Fibrodysplasia Ossificans Progressiva (FOP): Understanding the “Stone Man Syndrome”

Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare and disabling genetic disorder of connective tissue. It causes the body to gradually replace muscles, tendons, ligaments, and other soft tissues with bone, a process called heterotopic ossification. Over time, this leads to severe loss of mobility and permanent disability.

What Causes Fibrodysplasia?

FOP is caused by a genetic mutation on chromosome 2 in the ACVR1 gene. This mutation increases the activity of a signaling pathway that drives abnormal bone formation. Most cases are sporadic, meaning they occur without a family history, but some are inherited in an autosomal dominant pattern.

Symptoms of FOP in Children

Children with Fibrodysplasia Ossificans Progressiva are often born with malformations of the big toes (such as hallux valgus, shortened big toes, or monophalangy), which is a very characteristic and distinctive symptom of this disease. During early childhood, painful episodes called flare-ups may occur. These flare-ups can be triggered by:

• Soft tissue injuries (falls, bumps, or bruises)
• Intramuscular injections or surgeries
• Viral infections
• Fatigue or muscle stretching
  

Each flare-up can transform healthy muscle or connective tissue into bone. As the disease progresses, bone bridges form between joints and limit movement. Therefore, invasive medical procedures should be avoided in suspected FOP patients, as they can trigger ossification.

FOP Variants

In addition to the classic form of the disease, there are:

• FOP Plus: patients have typical FOP symptoms plus other rare conditions (such as aplastic anemia, childhood glaucoma, or growth retardation).
• FOP Variants: patients show unusual features, such as normal great toes or more severe skeletal malformations.
  

Prevalence 

Fibrodysplasia Ossificans Progressiva is extremely rare, with an estimated frequency of 0.6 cases per million people worldwide. In Poland, about 16 cases have been diagnosed.

Treatment and Research

Currently, there is no cure for Fibrodysplasia Ossificans Progressiva. Once heterotopic bone forms, it cannot be surgically removed, as surgery itself causes new bone growth.

Treatment focuses on:

• Avoiding triggers such as trauma and unnecessary medical procedures
• Managing inflammation and pain during flare-ups
• Supportive therapies to maintain quality of life

In 2023, the first drug for FOP — palovarotene — was approved by the FDA. Although not yet available in all countries (including Poland), this marks a promising step toward better management of the disease.

References

• Kaplan FS, Xu M, Glaser DL, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1 – PubMed
• Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects | Orphanet Journal of Rare Diseases
• IFOPA – International Fibrodysplasia Ossificans Progressiva Association