13
Fibrodysplasia ossificans progressiva

https://doi.org/10.1016/j.berh.2007.11.007Get rights and content

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-β/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

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

References (58)

  • J.M. Connor et al.

    Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients

    The Journal of Bone and Joint Surgery. British Volume

    (1982)
  • R. Smith

    Fibrodysplasia (myositis) ossificans progressiva: clinical lessons from a rare disease

    Clinical Orthopaedics and Related Research

    (1988)
  • F.S. Kaplan et al.

    Fibrodysplasia ossificans progressiva (FOP)

  • F.S. Kaplan et al.

    Heterotopic ossification

    The Journal of the American Academy of Orthopaedic Surgeons

    (2004)
  • F.S. Kaplan et al.

    The phenotype of fibrodysplasia ossificans progressiva

    Clinical Reviews in Bone and Mineral Metabolism

    (2005)
  • F.S. Kaplan et al.

    Fibrodysplasia (myositis) ossificans progressiva

  • F.S. Kaplan

    Fibrodysplasia ossificans progressiva: an historical perspective

    Clinical Reviews in Bone and Mineral Metabolism

    (2005)
  • J.A. Rosenstirn

    A contribution to the study of myositis ossificans progressiva

    Annals of Surgery

    (1918)
  • E.M. Shore et al.

    A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

    Nature Genetics

    (2006)
  • R.B. Cohen et al.

    The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva

    The Journal of Bone and Joint Surgery. American Volume

    (1993)
  • D.M. Rocke et al.

    Age and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1994)
  • F.S. Kaplan et al.

    The histopathology of fibrodysplasia ossificans progressiva: an endochondral process

    The Journal of Bone and Joint Surgery. American Volume

    (1993)
  • F.H. Gannon et al.

    Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1998)
  • D.L. Glaser et al.

    In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification

    The Journal of Bone and Joint Surgery. American Volume

    (2003)
  • R.J. Pignolo et al.

    The fibrodysplasia ossificans progressiva lesion

    Clinical Reviews in Bone and Mineral Metabolism

    (2005)
  • T.F. Lanchoney et al.

    Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva

    The Journal of Pediatrics

    (1995)
  • H.B. Janoff et al.

    Submandibular swelling in patients with fibrodysplasia ossificans progressiva

    Otolaryngology-Head and Neck Surgery

    (1996)
  • W. Luchetti et al.

    Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva

    Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics

    (1996)
  • D.L. Glaser et al.

    Catastrophic falls in patients who have fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1998)
  • R.F. Scarlett et al.

    Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva (FOP)

    Clinical Orthopaedics and Related Research

    (2004)
  • J.M. Moriatis et al.

    Limb swelling in patients who have fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1997)
  • F.S. Kaplan et al.

    Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva

    Clinical Reviews in Bone and Mineral Metabolism

    (2005)
  • E.M. Shore et al.

    The genetics of fibrodysplasia ossificans progressiva

    Clinical Reviews in Bone and Mineral Metabolism

    (2005)
  • J.A. Kitterman et al.

    Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva

    Pediatrics

    (2005)
  • A.A. Schaffer et al.

    Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome

    Spine

    (2005)
  • C.E. Levy et al.

    Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva

    American Journal of Audiology

    (1999)
  • P.B. Shah et al.

    Spinal deformity in patients who have fibrodysplasia ossificans progressiva

    The Journal of Bone and Joint Surgery. American Volume

    (1994)
  • W.G. Kussmaul et al.

    Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1998)
  • F.S. Kaplan et al.

    Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva

    Clinical Orthopaedics and Related Research

    (1994)
  • Cited by (0)

    View full text