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CH aged 6 years. Congenital deformities of both great toes which were surgically corrected. Flexion deformities of the interphalangeal joints.
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Fibrodysplasia ossificans progressiva (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 constant feature seen was a...
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... La fibrodisplasia osificante progresiva (FOP) es una rara enfermedad de etiología desconocida, un trastorno autosómico dominante del tejido conectivo, que se caracteriza por calcificaciones progresivas de las fascias, aponeurosis, ligamentos, tendones y tejido conectivo intersticial del músculo (1)(2)(3) (4, 5) esquelético . Su prevalencia es de 1:2.000.000 . ...
... Una manifestación más temprana, presente desde el nacimiento, es la morfología anormal del primer (5) metatarsiano . Las osificaciones heterotópicas por lo común se hacen evidentes alrededor de los 5 años, usualmente precedidas por un trauma en los tejidos blandos. ...
La fibrodisplasia osificante progresiva (FOP) es una enfermedad del tejido conectivo de etiología desconocida, de herencia autosómica dominante que se caracteriza por calcificaciones progresivas de las fascias, aponeurosis, ligamentos, tendones y tejido conectivo intersticial del músculo esquelético. Su prevalencia es de 1:2.000.000. Presenta desde el nacimiento morfología anormal del primer metatarsiano. Las osificaciones heterotópicas por lo común se hacen evidentes recién alrededor de los 5 años, posteriores a un trauma en los tejidos blandos. El compromiso funcional es progresivo y altamente incapacitante. Presentamos el caso de un niño de 6 años quien desde el año de edad inició las lesiones en las zonas de traumatismos, al comienzo acompañadas de dolor y signos inflamatorios que luego se petrificaban. Presentaba hállux valgus corto bilateral y se pudo corroborar la presencia de la misma malformación en un tío materno. Conflicto de interés: Los autores declaran no poseer conflicto de interés Recibido: 28/01/2019 Aceptado: 22/02/2020
... The presence of any kind of "metaphyseal abnormality" (referred as either "metaphyseal widening," "spur formation," "exostoses" or "osteochondroma") was already mentioned in the very early reports of FOP disease [21][22][23][24]. Subsequently, other works provided more insights into the knowledge of these abnormalities [25][26][27]. Finally, isolated proven cases of "enchondroma" [27] and "synovial chondromatosis" [29,30], as well as one patient with an osteochondroma located at an atypical skeletal site [31], were communicated. ...
... As a result, we found 370 studies published since 1918 through 2014. After refining the search, we finally included 13 informative articles (Table 2) [3,6,[21][22][23][24][25][26][27][29][30][31][32]. The study was approved by the Ethical Committee of the Rare Disease Research Institute from Carlos III Institute of Health (Madrid, Spain). ...
... In contrast, Connors and Evans report clear-cut bone exostoses in almost one-third of 34 patients personally evaluated [3]. And in the initial monographic work aimed to address this issue, "flaring and spiking at the end of the metaphyses" were shown, proposing that they represent a real feature of the disease [26]. The first histopathologically proven cases of osteochondroma [6] and enchondroma [28] associated with FOP disease were communicated in [31] have reported one isolated case of osteochondroma (located at an atypical skeletal area) in a child with FOP. ...
Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis.
... In a case series of thirty-four patients that was performed to define the natural history of the disease, Connor and Evans reported that eleven patients had fibrodysplasia ossificans progressiva with osteochondromas, most commonly of the proximal part of the tibia 9 . O'Reilly and Renton also reported the case of a patient with fibrodysplasia ossificans progressiva who had a proximal tibial osteochondroma 25 . Two cases 2,24 have been reported in which osteochondromas were excised from the proximal part of the tibia and the coronoid process of the mandible prior to the diagnosis of fibrodysplasia ossificans progressiva. ...
... Because of the rarity of fibrodysplasia ossificans progressiva, physicians often fail to recognize the disorder when patients present with congenital malformation of the great toes or preosseous soft-tissue masses during childhood. Consequently, surgical correction of the malformed toes and biopsy of softtissue lesions both lead to robust heterotopic ossification at the site of surgery, resulting in poor patient outcomes 2,8,24,25 . The frequent association of proximal tibial osteochondromas with fibrodysplasia ossificans progressiva adds a simple, diagnostically useful dimension to the disease, raising the physician's level of suspicion and allowing an earlier recognition of the diagnosis that should help to preclude inappropriate and dangerous invasive procedures. ...
... A detailed study to address this question is presently underway. In addition to the development of multiple osteochondromas, fibrodysplasia ossificans progressiva shares other skeletal similarities with multiple hereditary exostoses, including short broad femoral necks and metaphyseal widening, suggesting that the two conditions may share overlapping pathophysiologic mechanisms 24,25,32,33 . ...
Fibrodysplasia ossificans progressiva is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of skeletal muscle and soft connective tissues. The disorder is caused by a recurrent missense mutation in the glycine-serine activation domain of activin A receptor type I, a bone morphogenetic protein (BMP) type-I receptor, in all classically affected individuals. Osteochondromas of the proximal part of the tibia are benign osteochondral neoplasms or orthotopic lesions of skeletal remodeling associated with dysregulated BMP signaling and have been considered an atypical feature of fibrodysplasia ossificans progressiva, but they may be underdiagnosed because of their often asymptomatic nature. The purpose of the present study was to determine the prevalence and characteristics of proximal tibial osteochondromas in individuals who have fibrodysplasia ossificans progressiva.
Over a period of thirty months, we evaluated all patients with new and established fibrodysplasia ossificans progressiva for the presence of proximal tibial osteochondromas on the basis of medical history, physical examination, and radiographic studies. We quantified the prevalence of osteochondromas and characterized the types of osteochondromas to identify relevant trends.
Ninety-six patients (including fifty-two female patients and forty-four male patients) with fibrodysplasia ossificans progressiva were evaluated on the basis of a history and physical examination. Plain radiographs were available for sixty-seven patients. Ninety percent of all patients had osteochondroma of the proximal part of the tibia. These lesions usually were asymptomatic, most commonly were bilateral, and typically were located at the pes anserinus. Seventy-five percent of the lesions were pedunculated, and 25% were sessile.
Proximal tibial osteochondromas are a common phenotypic feature of fibrodysplasia ossificans progressiva, a finding that expands the recognized consequences of recurrent activating mutations in activin A receptor type I to include not only congenital skeletal malformations and heterotopic skeletogenesis but also benign osteochondral neoplasms or orthotopic lesions of skeletal modeling. The present study provides insight into the genetic basis of osteochondroma formation in patients with fibrodysplasia ossificans progressiva and possibly into that of more common conditions in which these lesions occur.
Trauma is the most common cause of lesions in the fossil record. Not only linked to bones themselves, traumatic injuries can be identified in footprints and teeth, although these seem to be less common. Scars, scratches, embedded teeth, pierced holes, and amputations are all event that can point to past injuries, but the physiological reaction of the injured body can also lead to formation of bone spicules or exostoses, suggesting some form of avulsions represent the attempt by the muscles and/or tendons to counterbalance the effect of the injury. Bony modifications due to external injuries can lead to diagnostic confusion. Exostoses should not be misdiagnosed as osteochondroma and osteochondritis that have a traumatic origin separate from that of osteochondrosis. The causes and rates of forming and healing are well characterized in human medicine, and their understanding in other animals (e.g., reptiles and birds) is continuously growing. This knowledge can be incorporated in paleopathology to decipher healing modes and tempo in extinct taxa, as well as the diversity of fractures and their impact on the lifestyle of the animals. Enthesiophytes are alteration of attachment site of tendons and ligaments. While exostoses can have a traumatic origin, they can also be found in non-pathological conditions (e.g., DISH) and perhaps aging (Long et al. 2021). Finally, osteoarthritis can have complicated injuries, but it is not associated with enthesophytes. The bony spicules characterizing osteoarthritis are osteophytes (van der Kraan 2007). Their location on diarthrodial joint is pathognomonic, whereas other features (eburnation, pitting joint deformation) lack specificity.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of connective tissue characterized by congenital malformation of the great toes and by progressive heterotopic osteogenesis that occurs in predictable anatomic patterns. The rate of disease progression is variable (1); however, onset of heterotopic bone formation typically occurs before age 10. Cumulative episodes of heterotopic ossification commonly result in ankylosis of all major joints of the axial and appendicular skeleton, preventing movement of affected joints. Most patients are confined to a wheelchair by the third decade of life and require lifelong assistance in performing activities of daily living. Surgical trauma associated with attempts to remove heterotopic bone typically leads to increased local ossification. There is currently no effective treatment.
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene of a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was −2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.
Patients with fibrodysplasia (myositis) ossificans progressiva (FOP) (n = 28) 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 (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. Despite the unique combination of skeletal abnormalities and ectopic ossification, the first diagnosis in patients with FOP was often wrong and usually delayed after ectopic ossification began (mean 2.7 years, range 0-14). 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. This series emphasizes the usually incorrect initial diagnosis, the misinterpretation of the histology, the unpredictable prognosis and the failure of current treatment. Despite its extreme rarity, there is a need for wider knowledge of this condition both to avoid clinical errors and to stimulate research.
The clinical features of seven children with myositis ossificans (circumscripta and progressiva) and radiographic signs of the disease are described. We recommend systematic radiological examination to seek other skeletal malformations for congenital hallux valgus in young children, for it may be the first sign of a myositis ossificans progressiva. The "zone phenomenon" observed on histology, along with differential diagnosis and evolution, is documented. The necessity of a biopsy and different forms of treatment are discussed.
Fibrodysplasia (myositis) ossificans progressiva is a rare dominantly inherited disorder, in which defects in skeletal patterning particularly affecting the big toes, are associated with progressive endochondral ossification of the large striated muscles in a specific order leading to prolonged disability. A recent series of 28 patients studied for as many as 24 years exemplifies the presentation and course of this disease. Painful swelling of muscles (myositis) leading to ossification began at a mean age of 4.6 years (range, 0-16 years) initially in the neck and upper spine (in 25 subjects) and later around the hips, other major joints, and jaw. The rate and extent of disability was unrelated to the time of onset. No form of treatment produced consistent benefit. Despite the unique clinical features, the initial diagnosis of fibrodysplasia ossificans progressiva was often wrong and usually considerably delayed. Mistaken histologic diagnoses such as soft tissue sarcoma or fibromatosis could lead to inappropriate treatment.
A 5-year-old boy underwent arthroscopic surgery because of a lateral discoid meniscus, which was followed by an overly strenuous rehabilitation program. At 6-week follow-up, a painful mass at the distal part of the thigh and a flexion restriction of the operated knee were detected, caused by myositis ossificans inside the vastus medialis muscle. The symptoms disappeared with an appropriate rehabilitation program and the patient recovered.
