Fibrodysplasia (Myositis) Ossificans Progressiva (FOP)

The mutation. FOP is caused by an autosomal dominant gain-of-function mutation in ACVR1 (ALK2), a BMP type I receptor. The canonical mutation is R206H.

Activin A and the second skeleton. The mutant receptor responds aberrantly to Activin A, which normally would not activate this pathway, and dysregulates BMP/SMAD signalling. Following an inflammatory or traumatic trigger, connective-tissue progenitor cells pass through a fibroproliferative, then chondrogenic, then osteogenic sequence that ends in mature heterotopic bone, turning muscle, tendon, ligament and fascia into what is effectively a second skeleton.

Why the biology matters. This molecular understanding underlies the emerging therapies: Activin A antibodies, ALK2 inhibitors and the retinoic-acid-receptor-gamma agonist palovarotene.

View larger

View larger

Two hallmarks. The first is a congenital malformation of the great toes, short, valgus and monophalangic. It is present at birth, it is the most penetrant feature, and it is the diagnostic clue, often visible before any heterotopic ossification. The second is the progressive heterotopic ossification (HO) itself, which usually begins in early childhood.

Flares. The ossification arrives as painful soft-tissue swellings, the flare-ups, which mature into bone. They are frequently triggered by trauma or illness, including intramuscular injections, biopsies, surgery, dental and mandibular blocks, falls and viral illness.

The pattern. HO progresses in a characteristic anatomical order, generally axial to appendicular, cranial to caudal, proximal to distal and dorsal to ventral. Ossification typically starts in the neck, back and shoulders in the first decade and reaches the hips and knees later.

The course. The disease advances in steps rather than smoothly: long quiet periods punctuated by flares, each of which may resolve or may leave permanent bone. Bridging bone across joints causes cumulative ankylosis and immobility, and by the third decade most patients need a wheelchair.

How it ends. Restrictive lung disease is the main cause of death, and thoracic insufficiency syndrome is the usual terminal pathway: costovertebral and chest-wall ossification with spinal deformity produces progressive restriction. Reported median survival is around the fourth to sixth decade, and death commonly follows a pneumonia the patient cannot clear, or right heart failure.

View larger

View larger

What accumulates along the way. Short of the terminal decline, these are the problems easily overlooked:

• Temporomandibular ankylosis restricts mouth opening, causes real nutritional compromise and weight loss, and makes the airway hazardous.
• Conductive hearing loss is present in a substantial minority and is often middle-ear in origin. It is worth screening for in children so that it does not impair speech and schooling.
• Falls and fractures. A rigid, unbalanced patient with a fused spine falls badly. Fractures in FOP generally heal normally, but the trauma of a fall or of aggressive handling can itself set off a flare.
• Pressure sores and contractures follow from immobility and the inability to reposition.
• Ankylosis in a poor position is unfixable. Unlike acquired heterotopic ossification, the bone cannot be excised, so posture and seating are managed by adapting the environment to the patient.

Diagnosis. The diagnosis is clinical, made from the pathognomonic malformed great toes plus progressive soft-tissue ossification, and is confirmed by ACVR1 genetic testing, not by biopsy. FOP is repeatedly misdiagnosed as cancer or aggressive fibromatosis, which leads to a harmful biopsy, so recognising the great-toe clue is critical.

Imaging, not biopsy. Plain radiographs and CT define the great-toe malformation and the mature heterotopic bone, and let you plan around it for the airway and anaesthesia. CT or bone scan can show an active flare. The disease is characterised on imaging:

• The great toe. Short and often valgus, showing monophalangism (a single, malformed phalanx) with a short or abnormal first metatarsal. It is the earliest radiographic clue, and the thumbs may also be short.
• The heterotopic bone. Early flares are radiographically occult soft-tissue swellings. Ossification then appears and bridges across joints and along fascial planes and muscle as ribbons, sheets and plates of mature bone, characteristically sparing the heart, smooth muscle, diaphragm, tongue and extraocular muscles.
• The cervical spine. Tall, narrow vertebral bodies with large posterior elements and early facet fusion, which helps distinguish FOP from juvenile idiopathic arthritis.
• Elsewhere. Broad, short femoral necks and proximal-medial tibial osteochondroma-like exostoses.

General heterotopic-ossification imaging is covered in Heterotopic Ossification; the point here is the FOP signature.

View larger

View larger

View larger

View larger

The great toe is the discriminator. Recognise the toe malformation with soft-tissue-to-bone progression and a presumed tumour is not biopsied. The mimics:

• Progressive osseous heteroplasia (POH) is the closest genetic mimic, a GNAS-inactivating disorder in which dermal or superficial ossification progresses from the skin into deeper tissue. The great toes are normal and there are no inflammatory flares, so the absent toe malformation and the top-down, skin-first pattern separate it from the deep, flare-driven ossification of FOP. POH is distinct from the GNAS-activating McCune-Albright syndrome.
• Acquired, localised heterotopic ossification, meaning post-traumatic myositis ossificans, neurogenic HO and post-surgical HO, is localised, follows a defined event, comes with normal toes, and can be excised once mature, the opposite of FOP.
• Osteosarcoma, extraskeletal osteosarcoma and aggressive fibromatosis (desmoid) are the malignant or aggressive soft-tissue mimics that prompt the catastrophic biopsy, because an early FOP flare can look like a soft-tissue mass.

The individual mimics are covered in Myositis Ossificans, Osteosarcoma and Desmoid Tumor.

There is no cure, so management is supportive and preventive.

How rare. FOP affects roughly one person in one and a half to two million, with no ethnic, geographic or sex predilection. Most clinicians will meet at most one case, which is a large part of why it is misdiagnosed.

The silent family history. FOP is autosomal dominant, but the overwhelming majority of cases arise from a spontaneous new mutation, so the family history is almost always negative and affected people rarely reproduce. A clinician who reasons "no family history, so it cannot be a dominant genetic condition" will reach the wrong conclusion and order the biopsy.

When it is inherited. Inherited cases do occur, and an affected parent transmits the mutation to half their children, which is what makes genetic counselling meaningful once a diagnosis is made.