Fibrodysplasia Ossificans Progressiva

Courtesy: ShivShankar Challa, MS, FRCS, MCh

 

MYOSITIS OSSIFICANS PROGRESSIVA

• Newer terminology – Heterotopic ossification
• Reactive lesion occurring in the soft tissue characterized by fibrous, osseous and cartilaginous proliferation and by metaplasia
• First described by Riedel in 1883
• Derived from Greek terminology.
• Hetero-other, Topos-location, Ossificans-bone formation

TRAUMATIC HO
• Fracture
• Dislocations
• Surgery
• Burns
COMMON SITES: Hip fractures, Elbow, Shoulder, Knee, Ankle, TM joint

Neurogenic HO
• After CNS insult :Head injury>spinal trauma
• InfectionsEncephalitis, Meningitis, Myelitis, Tetanus
• Genetic HO
• Fibrodysplasia ossificans progressiva
• Progressive osseous hyperplasia
• Albright hereditary osteodystrophy

• Myositis Ossificans Progressiva (MOP) is an older term for what is now more accurately known as Fibrodysplasia Ossificans Progressiva (FOP) — a rare and disabling genetic disorder in which soft connective tissues (like muscles, tendons, and ligaments) gradually turn into bone

• It is first described in 1692; gene identified in 2006
• Estimated prevalence: ~1 in 2 million people worldwide.

Epidemiology
Total known cases globally: Fewer than 1,000 confirmed living cases.

• FOP has no known racial, ethnic, or geographic predilection — it affects all populations equally
• No ethnic, racial, or geographic predisposition
• Usually presents in early childhood
• Symptoms typically begin in early childhood, often before age 10.
• Malformation of the big toes is usually present at birth — an early diagnostic clue.
• Heterotopic ossification often begins before age 5 and progresses over time
• Autosomal dominant inheritance, but:
• ~90% of cases are sporadic, caused by a new (de novo) mutation in the ACVR1 gene.
• If inherited, a parent with FOP has a 50% chance of passing it to a child.
• Autosomal dominant with complete penetrance
• Pathogenic variant: R206H in ~97% of patients

PATHOPHYSIOLOGY
• Abnormal BMP (bone morphogenetic protein) signaling
• Inflammatory flare-ups ? soft tissue ossification
• Skeletal muscle, ligaments, tendons affected
• Diaphragm, tongue, and smooth muscles spared

CLINICAL FEATURES
• Muscles ,Tendon and ligaments get gradually ossified
• Ossification around joint causes joint stiffness.
• Distribution of disease – dorsal, axial, cranial, proximal anatomic locations, ventral, appendicular, caudal and distal regions.
• Disease starts from neck and shoulders and flowing down trunk and into limbs.
• Loss of mobility is the primary disability.
• Involvement of TMJ – inability to open mouth difficulty in speech and eating.
• Most are bedridden by early twenties.
• Sporadic episodes of painful soft tissue swellings can occur in early childhood.
• Diaphragm, tongue and intraocular muscles are spared
• Phenotypic skeletal abnormalities
• Proximal medial tibial osteochondromas.
• Clinodactyly.
• Short broad femoral necks.
• Orthotopic ankylosis of costovertebral joints.
• Intercostal muscles ossification.
• Sensorineural hearing loss – involvement of cochlea or vestibulocochlear nerve.
• Conductive hearing loss – middle ear ossification.

Atypical features (FOP plus)
• Head and neck – sparse and atrophic scalp hair, cognitive impairment, diffuse cerebral dysfunction causing seizures, craniopharyngioma, cerebellar abnormalities, cerebral cavernous malformations.
• Eyes – cataract, retinal detachment, childhood glaucoma.
• Skeletal – synovial osteochondromatosis of hips and osteoarthritis, polyostotic fibrous dysplasia
• Severe growth retardation, persistence of primary teeth in adulthood, primary amenorrhea, aplastic anemia, hypospadias
• Most patients die from restricted lung disease, pneumonia, malnutrition, right sided heart failure.
• Median life span is 40 years.
• Female patients that get pregnant suffer increased risk. They can get acute flare-ups, breathing difficulty, necessary C-section and risk of general anesthesia.
• Fetal risk – FOP, prematurity, fetal distress, cerebral palsy

• Clinical suspicion based on:

DIAGNOSTIC CRITERIA
• Hallux valgus of great toes
• Progressive heterotopic ossification
• Confirmatory genetic testing (ACVR1 mutation)
• Avoid biopsy (risk of inducing ossification)

INVESTIAGTIONS
• Fibrodysplasia Ossificans Progressiva can be misdiagnosed easily
• It can be avoided by examining the individual’s toes for the hallux valgus and the short great toe feature, along with a thorough clinical examination and a positive test for the ACVR1 gene.
• Genetic testing can now be done to confirm the diagnosis of FOP before the appearance of heterotropic ossification, which may avoid possible invasive treatments and diagnostic testing.
• Blood Samples: Positive for heterozygous R206H mutation of the ACVR1 gene.

• XRAYS, MRI, CT

DIFFERNTIAL DIAGNOSIS
• Myositis ossificans traumatica
• Alkaline phosphatase disorders
• Soft-tissue sarcoma
• Progressive osseous heteroplasia

PROGRESSIVE OSSEOUS HYPERPLASIA
• It is a genetic disorder
• Heterozygous inactivating mutations in the GNAS1 gene
• Autosomal dominant disorder
• Extensive dermal ossification during childhood
• Followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue.

ALBRIGHT HEREDITARY OSTEODYSTROPHY
• It is a syndrome with a wide range of manifestations
• Short stature, obesity, rounded face, subcutaneous ossifications
• Characteristic shortening and widening of long bones in the hands and feet (brachydactyly mostly affecting the 4th and 5th rays).
• Anklylosis of TMJ

MANAGEMENT
• No specific treatment available.
• Attempted bone removal causes more extensive bone formation.
• Limited benefits reported with corticosteroids (short 4 day course during acute flare-ups)
and etidronate.
• NSAIDs to control further symptoms.
• Corticosteroids for early flare-ups
• NSAIDs, COX-2 inhibitors
• Bisphosphonates (limited evidence)
• Ongoing trials: Palovarotene (retinoic acid receptor ? agonist)
• Life-style modification.
• Restriction of outdoor activity and impact sports in children to prevent trauma.
• Household safety measures to prevent fall.
• Protection from respiratory decline (incentive spirometry).