Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, ... Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner, with most patients being confined to a wheelchair by the third decade of life and requiring lifelong care (summary by Petrie et al., 2009).
Kaplan et al. (1993) reviewed histopathologic specimens from 11 patients, all children in whom the biopsy had been performed to exclude a malignant lesion. In no instance was the diagnosis of FOP considered before the biopsy. In 6 ... Kaplan et al. (1993) reviewed histopathologic specimens from 11 patients, all children in whom the biopsy had been performed to exclude a malignant lesion. In no instance was the diagnosis of FOP considered before the biopsy. In 6 children the findings were misinterpreted as indicating fibromatosis or sarcoma, at an early stage before the roentgenographic appearance of ossification. Immunohistochemical studies of sections of the earliest lesion demonstrated S-100 antigen positivity before the histologic appearance of differentiated osteochondral tissue. The biopsies in all 11 patients showed endochondral osteogenesis that was normal except for the ectopic site. They suggested that biopsy is not required to make the diagnosis because of the consistency of the findings in the great toe, and indeed should be avoided since biopsy uniformly exacerbates the condition. Lin et al. (2006) stressed the importance of examining the feet of children with a history of heterotopic bone formation to arrive at the correct diagnosis and avoid the risk of further injury. Kitterman et al. (2005) surveyed the 269 patient-members of the International FOP Association, comprising more than 90% of all known FOP patients worldwide, and received 138 responses to the questionnaire (51% response rate) from 25 countries. Incorrect diagnoses were given initially to 87% of individuals with FOP; the most common incorrect diagnosis was cancer. The mean period from onset of symptoms to correct diagnosis was 4.1 years, and the median number of physicians consulted prior to correct diagnosis was 6. Unnecessary invasive procedures (biopsies) were performed in 67% of patients, and 68% received inappropriate therapies. Almost half of the responders (49%) reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic ossification. Kitterman et al. (2005) also reviewed 184 English-language textbooks in relevant specialties and found that only 8% contained adequate descriptions of FOP, including the caution that trauma can accelerate the process of heterotopic ossification. The authors concluded that iatrogenic harm resulting from diagnostic failures for this rare disorder is common worldwide and has shaped the natural history of the disease for most affected individuals.
Fibrodysplasia ossificans progressiva is a rare disorder characterized by physical handicap due to intermittently progressive ectopic ossification and malformed big toes which are often monophalangic. Occasional features include short thumbs, fifth finger clinodactyly, malformed cervical vertebrae, short broad ... Fibrodysplasia ossificans progressiva is a rare disorder characterized by physical handicap due to intermittently progressive ectopic ossification and malformed big toes which are often monophalangic. Occasional features include short thumbs, fifth finger clinodactyly, malformed cervical vertebrae, short broad femoral necks, deafness, scalp baldness, and mild mental retardation. Although most cases are sporadic, several examples of affected twins and triplets have been reported. Furthermore, dominant inheritance is supported by observations of 2 or 3 successive generations affected and the finding of a paternal age effect in sporadic cases (Tuente et al., 1967). Connor and Evans (1982) found a point prevalence of 0.61 per million in the United Kingdom and gave a direct estimate of the mutation rate of 1.8 per million gametes per generation. Schroeder and Zasloff (1980) analyzed malformations of the hand and foot in 16 cases of FOP. Connor (1983) provided a comprehensive discussion based on a large personal experience as well as on the literature. Cohen et al. (1993) described the natural history of heterotopic ossification in FOP on the basis of responses to a mail questionnaire. The age of patients at the time of response ranged from 3 to 69 years (average age, 27). The average age at onset of ossification was 5 years (range, birth to 25 years). The most common sites of early heterotopic ossification were the neck, spine, and shoulder girdle. Some restrictive heterotopic ossification was present by age 7 years in 35 of the patients (80%). By the age of 15 years, 42 (more than 95%) of the patients had severely restricted mobility of the arms. Heterotopic ossification proceeded in a direction that was axial to appendicular, cranial to caudad, and proximal to distal. Connor et al. (1993) reported FOP in 5 persons in 3 successive generations. The affected individual in the first generation was a male. He had 2 affected daughters and 2 affected granddaughters. A wide range of phenotypic severity was demonstrated, from disabling ectopic bone formation and premature death to an asymptomatic adult with characteristic malformations of the big toe. The affected man in the first generation was asymptomatic until he developed back and neck stiffness after trauma. His jaw also became fixed after trauma and by his forties he had developed a limp. With the use of a stick he remained ambulant, however, until his early seventies; he died at 72 years of age from a myocardial infarction. Diagnosis of FOP was confirmed at the Royal National Orthopaedic Hospital, London, where x-rays were preserved. These showed malformed big toes with superimposed ankylosis, progressive ankylosis of the cervical spine, and multiple areas of soft tissue ossification. One of his daughters was asymptomatic until 22 years of age when she developed jaw fixation after extraction of wisdom teeth. Jaw fixation recurred 1 week after replacement of the right temporomandibular joint with a titanium prosthesis. Her sister was well until 15 years of age when spontaneous swelling of the left leg occurred. After biopsy the family was told she had a fibrosarcoma. In her late teens, she developed limitation of movement at the right elbow after trauma. In her twenties, she developed a succession of painless lumps on her back. Thereafter she became gradually more disabled and was bed-bound for a year before her death from pneumonia at 28 years of age. One of the granddaughters had developed painful lumps on the back beginning at the age of 13 years and at age 23 years showed an ectopic bony bar in the left lumbar area. A feature not previously described in FOP was multiple osteochondromata of the hip joints. Kaplan et al. (1993) documented the transmission of FOP from a sporadically affected father to each of his 3 children, 2 daughters and a son. The father, aged 27 years, was the third son of a 33-year-old mother and a 38-year-old father. He had onset of fibrous nodules in infancy and, at the age of 2 years, heterotopic ossification of the neck developed after blunt trauma. His disorder progressed to severe abnormality, as indicated by the published photographs. Typical deformity of the great toes was present. Characteristic widening of the femoral neck was demonstrated radiographically. All 3 children had malformation of the great toes at birth and subsequently developed typical clinical features. One child developed ossification in the quadriceps after an intramuscular injection in the anterior aspect of the left thigh at the age of 2 months. Another child first developed soft tissue nodules at the age of 3 months. Janoff et al. (1996) observed classic findings of FOP in 2 Native-American half sisters with the same unaffected mother and different unaffected fathers. The findings were interpreted as suggesting maternal gonadal mosaicism. Smith et al. (1996) reviewed FOP on the basis of 28 patients studied for up to 24 years. Ossification in the large skeletal muscles began from birth to 16 years (mean age 4.6 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. The initial diagnosis was usually wrong and the mean delay in correct diagnosis after ectopic ossification began was 2.7 years (range 0-14). This delay was mainly due to failure to recognize the significance of the abnormal toes, which were present and potentially recognizable at birth in all cases. Radiographic changes were observable in other bones such as the cervical spine and the metaphyses of the long bones where exostoses were found. Furuya et al. (2008) described a 62-year-old Japanese man who developed difficulty in moving his shoulders at age 10 years due to contractures of both shoulder joints. The joint contractures progressed slowly in his extremities, and he was unable to walk at age 36 years and bedridden at age 55 years, at which time he had rigid spine, baldness, and sensory hearing loss, accompanied by abnormal ossification but no respiratory failure. He also had severe hypodactyly with short thumbs in both hands and a severe defect of both great toes. Extensive heterotopic bone formation was seen radiographically. His parents died at advanced age with no symptoms reminiscent of FOP, and he had 2 healthy sibs. Barnett et al. (2011) described a female patient with so-called 'variant FOP' who had normal great toes and late-onset heterotopic ossification and was misdiagnosed with ankylosing spondylitis for several years. The patient presented at 21 years of age with a 'stiff back,' but had a normal x-ray and was unsuccessfully treated with sulfasalazine for a year for 'nonspecific spondyloarthropathy;' several years later she was treated with sulfasalazine and methotrexate for continuing severe back pain that was diagnosed as ankylosing spondylitis, but she discontinued treatment after several months without improvement. Around that time, the patient underwent fine needle aspiration of a painless mass of the mandible that was suggestive of a reactive or inflammatory process in skeletal muscle; the mass resolved completely over 3 months. She later developed right scapular pain that appeared to be myositis of the right rhomboid major, serratus anterior, and intercostal muscles on MRI; this resolved spontaneously over several months. At 27 years of age, upon evaluation of a painless mass in the thyroid region, the patient had plain films and CT scan of the entire spine that revealed extensive ossification of the ligamentum flavum in the thoracic spine and of the interspinous ligament in the lumbar spine, as well as a thin layer of ossification between the right trapezius and rhomboid, consistent with ossification of the previous inflammatory lesion. The diagnosis of FOP was suggested based on the clinical and radiologic findings, and examination revealed significant limitation of neck and lumbar spine movement, particularly flexion and extension, as well as 2 small asymptomatic ossified masses, 1 over the right scapula and 1 over the right lower lumbar spine. Clinical and radiologic examination of the feet was normal; Barnett et al. (2011) stated that this was only the fifth reported FOP patient with bilaterally unaffected great toes. Hammond et al. (2012) delineated the common facial characteristics of 55 patients with molecularly confirmed FOP by analyzing their 'face signature' (face shape differences normalized against age- and sex-matched controls) and associated face signature graphs. The analysis identified 10 affected individuals whose face signature was more homogeneous than others with FOP; distinctive features included the previously identified reduced mandible and maxillary overbite, as well as low-set ears, underdevelopment of the upper orbit/supraorbital ridge, and infraorbital prominence. Hammond et al. (2012) suggested that the canonical FOP mutation variably affects the postnatal morphogenesis of the normotopic cranial skeleton in the upper midface and mandible.
Shore et al. (2006) conducted a genomewide linkage analysis using a subset of 5 families with the most stringent and unambiguous features of FOP, congenital malformation of the great toes and progressive heterotopic ossification in characteristic anatomic patterns, ... Shore et al. (2006) conducted a genomewide linkage analysis using a subset of 5 families with the most stringent and unambiguous features of FOP, congenital malformation of the great toes and progressive heterotopic ossification in characteristic anatomic patterns, in all affected family members. This approach identified linkage of FOP to chromosome 2q23-q24, a genetic interval including the ACVR1 gene. Sequence analysis of all ACVR1 protein-coding exons and splice junctions identified a heterozygous mutation (R206H; 102576.0001) in all examined familial individuals, including all 5 families used for linkage analysis, and in 32 of 32 sporadic FOP patients with unambiguous clinical features. The examined individuals with the R206H mutation included an individual who was previously reported by Semonin et al. (2001) with an unverifiable mutation in the NOG gene (602991); see Xu et al. (2002, 2000). In a 3-year-old Taiwanese girl with dysplasia of the first metatarsal bones and progressive heterotopic ossificans of the right thigh due to routine childhood immunizations and several inappropriate surgical interventions, Lin et al. (2006) identified a de novo R206H mutation in the ACVR1 gene. Nakajima et al. (2007) identified the R206H mutation in 3 unrelated sporadic Japanese patients with FOP, indicating that this mutation is common and recurrent in the global population. In a 62-year-old Japanese man with slowly progressive FOP, Furuya et al. (2008) identified heterozygosity for a de novo missense mutation (G356D; 102576.0002) in the ACVR1 gene. The mutation was not found in his unaffected sibs or in 150 controls. The authors suggested that the patient's longevity and slow progression of respiratory difficulties might be related to the position of the G356D mutation in the protein kinase domain rather than in the functionally important glycine/serine-rich domain where the R206H mutation is located. Bocciardi et al. (2009) identified the R206H mutation in 15 of 17 unrelated Italian patients with FOP. In 2 unrelated Italian patients, they identified heterozygosity for a different mutation (R258S; 102576.0003). The authors noted that there was extreme variability among the 17 patients in the severity of the disease; in addition, of the 2 patients with the R258S mutation, 1 did not have the great toe malformation, and the other had it to a 'rather mild' degree. - Clinical Variability Kaplan et al. (2009) studied 112 FOP patients, of whom 104 were sporadic cases and 8 were familial cases. Classic FOP was found in 82 sporadic cases and 7 familial cases, whereas 20 sporadic cases and 1 familial case had atypical FOP. The atypical patients formed 2 classes: so-called 'FOP-plus,' in which patients had the classic defining features of FOP plus 1 or more atypical features; and 'FOP variants,' in which there were major variations in 1 or both of the 2 classic defining features of FOP. The recurrent ACVR1 mutation R206H (102576.0001) was found in all of the patients with classic FOP and most of those with FOP-plus, whereas the G356D mutation (102576.0002) or novel ACVR1 mutations were identified in patients with FOP variants and in 2 cases of FOP-plus (see, e.g., 102576.0004-102576.0007). Kaplan et al. (2009) noted that all mutations in ACVR1 associated with FOP in any form were located in or adjacent to the GS regulatory region or active site of the kinase, and all were predicted by protein structure homology modeling to activate the ACVR1 protein and enhance receptor signaling. In a 20-year-old woman with FOP, who had a later onset and relatively mild course of disease, Petrie et al. (2009) identified heterozygosity for an R202I mutation in the ACVR1 gene (102576.0008). In a 52-year-old woman with FOP, first reported by Smith et al. (1976) and later reviewed by Connor and Evans (1982), who was born with severe reduction deformities of all digits, Petrie et al. (2009) identified a heterozygous G328E mutation (102576.0008). In a female patient with variant FOP, who had normal great toes and late-onset heterotopic ossification and was misdiagnosed with ankylosing spondylitis for several years, Barnett et al. (2011) identified heterozygosity for the R202I mutation in the ACVR1 gene.