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The Curious Case Files: Fibrodysplasia Ossificans Progressiva (FOP)

  • Writer: Shrada Gopal
    Shrada Gopal
  • May 7
  • 3 min read

Dear Prospective Medical Students, it's time to scrub in.

Let us dissect the incredibly rare and intriguing case that is Fibrodysplasia Ossificans Progressiva.

Overview & Cause

FOP is an extremely rare, autosomal dominant, genetic disorder estimated to affect only 1 out of 2 million people worldwide. Tendons, muscles, and connective tissue eventually metamorphose into bone, forming a second skeleton (NORD). The disorder restricts movement due to the bone taking the place of soft tissue and will progressively worsen, possibly even leading to total immobility.

The disease is caused by a mutation in the ACVR1 gene. This gene, when healthy, ‘provides instructions for making the activin receptor type-1 (ACVR1) protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors’ (Medline). The BMP pathway regulates osteoblast (bone-forming) activity. When the BMPs bind to ACVR1 receptors, it trigger new bone formation and regulate the metamorphosis of existing cartilage into bone. In normal cells, the ACVR1 is activated in the development of children, where bone must grow or when there is physical trauma that requires bone repair. In FOP, this receptor is overactive, and cells receive constant signals for stem cells to form osteoblasts, therefore forming new bone. Minor injuries can trigger bone formation, causing the disorder to progress, eventually leading to complete immobility where the body’s tissues and ligaments have been overtaken by bones.


Symptoms


  • A hallmark feature is malformed big toes in the early years

  • Painful bumps under the skin (will develop into bone over time)

  • Loss of mobility due to “locked” areas like the jaw, neck, limbs, etc.

  • Shortened lifespan, typically due to respiratory problems caused by abnormal bone growth around the ribs/thoracic region


(ifopa)

Diagnosis

Look out for…

  • Clinical features 

  • Malformed toes

  • Painful bumps (nodules) under the skin

  • Genetic testing

  • ACVR1 gene sequencing, where a blood or saliva sample is taken and the DNA is extracted to identify any mutations within the ACVR1 gene

  • Imaging (X-rays, MRIs or CTs)

  • May show the abnormal bone growth within an area of soft tissue

 BUT BE AWARE: FOP can be misdiagnosed as cancer, and so biopsies can be taken, which will further worsen the disorder and trigger heterotopic ossification (formation of bones outside the skeleton)


Management & Treatment

Unfortunately, FOP has no definitive cure and can only be managed to help prevent complications. Maybe one of us, future doctors, will solve this problem in the future. For now, this is all we can do…


  • Prevent Flare-ups

    • Physical Injury and inflammation are seen to trigger abnormal heterotopic ossification, and so any and all invasive procedures and physical trauma should be prevented.

  • Therapy 

    • Physiotherapy will be provided to maintain flexibility and manage the development of muscle weakness as ossification limits movement and use of these muscles.

    • Physiotherapy will allow gentle exercises; however, they must be done very carefully to prevent inflammation

    • Occupational therapy should be provided to reduce day to day strain that could trigger inflammation

  • Medical Management

    • Corticosteroids reduce inflammation and, therefore, can limit progression into ossification

    • Palovarotene, a retinoid (Vitamin A derivative), has shown promise to slow ossification by reducing BMP signalling (PubMed1)(ifopa)

  • Genetic Counselling

    • If a parent is diagnosed with FOP, then genetic counselling and prenatal genetic testing can help identify the risks of a fetus inheriting the ACVR1 gene, as the disease is autosomal dominant.

  • CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)

    • ‘The CRISPR/Cas9 system has been developed as a genome-editing tool that can correct DNA mutations underlying human diseases.’ (PubMed2). 

    • CRISPR could potentially cut out the mutated DNA and replace it with the normal, correct sequence for a fully functioning ACVR1. 

    • It could even be used in IVF or gene editing embryos to prevent passing on the mutation to future generations

    • For the treatment of FOP, it is still within the realm of research due to various ethical issues around the idea of “designer babies” and the difficulties around delivering the Cas9 protein to the correct target cells. (PubMed3)


 
 
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