Fibrodysplasia (Myositis) Ossificans Progressiva (FOP)

The course, and what accumulates along the way

The disease advances in steps rather than smoothly - long quiet periods punctuated by flares, each of which may resolve or may leave permanent bone. Ossification typically starts in the neck, back and shoulders in the first decade, reaching the hips and knees later, and by the third decade most patients need a wheelchair. Reported median survival is around the fourth to sixth decade, with thoracic insufficiency syndrome the usual terminal pathway: costovertebral and chest-wall ossification with spinal deformity produces progressive restriction, and death commonly follows a pneumonia the patient cannot clear or right heart failure.

The problems that accumulate short of that are the ones easily overlooked:

• Temporomandibular ankylosis, which restricts mouth opening and causes real nutritional compromise and weight loss as well as making the airway hazardous. Dental care must avoid mandibular blocks and forced opening.
• Conductive hearing loss, present in a substantial minority and often middle-ear in origin, worth screening for in children so it does not impair speech and schooling.
• Falls and fractures: a rigid, unbalanced patient with a fused spine falls badly, and 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 from immobility and the inability to reposition.
• Ankylosis in a poor position, which is unfixable - unlike acquired heterotopic ossification, the bone cannot be excised, so posture and seating are managed by adapting the environment to the patient.

Treating a flare: the specifics

"High-dose corticosteroids" needs numbers and, more importantly, limits. The widely used regimen is prednisone around 2 mg/kg/day (to a ceiling of about 100 mg) for four days, started within 24 hours of the flare beginning - later than that and the window has largely passed. It is a short burst, not a taper and not a maintenance drug.

The limitation matters as much as the dose. Steroid bursts are reserved for flares affecting major joints, the jaw, or the submandibular region - the sites where a single flare can cost a joint or an airway. They are not used for flares of the back, neck and trunk, which are frequent and recurrent, because repeated courses would deliver a substantial cumulative steroid burden for a flare that is not threatening a critical structure. Those are managed with NSAIDs or COX-2 inhibitors and symptom control.

A submandibular flare is an emergency. Swelling in the floor of the mouth threatens the airway and swallowing in a patient who may already have limited mouth opening and a fused cervical spine, and it warrants urgent assessment rather than reassurance.

Palovarotene: approved, but not a benign drug

Palovarotene reduces new heterotopic ossification, and the pivotal open-label phase 3 trial is worth knowing in full, because what it cost is exactly what an orthopaedic surgeon needs to weigh:

• Efficacy was real but hard-won. The twelve-month interim analysis met futility criteria and dosing was paused; the trial continued on the recommendation of its data monitoring committee, and the benefit - roughly a 60% lower mean annualised new HO volume than natural-history controls - rests substantially on post hoc analyses rather than the prespecified one.
• Premature physeal closure occurred in 21 of 57 patients under 14 years - about 37%. In a growing child this is a drug that trades heterotopic bone for growth plates, which is precisely the trade an orthopaedic surgeon should be able to discuss. It is the reason for weight-adjusted dosing in the skeletally immature and for skeletal monitoring during treatment.
• Retinoid toxicity is near-universal (mucocutaneous effects in almost every patient), and post hoc imaging analysis suggested reduced vertebral bone mineral density and strength with increased vertebral fracture risk.

None of that means the drug should not be used - FOP is a devastating disease and the alternative has been nothing - but it is a genuine risk-benefit conversation in a skeletally immature patient, not a straightforward win. Garetosmab, an anti-activin A antibody, and ALK2 inhibitors are the agents in development behind it.

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

The inheritance point is the practically important one. 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. 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.