Fibrodysplasia ossificans progressiva (FOP) is a progressive, disabling,
ultra-rare
Ultra-rare The Food and Drugs Administration defines a rare disease as any condition affecting less than 200,000 people. There is no formal definition of an ultra-rare disease in the US,29 but in the UK the National Institute for Health and Care Excellence has defined it as a prevalence of <1 per 50,000 people.30
genetic disorder characterized by cumulative and irreversible
heterotopic ossification (HO)
Heterotopic ossification Heterotopic ossification or HO is the presence of bone where bone should normally not exist.3
that leads to loss of mobility and shortened life expectancy.1–3
In patients with FOP, anatomically normal bone forms at extraskeletal sites within soft and connective tissues such as skeletal muscles, tendons, ligaments, fascia and aponeuroses.3,4
FOP is caused by a mutation in the ALK2/ACVR1 gene, a BMP type 1 receptor.12
Bone morphogenetic proteins (BMPs) are extracellular ligands belonging to the TGF-β superfamily, and play a key role in tissue homeostasis.19–22
Approximately 97% of patients with FOP have the same gain-of-function mutation: R206H in the ALK2/ACVR1 gene9,12,23
Other mutations in the ALK2/ACVR1 gene have been identified in approximately 3% of patients with FOP.23
The mutation is not inherited in most cases of FOP, it arises from a spontaneous missense mutation in the ALK2/ACVR1 gene.12 This mutation changes the ligand response profile of the ACVR1 receptor, so that it becomes activated by the usually antagonistic activin A ligand. This causes increased BMP signaling, leading to abnormal bone formation and in turn, heterotopic ossification (HO).24,25
The R206H gain-of-function mutation in the ALK2/ACVR1 gene causes FOP by changing the response to ligands24,25
The characteristic sign of FOP is congenital bilateral great toe malformation. Almost all patients with FOP are born with this malformation13,14
Other signs and symptoms of FOP begin in early childhood and include tumor-like swellings in the head, neck or back13,26
Another sign of FOP in young children is that instead of crawling they will scoot on their buttocks, because of limited neck movement27,28
Patients living with FOP share their stories of what life is like living with this condition
Watch Danie’s Story
Danie describes her experience growing up and living with FOP.
Watch Nadine’s Story
Nadine, patient living with FOP, discusses the symptoms that had the biggest impact on her quality of life.
Flare-ups often present as painful soft-tissue swellings that are warm to the touch.14
Patients experience episodes of soft tissue swelling, warmth, pain, stiffness and reduced movement, known as flare-ups.14 Flare-ups appear spontaneously or after muscle fatigue, trauma, intramuscular injections or viral infections.29-31 Although some flare-ups regress spontaneously, many lead to HO, which transforms soft and connective tissues, including aponeuroses, fascia, ligaments, tendons and skeletal muscles, into heterotopic bone.3,4
Typically, HO begins in the dorsal, proximal, axial and cranial regions of the body (neck, shoulders, back) and progresses into ventral, caudal and distal regions (trunk and limbs).29-31 HO develops into ribbons, sheets, and plates of extra bone throughout the body and across joints, progressively restricting movement.4,33
Other clinical features observed in patients with FOP are proximal medial tibial osteochondromas, cervical spine malformations, short, broad femoral necks, hearing impairment, and malformations of the thumbs.34
The process of HO begins early in childhood. Some flare-ups occur as a result of viral infection or injury, but others occurs spontaneously.14
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