1. Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. FOP is the most catastrophic disorder of HO in humans. Flare-ups are episodic; immobility is cumulative. 

A common mutation in the activin receptor IA (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor, exists in all sporadic and familial cases with a classic presentation of FOP. 

An estimated 97% of individuals with FOP have this recurrent mutation. Approximately 3% of affected individuals have different pathogenic variant mutations in ACVR1. However, all known individuals with FOP have mutations in the ACVR1 gene. 

The discovery of the FOP gene established a critical milestone in understanding FOP, revealing a highly conserved therapeutic target in the BMP signaling pathway, and propelling approaches for the development of novel inhibitors of ACVR1-mediated BMP pathway signaling. While effective therapies for FOP will likely be based on interventions that modulate overactive ACVR1 signaling or specifically block postnatal HO, present management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. 

Here, we briefly review the clinical and basic science background of FOP, the scientific basis for the use of various medications, special medical considerations, and guidelines for the symptomatic relief of symptoms of FOP based upon currently available knowledge. This report is not intended to present a specific approach for managing the symptoms of FOP, but rather is intended to present views, statements, or opinions of the authors that may be helpful to others who face similar challenges. 

Further advances in therapeutics will be based on knowledge of disease mechanisms at the molecular and cellular level, the refinement of genetically based animal models for drug testing, and rigorous clinical trials to assess novel and emerging treatment and prevention strategies.