Fibrodysplasia

Ossificans
Progressiva (FOP)
By Peyton Kinon
What Is It?

● FOP is an autosomal dominant disorder

● The soft tissue of people with FOP are susceptible to ossification
○ Usually occurs after some trauma to the tissue
○ Trauma causes lumps to appear which eventually turn to bone
● Renders affected individuals unable to move after some time
● Average lifespan of someone who has FOP is about 40 years
History

● First known encounter in 1692 by French Physician Guy Patin

● 1736, British Physician John Freke describes the diagnosis of a boy who has symptoms of
FOP in detail
● 1900s, The disorder was named myositis ossificans progressiva
● 1970s, Its name was officially changed to Fibrodysplasia Ossificans Progressiva
● April 2006, The single gene mutation was pinpointed
Symptoms / Impact on the Family

● After the body is exposed to some trauma (falling, surgery, etc.) lumps will develop on the
affected area
○ The lumps will eventually ossify
● After many years, the affected individual will lose the ability to move certain limbs and
body parts, maybe even lose the ability to move anything at all

● Renders the individual completely dependant on their family in the later half of their life
● Family will have to be super cautious when the affected individual is young to make sure
they don’t fall and have a flare up
● Also, the short life expectancy can put severe emotional trauma on the family
Cause

● Caused a mutation in the ACVR1 gene

○ An arginine in codon 206 is changed to histidine due to a substitution mutation
○ Leads to an abnormal ACVR1 protein which activates and turns connective and muscle tissue to
bone (ossification)
● The gene is on chromosome 2
● Ossification usually stops when you are around 2-3 years old, but if you have FOP, the
gene is overactive and abnormal and continues ossifying
Treatments for FOP

● There is no cure for FOP yet

● Systemic Steroids can help smaller flare ups
● Acetic Acid and Iontophoresis (administration of medicine with an electric current) can
improve range of motion

● One hypothesized treatment is to create a drug which will block Activin-like Kinase 2
○ Activin-like Kinase 2 is a step in the ACVR1 gene’s protein signaling pathway
○ Blocking this kinase will effectively stop the gene from creating the mutated protein and could
stop ossification from occurring
Identification

● It is possible to do a chromosome analysis to see if your child might have FOP before they
are born
● If you don’t do the chromosomal analysis, people with FOP have distinctive toes which
can be seen at birth
● The disease is misdiagnosed 80% of the time
● Since the disease is so rare, doctors misdiagnose the lumps as cancer
○ They usually try to remove the lumps or amputate the affected limbs through surgery
○ This makes the disease flare up and is extremely harmful to an affected individual
Spreadsheet Calculations
https://docs.google.com/spreadsheets/d/1ok5iBSVoxRBhIFk4XgpLnEARGRFUsHRnDtr-
tpH6pWU/edit#gid=1552043631

1 in every 2,000,000 people have FOP. To find the p value, I first needed to find the q value.

PInitial = 0.00000025 (dominant allele, FOP) PFinal= 0

QInitial= 0.99999975 (recessive allele, no FOP) QFinal= 1

Spreadsheet Info
https://docs.google.com/spreadsheets/d/1ok5iBSVoxRBhIFk4XgpLnEARGRFUsHRnDtr-
tpH6pWU/edit#gid=1552043631

After 10 generations, the P (dominant) allele frequency was so small, it was essentially 0. The
model showed that nobody in any of the 10 generations developed the disease.

The P frequency each generation after the 1st was essentially 0

The Q frequency each generation after the 1st was essentially 1

Ethical Dilemma

Since the disease is autosomal dominant, if an affected individual has children, it is almost
guaranteed that their children will have it.

Because of this, some affected individuals might choose not to have kids because they don’t
want their children to have the disease. They also might not want to spread the disease and
increase its prevalence in the population.

However, my spreadsheet shows that this will not happen

https://docs.google.com/spreadsheets/d/1ok5iBSVoxRBhIFk4XgpLnEARGRFUsHRnDtr-
tpH6pWU/edit#gid=1552043631
Initial P Value: 0.00000025 Final P Value (10th Gen.): 0

Initial Q Value: 0.99999975 Final Q Value (10th Gen): 1

Ethical Dilemma (pt. 2)

To calculate this ethical dilemma, I decreased the amount of A (dominant) alleles in the
population each generation by 20%.

Since the frequency of the dominant allele is so little, it is essentially zero. Because of this, the
model didn’t report a single person with the disease.

If a single generation conainted 2,000,000 individuals, only one would have FOP, so it would
make sense that nobody had it.
Extra Content

Videos / Documentaries on the Disorder:

https://www.youtube.com/watch?v=cTxYXBi2Tpw&t=241s

https://www.youtube.com/watch?v=t0r44TcHlq8

https://www.youtube.com/watch?v=RttqmObTQiY

https://www.youtube.com/watch?v=RttqmObTQiY
Works Cited

“Fibrodysplasia Ossificans Progressiva - Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health,
ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva#genes.

“ACVR1 Gene - Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health,
ghr.nlm.nih.gov/gene/ACVR1.

“History of FOP.” IFOPA - International Fibrodysplasia Ossificans Progressiva Association, www.ifopa.org/history_of_fop.

“What Is FOP?” What Is FOP? | FOP Friends, www.fopfriends.com/what-fop.

“Fibrodysplasia Ossificans Progressiva.” Wikipedia, Wikimedia Foundation, 28 Feb. 2018,

en.wikipedia.org/wiki/Fibrodysplasia_ossificans_progressiva.

McKusick, Victor A, and Marla J. F. O'Neill. “FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; FOP.” Online
Mendelian Inheritance in Man, 4 June 1986, www.omim.org/entry/135100.

“Fibrodysplasia Ossificans Treatment & Management.” Fibrodysplasia Ossificans Treatment & Management:
Medical Care, Surgical Care, 18 July 2017, emedicine.medscape.com/article/1112501-treatment.