13Fibrodysplasia ossificans progressiva
Section snippets
Historical descriptions of FOP
Possible cases of FOP date back to antiquity. FOP, known by many names throughout history, was first described in detail more than 250 years ago by a London physician. In a letter to The Royal Society of Medicine, dated 14 April 1736 (published in 1740), John Freke of Saint Bartholomew's Hospital, London wrote: ‘There came a boy of healthy look, and about 14 years of age, to ask of us at the hospital, what should be done to cure him of many large swellings on his back, which began about 3 years
Classic clinical features of FOP
Two clinical features define classic FOP: malformation of the great toes; and progressive HO in specific spatial patterns (Figure 1). Individuals with FOP appear normal at birth except for the characteristic malformations of the great toes which are present in all classically affected individuals.9 During the first decade of life, children with FOP develop painful and highly inflammatory soft tissue swellings (or flare-ups) that transform soft connective tissues, including aponeuroses, fascia,
Misdiagnosis of FOP
FOP is commonly misdiagnosed, as clinicians often fail to associate the rapidly developing soft tissue swellings that appear on the head, neck and upper back with the malformed great toes.24 The correct diagnosis of FOP can be made clinically even before radiographic evidence of HO is seen if rapidly waxing and waning soft tissue lesions are associated with symmetrical malformations of the great toes. When such associations are not made, FOP is commonly misdiagnosed as aggressive juvenile
Cervical spine anomalies in FOP
In addition to malformations of great toes and thumbs, early developmental anomalies are frequently observed in the cervical spine.25 Stiffness of the neck is an early finding in most patients and can precede the appearance of HO at that site. Characteristic anomalies of the cervical spine include large posterior elements, tall narrow vertebral bodies, and fusion of the facet joints between C2 and C7; findings that are strikingly similar to those seen in mice with homozygous deletions of the
Other skeletal anomalies in FOP
Other skeletal anomalies often associated with FOP include short malformed thumbs, clinodactyly, short broad femoral neck and proximal medial tibial osteochondromas. The latter two findings are reminiscent of patients who have multiple hereditary exostoses, although the genes associated with multiple hereditary exostoses are not mutated in patients who have FOP. Nevertheless, these shared clinical findings may illuminate common pathway anomalies.*1, 2, 3, *5
The temporomandibular joint in FOP
Patients with FOP may have developmental anomalies of the temporomandibular joints (TMJs), although a comprehensive study of TMJ anatomy has not yet been undertaken in the FOP community. Spontaneous or post-traumatic extra-articular ankylosis of the TMJs is common, and leads to severe disability with resultant difficulties in eating and poor oral hygiene.*1, 2, 3, *5
Submandibular swelling in FOP
Submandibular swelling can be a life-threatening complication, especially when associated with massive anterior neck swelling and difficulty in swallowing.17 Special measures to decrease swelling, including a course of glucocorticoids and respiratory support, may be warranted.17
Hearing impairment in FOP
Hearing impairment is a common feature of FOP and occurs in approximately 50% of patients. The onset is usually in childhood or adolescence, and is generally slowly progressive. Hearing loss is usually conductive in nature and may be due to middle ear ossification; however, in some patients, the hearing impairment is neurological in nature.26
Cardiopulmonary function in FOP
Patients with FOP develop TIS that can lead to life-threatening complications. Features contributing to TIS in patients with FOP include: costovertebral malformations with orthotopic ankylosis of the costovertebral joints; ossification of intercostal muscles, paravertebral muscles and aponeuroses; and progressive spinal deformity including kyphoscoliosis or thoracic lordosis. Pneumonia and right-sided heart failure are the major life-threatening hazards that result from TIS in patients with
Radiographic features of FOP
Joint malformations and soft tissue ossification are the characteristic radiographic features of FOP. Malformation of the great toes, thumbs, cervical spine and proximal femurs, along with the presence of proximal medial tibial osteochondromas, can make the diagnosis more certain.*1, 2, 3, *5
Radiographic and bone scan findings suggest normal modelling and remodelling of heterotopic bone.29, 30 The incidence of fractures is not increased in patients with FOP, although fracture healing is
Laboratory findings in FOP
Routine biochemical evaluations of bone mineral metabolism are usually normal, although serum alkaline phosphatase activity may be increased, especially during disease flare-ups.3, *5, 6 Urinary basic fibroblast growth factor levels may be elevated during disease flare-ups coinciding with the pre-osseous angiogenic phase of fibroproliferative lesions.32 Nephrolithiasis is more common in older patients with FOP, and may be due to increased immobilization and dehydration in the setting of
Histopathology of FOP lesions
The histological stages of FOP lesions have been well described.12, 13, 14, 15 Early FOP lesions contain an intense perivascular B-cell and T-cell lymphocytic infiltrate. Subsequent migration of mononuclear inflammatory cells into affected muscle precedes widespread myonecrosis.13
Following a brief inflammatory stage, an intense fibroproliferative reaction associated with robust angiogenesis and neovascularity is noted.13, 14 These early- to intermediate-stage lesions are microscopically
Epidemiologic, genetic and environmental factors in FOP
FOP is extremely rare with a worldwide prevalence of approximately one in two million. There appears to be no ethnic, racial, gender or geographic predisposition.3, 6 Most cases arise as a result of a spontaneous new mutation. When observed, genetic transmission is autosomal dominant and can be inherited from either mothers or fathers.23, 35
Both genetic and environmental factors affect the phenotype of FOP. A study of three pairs of monozygotic twins with FOP found that within each pair,
FOP and the BMP signalling pathway
The classic and invariable FOP phenotype of great toe malformations and progressive heterotopic endochondral ossification suggested that the primary molecular pathology involves the bone morphogenetic protein (BMP) signalling pathway.37 A number of seminal discoveries provided evidence of profound dysregulation of the BMP signalling pathway in cells from patients who had FOP.*38, 39, 40, *41, 42, *43, 44, *45, 46, 47
Discovery of the FOP gene
In order to identify the chromosomal locus for the FOP gene, a conservative genome-wide linkage analysis was conducted using a subset of five families with the most stringent and unambiguous features of FOP. This approach identified linkage of FOP to 2q23–24.9 The gene encoding activin receptor IA (ACVR1) [also known as activin-like kinase 2 (ALK2)], a BMP type I receptor, was identified in the linkage interval. DNA sequencing of the ACVR1 gene determined that the same heterozygous mis-sense
Protein modelling of the FOP mutation
ACVR1/ALK2 is a BMP type I receptor, and protein structure homology modelling of the recurrent mutation predicts destabilization of the GS domain, consistent with an overactive BMP signalling pathway as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusion seen in FOP. This mutation is consistent with a wealth of previous findings of an overactive BMP signalling pathway in FOP cells, and provides a rational basis for understanding both the postnatal HO and the
ACVR1/ALK2: a pharmaceutical target for the second skeleton
The ultimate goal of FOP research is the development of treatments that will prevent, halt or even reverse progression of the condition. The prevention and treatment of HO in FOP, as for any of the more common forms of HO, will be based on at least one of four principles: disrupting the relevant inductive signalling pathways; suppressing the immunological and/or inflammatory triggers; altering the relevant osteoprogenitor cells in the target tissues; and/or modifying the tissue environment
Animal models of FOP
Animal models of FOP will be important for understanding the pathophysiology of FOP and for testing possible therapies.52 Laboratory-generated animal models with some features of FOP have provided the opportunity to better understand the biology of HO and to study the effectiveness and safety of currently available and emerging therapies. Development of a knock-in mouse model carrying the specific FOP-disease-causing mutation in ACVR1/ALK2 will be necessary to establish specificity of treatment
Current management of FOP
The rarity, variable severity and episodic clinical course of FOP pose substantial uncertainties when evaluating experimental therapies.53 Accordingly, medical intervention is currently supportive. Surgical release of joint contractures is generally unsuccessful and risks new, trauma-induced HO. Osteotomy of heterotopic bone or surgical removal of heterotopic bone to mobilize joints is generally counterproductive because additional HO develops at the operative site. Rarely, a joint may be
Prophylactic issues in FOP
Dental therapy must involve assiduous attention to prophylaxis of caries and must avoid intramuscular injection of local anesthetics, especially mandibular blocks and stretching of the jaw.54 All intramuscular injections must be avoided.16 Prevention of falls is crucial.19 Prophylaxis against influenza and pneumonia, as well as measures to prevent respiratory infection and cardiopulmonary complications of restrictive chest well disease, are vitally important.20
Anaesthesia in patients with FOP
General anaesthesia is particularly dangerous in patients with FOP. Guidelines for general anaesthesia have been reported.54 Overstretching of the jaw for intubation may cause additional trauma to the TMJs, and lead to disease flare-ups. In older patients whose TMJs are ankylosed, oral access for intubation may not be possible. General anaesthesia in FOP patients should be accomplished through an awake fibre-optic nasal intubation under light sedation so that the patient can control secretions.
Rehabilitation issues in FOP
As heterotopic bone accumulates in FOP, range of motion is progressively lost leading to near-complete immobility. Present and future rehabilitation approaches should be focused on enhancing activities of daily living. Occupational therapy and vocational education consultations may be useful. Despite the widespread HO and progressive disability, most patients lead productive and fulfilling lives.55
The international FOP association
The International FOP Association (IFOPA) was founded in June 1988 to educate patients, doctors and the public about FOP; to support medical research into FOP; and to support patients with FOP and their families by providing a network of communication to help end the isolation that accompanies this rare and severely disabling condition. Additional information can be found on the IFOPA website (www.ifopa.org). In recent years, many regional FOP organizations have arisen worldwide to support
Research agenda and summary
While the mutation that causes classic FOP has been discovered, much work remains to elucidate the molecular mechanism by which this mutation leads to the complex disease phenotype of skeletal malformations and episodic progression of HO.
It will be essential to fully understand the role of the inflammatory pathways in triggering flare-ups of the disease, and to better understand the interaction of the immune system with the as-yet-unidentified connective tissue progenitor cells that are
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