows, and ankles. Regions with apparently increasing risk include the jaw, wrists, hips, and knees. This analysis allows clinicians to estimate the risk of new involvement for any joint at any patient age, as well as the fraction of patients with uninvolved joints at any age. The variation of ossification risk by joint provides a clinically useful guide to the patterns of progression of the disease. Such a guide will help in planning for individual patient needs, as well as anticipating auxiliary social services and rehabilitation programs.

This article summarizes recent research discoveries that were featured in the August 30, 1996 issue ofThe New England Journal of Medicine.

The authors studied lymphopastoid cell lines established from peripheral-blood mononucleaur cells of patients with FOP. Among the bone morphogenetic proteins and mRNAs examined, only BMP 4 and its mRNA were present in increased levels in cells derived from an early fibroliferative lesion in a patient with FOP. BMP-4 mRNA was expressed in the lymphoblastoid cells lines from 26 of 32 patients with FOP but from only 1 in 12 normal subjects.

Roentgenograms and clinical records are reviewed in order to characterize the spinal deformity in forty patients with an established diagnosis of FOP. Twenty six (65%) of the patients had scoliosis, which, according to clinical records and the recollection of the patients, had been present during childhood. A spinal orthosis was used to treat scoliosis in two patients, but this method resulted in the breakdown of the skin and failed to halt progression of the curve. Five patients had operative procedures to correct the scoliosis in the hope of obtaining a balanced fusion of the spine. Five of the procedures either failed to halt progression of the curve or were associated with exacerbation of heterotopic ossification.

Patients with FOP were studied for up to 24 years. All had characteristic short big toes potentially recognizable at birth; there were radiographic changes in the toes, thumbs, cervical spine and metaphyses of the long bones, including exostoses. Ossification in the large skeletal muscles began from birth to 16 years initially in 25 patients in the neck and upper spinal muscles, and later around the hips, major joints, and jaw. The rate and extent of disability was unrelated to the time of onset. There was no evidence that any form of treatment produced consistent benefit. Despite the unique combination of skeletal abnormalities and ectopic ossification, the first diagnosis in FOP patients was often wrong and usually delayed after ectopic ossification began. Except where presentation was unusual, such as progressive stiffness, this delay was mainly due to failure to recognize the significance of the abnormal toes. The most frequent erroneous histological diagnoses were soft tissue sarcoma or fibromatosis.

The purpose of this case report is to document the treatment of a patient who had traumatic myositis ossificans with acetic acid iontophoresis. A 2% acetic acid solution was administered via iontophoresis into the myositis ossificans, followed by 8 minutes of pulsed ultrasound at 1.5 W/cm2. The treatment was performed three times per week for 3 weeks.

Retinoids are a plausible family of therapeutic agents for this condition due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. Data from a study of FOP patients indicated that 13-cis-retinoic acid at steady-state doses of one to two milligrams per kilogram per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions by more than five-fold compared to age-controlled and disease severity-controlled external control group. However, 13-cis-retinoic acid had no protective effect at those regions even minimally involved at the beginning of therapy. The regions that were most protected by the use of oral 13-cis-retinoic acid therapy were the major joints of the lower limbs, especially the hips and knees.