Abstract
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Heterotopic ossification is usually progressive leading to severe deformities in the trunk and extremities. Early clinical diagnosis is important to prevent unnecessary iatrogenic harm or trauma. Clinicians should become aware of early detectable skeletal malformations, including great toe deformities, shortened thumb, neck stiffness associated with hypertrophy of the posterior elements of the cervical spine, multiple ossification centers in the calcaneus, and osteochondroma-like lesions of the long bones. Although there is presently no definitive medical treatment to prevent, stop or reverse heterotopic ossification in FOP, exciting advances of novel pharmacological drugs focusing on target inhibition of the activated ACVR1 receptor, including palovarotene, REGN 2477, rapamycin, and saracatinib, have developed and are currently in clinical trials.
Highlights
Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissues characterized by progressive heterotopic ossification in the skeletal muscles, ligaments, tendons, fascia, and aponeuroses, and malformations of the great toes
We describe various skeletal manifestations suggestive of FOP that can usually be seen before the appearance of heterotopic ossification, to make clinicians aware of these early signs and symptoms of FOP
HSPGs bind to and modulate the activity of Indian hedgehog (Ihh), which is expressed in prehypertrophic chondrocytes and regulates chondrocyte maturation, and the abnormal modulation of the tightly regulated Ihh/parathyroid hormone related peptide (PTHrP)-negative feedback loop has been proposed as a molecular model of osteochondroma formation in multiple hereditary exostoses, which is caused by mutations in EXT1, EXT2, or EXT3 genes, encoding tumor suppressors and glycosyltransferases involved in the biosynthesis of heparan sulfate proteoglycans (HSPGs) [35]
Summary
Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissues characterized by progressive heterotopic ossification in the skeletal muscles, ligaments, tendons, fascia, and aponeuroses, and malformations of the great toes. Flare-ups usually begin in the first decade of life, and several patients with FOP are misdiagnosed as having soft tissue tumors or aggressive fibromatosis before the appearance of heterotopic ossification [1]. They sometimes undergo dangerous and unnecessary diagnostic procedures that provoke heterotopic ossification formation leading to permanent harm and lifelong disability [2]. We describe various skeletal manifestations suggestive of FOP that can usually be seen before the appearance of heterotopic ossification, to make clinicians aware of these early signs and symptoms of FOP.
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