Fibrodysplasia ossificans progressiva

Fibrodysplasia Ossificans Progressiva

X-ray of a patient with fibrodysplasia ossificans progressiva showing extensive heterotopic ossification.

Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling genetic disorder characterized by the abnormal development of bone in muscles, tendons, ligaments, and other connective tissues. This process is known as heterotopic ossification, and it leads to the progressive restriction of movement as the joints become encased in bone.

Genetics

Electropherograms showing typical and atypical mutations in the ACVR1 gene associated with FOP.

FOP is caused by mutations in the ACVR1 gene, which encodes the activin A receptor type I, a bone morphogenetic protein (BMP) type I receptor. The most common mutation is a single nucleotide substitution, c.617G>A, resulting in the amino acid substitution R206H. This mutation leads to the constitutive activation of the BMP signaling pathway, causing inappropriate bone formation.

Pathophysiology

File:BMP pathway.JPG

Diagram of the BMP signaling pathway involved in FOP.

The BMP signaling pathway plays a crucial role in bone development and repair. In FOP, the mutation in the ACVR1 gene causes the receptor to be overly active, even in the absence of its ligand. This results in the continuous activation of downstream signaling pathways that promote the differentiation of mesenchymal stem cells into bone-forming cells, leading to heterotopic ossification.

Clinical Features

FOP is characterized by the presence of congenital malformations of the great toes, which are often short and bent. The hallmark of the disease is the episodic and progressive formation of bone in soft tissues, typically beginning in early childhood. Flare-ups can be triggered by trauma, viral infections, or spontaneously, and they lead to the formation of new bone, further restricting movement.

History

Gui Patin, one of the early physicians to describe a case of FOP.

The first known description of FOP dates back to the 17th century, when French physician Gui Patin documented a case. However, it was not until the 20th century that the condition was more thoroughly studied and understood.

Research and Advances

Victor McKusick, a pioneer in the study of genetic disorders, including FOP.

Significant advances in the understanding of FOP have been made in recent decades, particularly through the work of researchers such as Victor McKusick, who contributed to the field of medical genetics.

Dr. Frederick S. Kaplan, a leading researcher in FOP.

Dr. Frederick S. Kaplan and his team have been instrumental in identifying the genetic mutation responsible for FOP and in advancing research into potential treatments.

Dr. Eileen Shore, a prominent researcher in the field of FOP.

Dr. Eileen Shore has also played a key role in understanding the molecular mechanisms underlying FOP and in exploring therapeutic approaches to manage the condition.

Management

Currently, there is no cure for FOP, and treatment focuses on managing symptoms and preventing flare-ups. Avoidance of trauma and unnecessary surgical procedures is crucial, as these can exacerbate the condition. Research into potential therapies, including inhibitors of the BMP pathway, is ongoing.

Related Pages

• Heterotopic ossification
• Genetic disorders
• Bone morphogenetic protein