Fibrodysplasia (Myositis) Ossificans Progressiva

DEFINITION AND PATHOGENESIS

• (Munchmeyer's disease)
  • 1st reported by Patin in 1648
    • Described a woman who "turned to wood"
• Catastrophic heritable disorder in which massive progressive crippling heterotopic ossification from diffuse fibroblastic proliferation occurs
  • (Mendelian Inheritance in Man [MIM] #135100)
• Maps to chromosome 2q23-24
  • Heterozygous activating mutation of the gene encoding activin receptor A type I/activin-like kinase 2 (ACVR1/ALK2)
    • < 2% of pts with FOP have phenotypic and genotypic variants
• Two genes involved in FOP
  • Single base pair mutation (R206H) in the activin A type I receptor (ACVRI) gene
    • 617G>A mutation found in 52% of pts
    • 605G>T, 983G>A, 774G>C also described
  • Five mutations of the noggin gene have been described
    • delta 42, 274G>C, 275G>A, 276G>A, 283G>A
• The protein is a receptor for BMP4, being expressed in skeletal muscle and chondrocytes
• The mutation upregulates BMP4 and downregulates bone morphogenetic protein antagonists
• Has been reported in various animals (AD in pigs)
• Probable defect in endochondral osteogenesis induction
• Urinary basic fibroblast growth factor during acute flareups of the disease
• BMP4 overexpression involved in the pathogenesis of the disease, possibly inducing extraskeletal mesenchymal perivascular cells to become osteogenic cells
• International Fibrodysplasia Ossificans Progressiva Association

IMPORTANCE

• Bx is contraindicated as provocation of ossification will likely occur

CLINICAL FEATURES

• Usually affects children < 10 years of age presenting as lumps in the neck or back muscles
  • No racial or ethnic predilection
  • Masses mare be indurated
• By age 15, >95% have ? mobility of UE(s)
• May be precipitated by localized trauma
  • Has been precipitated by a lumbar puncture for a fever workup
  • Heterotopic ossification has been reported after diphtheria-tetanus-pertussis immunization
  • Episodic hectic flare-ups with cumulative disability
    • Flare-ups are like influenza-like viral illnesses
      • Culture-confirmed influenza B infections have been demonstrated as flare-up triggers
      • ? 3X ?­­ risk of FOP flare-up during influenza-like viral illness
  • Excision of a pterygium-like lesion followed by the formation of a corneal keloid has been reported
• Progressive heterotopic ossification
  • Begins at mean age of 4.6 yrs (0-16 yrs)
  • Traumatic fxs of HO bone can occur
  • May present with scalp nodules
• Axial involvement, then proximal, then distal extremity involvement
• Neck, spine, and shoulder are sites of early involvement
• Conductive deafness can occur
• Short (single phalanx) great toes with hallux valgus deviation
• Abnormality in the tibial aspect of the proximal phalangeal epiphysis of the hallux
• Short thumbs with short first MC
• Especially affects back, shoulder, and neck (sternocleidomastoid muscle)
• Relentless clinical course from early childhood
• Diffuse or multinodular soft tissue involvement
• ­Increased familial incidence (AD with variable expression)
  • Has been described in nomozygotic twins
• F=M
• Painful, doughy, soft tissue swelling
• "Chin-on-chest" deformity
• Superior subluxation of the shoulder
  • 21% of skeletally immature pts and 74% of skeletally mature pts
  • Synostosis of the humeral shaft to the chest wall by age 7
    • Continued growth of the humeral head causes the humeral head to migrate superiorly
• 90% reported to have a proximal tibial osteochondroma
  • Most commonly bilateral
  • Typically located at the pes anserinus
• 65% with scoliosis (15-80?)
  • (See below)
• EKG:
  • RBB
  • ? incidence of R ventricular abnormalities
• PFTs: restrictive defect and ? lung volume
  • Thoracic insufficiency syndrome with cardiorespiratory failure
    • Progressive dyspnea
    • Edema
    • Elevated jugular venous pressure with marked V waves
    • R ventricular heave
    • Hypoxemia
    • EKG evidence of R ventricular dysfunction
    • Pulmonary hypertension
      • Overactive BMP signaling may cause a direct pulmonary vascular problem from aberrant ACVR1/ALK2 signaling
    • Eventual cor pulmonale
• Brainstem mass requiring surgery for hydrocephalus has been reported
• Mandibular mass may present with trismus

RADIOLOGIC FEATURES

• Microdactyly; adactyly hand/feet symmetrical malformations
• Single great toe phalanx and short thumb MC
• Associated diseases
  • One reported associated phalangeal enchondroma has been reported
  • Two cases of synovial chondromatosis reported
  • Pseudohypoparathyroidism and fibrous dsyplasia reported
• Calcification and ossification of subcutaneous fat, muscles, tendons, aponeuroses, and ligaments
• Cervical spine abnormalities (similar to those seen in mice with homozygous deletions of the gene-encoding noggin (BMP antagonist) (though the noggin gene, NOG, is not mutated in pts with FOP)
  • Large posterior elements
    • Synostosis of the spinal processes may be seen
  • Tall narrow vertebral bodies
  • Fusion of the facet joints between C2 and C7
  • Segmentation defects
• Spinal deformities
  • 65% with scoliosis
    • 88% unbalanced C-shaped curves (15-80?)
      • 91% involved TL- or L-spine
    • 12% balanced S-shaped curves
  • 55% with osseous bridge between iliac crest and rib cage
    • High risk (86%) of these pts developing scoliosis
  • Ossification of paravertebral muscles limits development of normal thoracic kyphosis
  • Orthoses fails to halt curve progression and results in skin breakdown

GROSS PATHOLOGY

• Early: muscles are reddish-yellow and edematous; connective tissue swelling
• Ectopic bone attached to the skeleton or free in the muscles

HISTOLOGIC FEATURES

• Earliest finding is intense lymphocytic infiltration around vessels in apparently normal skeletal muscle
  • Inflammatory mast cells present at every stage but most pronounced at the highly vascular fibroproliferative stage
    • Mast cells at the periphery lesional tissue 40-150X > than normal muscle
      • Higher than any other inflammatory myopathy
• May be confused with fibromatosis early
• Endochondral ossification
• Immunohistochemistry
  • + vimentin
  • + keratin
  • ++ CD34 (endothelial cell marker)
  • +S-100 (probably early differentiating chondroblasts)
• Stromal cells express smooth muscle lineage markers and osteogenic transcription factor Runx2/Cbfa-1

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

• A dx of isolated congenital hallux valgus at a young age should raise suspicion, esp if a mass on the back occurs
• Rarely is the dx of fibrodysplasia ossificans progressiva considered prior to bx of what is suspected to be a malignancy (look at the toes!)
• Soft tissue sarcomas
• Pseudomalignant HO
• Idiopathic calcification in Weber-Christian disease
• Calcinosis circumscripta and universalis
• Dermatomyositis with calcinosis
• Progressive osseous heteroplasia

DISEASE COURSE AND TREATMENT

• Development of small molecule signal transduction inhibitors for activin-like kinase-2 in the BMP signaling pathway is a hopeful future tx
• Neck motion limitation
• Surgery helpful in repositioning a fixed joint, or for correcting hallux valgus
• Surgical correction of scoliosis fails to halt curve progression and exacerbates remote sites of HO
• Surgical removal of the masses, even a bx, exacerbates the condition
• Subluxation of the shoulder occurs because humeral shaft-chest wall synostosis is present and proximal humeral physis continues to grow
• Fxs have been reported in the normotopic and the heterotopic skeleton; both heal with non-operative tx
• High risk for catastrophic falls requires precautionary safety measures
• IV etidronate and PO corticosteroids or isoretinoin may have limited benefits
• Rosiglitazone (initially 4 mg, then 8 mg daily) and 5 mg prednisone daily reported to ? flareup episodes and ? articular mobility
• Pts often wheelchair bound by age 30
• Death due to pneumonia
  • Average age of death is 40 yrs (28-60 yrs)
• Death due to cardiorespiratory failure from thoracic insufficiency syndrome (most common cause of death)
  • Average age of death is 42 yrs (8-58 yrs)
  • Contributing factors
    • Costovertebral malformations with early orthotopic ankylosis of the costovertebral joints
    • Fusion of the ribs
    • Ossification of intercostal muscles
    • Ossification of paravertebral muscles
    • Ossification of aponeuroses
    • Progressive spinal deformity
      • Kyphoscoliosis
      • Throacic lordosis
  • Cor pulmonale
    • Echocardiograms may be normal
    • 40% with EKG evidence of R ventricular dysfunction (periodic EKGs warranted)
      • R ventricular hypertrophy
      • Cor pulmonale
      • Incomplete RBBB
      • R ventricular strain pattern
  • Unmonitored O2 tx should not be used because of chronic hypercarbia
    • Respiratory drive will fail with O2 use, leading to death
  • Thickening of the aortic valve cusps and mitral valve leaflets as well as shortening and thickening of the chordae tendineae of the mitral valve has been reported on autopsy
• Death from catastrophic falls and complications of head injuries
  • Average age of death is 41 yrs (32-46 yrs)
  • Even if fall isn't fatal, flareup of disease usually leads to permanent loss of movement
• Median lifespan 56 yrs (95% confidence interval, 51-60 yrs)

SPECIAL CONSIDERATIONS

Familial Fibrodysplasia Ossificans Progressiva

Limited Fibrodysplasia Ossificans Progressiva

• Familial disease with limitation to the mandibular area has been reported
• Mild form of Fibrodysplasia Ossificans Progressiva* An 80-year-old man whose daughter had classic features of FOP, lacked the great toe deformity and was reported to experience slow progression of the disease
• Late onset of HO has been reported

Animal Model

• A fibrodysplasia ossificans progressiva-like condition has been reported in cats

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Bizarre Parosteal Osteochondromatous Proliferation

Heterotopic Ossification