Fibrodysplasia ossificans progressive (FOP) is a very rare inherited disorder of connective tissue, characterized by pro- gressive ectopic ossification and congenital malformation of the great toes. It is also known as myositis ossificans progres- siva. The prevalence is approximately one affected patient in 1.64 million people in the United Kingdom.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Usually sporadic in occurrence. Very few affected individuals have children because of the devastating nature of the disease
b. Autosomal dominant inheritance i. Complete penetrance ii. Variable expression 2. Cause
a. Mutations within the bone morphogenic protein (BMP) gene family, contributing both to limb pattern- ing and to ossification. An abnormal regulation of BMP-4 expression was described in FOP. The secreted polypeptide noggin binds and inactivates BMP-4 b. Mutations of the Noggin (NOG) gene (However, link-
age between NOG and FOP has been excluded and no disease-causing mutations was noted by one group) c. Mapping of the FOP gene
i. Chromosome 4q27-31 ii. Chromosome 17q21-22
3. Presence of two skeletons in patients with FOP
a. A normotopic bone formation during embryogenesis i. Grossly normal normotopic skeleton
ii. Exceptions
a) Segmentation defects in the cervical spine b) Malformation of the great toes at birth due to
shortening of the first metatarsal and proxi- mal phalanx
c) Monophalangic great toes due to synostosis:
the earliest phenotypic feature of fibrodys- plasia ossificans progressiva
b. A heterotopic bone formation
i. Usually beginning in the first decade of life ii. Progressing in characteristic anatomic patterns iii. Typically involving upper back and neck
iv. Heralded by large painful swellings of highly vascular fibroproliferative tissue involving lig- aments, tendons, and skeletal muscle, often following minor trauma
v. Early swelling regresses spontaneously but often matures to true heterotopic bone
4. Pathogenesis:
a. Overexpression of bone morphogenetic protein 4 (BMP-4), which maps to 14q22-q23
b. Inability of the altered noggin polypeptide of the FOP patient to bind efficiently to BMP-4: possible patho- genesis of the disease
c. NF-κB may play an important functional role in the pathogenesis of the disease because of its multiple roles in inflammation, skeletogenesis, and bone morphogenetic protein-4 regulation
5. Precipitating factors for ectopic ossification a. Biopsies
b. Intramuscular injections c. Dental therapy
d. Prolonged pressure on the body, such as tight clothing e. Aggressive physical therapy
f. Falls g. Injuries
h. Exacerbation of bone formation common in response to surgery and other tissue trauma
CLINICAL FEATURES
1. Extra-skeletal abnormalities
a. Progressive widespread heterotopic ossification of muscles, tendons, ligaments, aponeurosis, and fascia.
The heterotopic bony masses lead to progressive disability
b. Onset: about 4 years of age in majority of patients c. Typical course of lesional progression at any site
i. Early lesions during the first few weeks: charac- terized by pain, erythema, swelling, warmth, and tenderness
ii. Intermediate lesions after several weeks a) Swelling beginning to subside
b) Decrease in pain, tenderness, and erythema iii. Late lesions after approximately 12 weeks
a) Disappearance of swelling
b) A hard, non-tender lesion remains. It is roentgenographically a new area of hetero- topic ossification
d. Characteristic anatomical progression of heterotopic bone formation
i. Typical earliest involvement: dorsal, axial, cranial and proximal regions of the body
ii. Later involvement: ventral, appendicular, caudal, and distal regions of the body
e. Variation in size of soft tissue nodules involving the neck and back: often the first indication of heterotopic ossification in a child
f. Progressive ankylosis i. Shoulder joints ii. Elbow joints iii. Hip joints
iv. Knee joints
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v. Neck: painful swelling or stiffness of the neck in most patients
vi. Spine
a) Leading to complete fusion b) Mimicking ankylosing spondylitis
c) Pain and stiffness of the spine present in most patients
vii. Muscles of mastication
a) Leading to limited mouth opening b) Inability to feed orally
c) Poor oral hygiene d) Subsequent cachexia g. Severe restrictive pulmonary disease
i. Causes
a) Scoliosis of the thoracolumbar spine b) Ankylosis of costovertebral joints
c) Ossification of the chest wall with resultant dependence on diaphragm for respiration ii. Severely reduced lung volume
iii. Constrictive airway dysfunction developing over time
iv. Recurrent pulmonary infections secondary to ineffective cough: a common cause of death in the third or fourth decade
h. Eventual confinement to wheelchair
2. Congenital malformation of the great toes and thumbs (75–90%)
a. Association with congenital great toe malformation i. Mainly short big toes with single phalanx (a
cartilaginous anlage of the first metatarsal and proximal phalanx) present at birth
ii. An important early diagnostic clue b. Shortened thumbs
c. Clinodactyly of the 5th fingers 3. Other features
a. Patients with FOP are prone to fractures with poor outcome
b. Occasional baldness
c. Occasional conductive hearing loss secondary to calcification and fusion of the ligaments, tendons, and bones of the middle ear
d. Markedly reduced reproductive fitness
e. Reduced life span but most patients survive to adulthood 4. Natural history
a. Mobility becomes more restricted as the disease advances b. Typically confined to bed or wheelchair by early 30s
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Extra skeletal ossification
i. Progressive widespread heterotopic ossification of muscles, tendons, ligaments, and fascia ii. Ankylosis
a) Shoulder joints b) Elbow joints
c) Hip joints: prevent ability to ambulate d) Knee joints
e) Muscles of mastication
b. Phalangeal abnormalities
i. Characteristically affecting the great toes a) Shortened first digits
b) Delta-shaped proximal phalanges
c) Often monophalangism with absence of the interphalangeal joint of the great toes ii. Shortened thumbs
iii. Clinodactyly of the 5th fingers c. Less common congenital malformations
i. Small vertebral bodies and enlarged pedicles in early childhood
ii. Variable degrees of vertebral fusion, especially apophysial joint fusion in late childhood iii. Short, broad femoral necks
iv. Ossification of ligamentous insertions producing exostoses of the proximal tibia
v. Delay in skeletal maturation vi. Enchondroma formation
vii. Association with synovial chondromatosis 2. Bone scintigraphy (radionuclide imaging)
a. A very sensitive technique for new bone formation in FOP
b. Reveals multiple foci of increased uptake in affected areas
3. CT scan
a. Useful for diagnosis because CT scan is very sensitive for calcification
b. Soft tissue swelling in the fascial planes and muscle in the early course of FOP
c. Evidence of soft tissue calcification, typically in the form of shell seen within days to a few weeks d. Calcification appearing as spicules in the soft tissue
or in thin planes along the fascia often encircling muscle
e. Able to delineate the presence or absence of bone destruction, differentiating FOP from invasive pro- cesses such as infection and tumor
4. MRI: a sensitive imaging technique for soft tissue abnor- malities but not particularly useful for diagnosis
5. Ultrasonography to demonstrate echogenic and shadowing mass
6. Audiography: mixed-type hearing loss with prominent conductive component
7. Histopathology
a. Earliest finding: an intense perivascular lymphocytic infiltration
b. Followed by death of skeletal muscle and replace- ment by a highly vascular fibroproliferative soft tissue, which rapidly progresses through an endo- chondral process to form heterotopic bone
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless a parent is affected or has gonadal mosaicism
b. Patient’s offspring: 50%
2. Prenatal diagnosis: no prenatal diagnosis available cur- rently
3. Management
a. No effective treatment available
i. Avoid multiple biopsies, trauma, intramuscular injections, and dysfunctional IV catheters to pre- vent precipitating the heterotopic ossification and exacerbating the disease
ii. Physical therapy in general not recommended as stretching of the soft tissues around a joint can lead to a painful flare-up
iii. Steroids, non-steroid anti-inflammatory agents, disodium etidronate, warfarin, and radiotherapy a) Used to halt the progression of disease b) Without proven benefit
iv. Isotretinoin
a) Principle based on its ability to inhibit dif- ferentiation of mesenchymal tissue into car- tilage and bone
b) Questionable benefit to decrease the inci- dence of heterotopic ossification at unin- volved anatomical sites
v. Etidronate
a) Blocks ectopic calcification and is approved by Food and Drug Administration for treat- ment of postoperative heterotopic ossification b) Short-term effect of bone metabolism shows
diminished bone turnover rate
c) Long-term effect on ectopic calcification is unchanged in most cases with few exceptions b. Primary therapy for the debilitating disease: support-
ive care
i. Active range-of-motion exercises encouraged if the movements are comfortable
ii. Available adaptations or modifications pre- scribed to a disabled patient with FOP to achieve functional independence in the home and community
a) Shoes b) Canes c) Wheelchairs c. Surgery
i. Nearly always contraindicated since new hetero- topic ossification occurs at the operative site ii. Surgical removal of heterotopic bone
a) Ineffective
b) Leading to catastrophic exacerbation of the disease
iii. Existence of intercurrent problems occasionally requiring surgery
d. Anaesthesia
i. Presenting numerous difficulties to the anesthe- siologist including cervical spine ankylosis and restrictive pulmonary disease
ii. Avoid tissue trauma in the form of local anes- thetic injections
iii. Presence of anatomical airway abnormalities iv. Alternative methods preferred
a) Nebulized lidocaine b) IV sedation
c) Nasotracheal intubation
v. Proper positioning and padding perioperatively vi. Vigorous chest physiotherapy and pulmonary
toilet postoperatively
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Fig. 1. A boy with fibrodysplasia ossificans progressiva showing a stiff neck, a narrow chest, and inability to raise arms upward due to ossifi- cation of the soft tissues on the lateral chest wall and axillary region, illustrated by the chest radiograph. The radiographs of both feet showed shortened 1st toes and hallux valgus with delta-shaped proxi- mal phalanges, monophalangism with absence of the interphalangeal joint of the great toes. The radiographs of both hands showed shorten- ing of the first metacarpal and the middle phalanx of the 5th fingers with clinodactyly.
