FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

Fibrodysplasia OssificansProgressiva: FOP

Maya BašaHuman Biology 2

Victoria Savoie-SwanMarch 25th 2013

1

Introduction

Fibrodysplasia ossificans progressiva, or FOP, is a rare

genetic, congenital disease where the patient’s muscle

progressively turns into bone, creating a ‘second skeleton’. In

this sense, the muscle tissue becomes ‘ossified’. The

involvement of the muscle tissue also explains the previous

names used for this disease, such as myositis ossificans,

myositis ossificans progressiva, progressive myositis

ossificans, and progressive ossifying myositis ("Fibrodysplasia

ossificans progressiva," 2013). Myositis is a term which

basically means an inflammation of muscular tissues ("The john

hopkins," ), which refers to the flare-ups associated with this

disease, that occur in the area where the extra bone will later

grow. Although this disease does involve the muscle tissue, the

problem is not with the muscle tissue, which is why the

currently used name now focuses on the ‘ossificans’, the bone

formation.

Cause

The sense in which the muscles are involved in this

condition, is that damage to the muscle tissue is what

instigates the proliferation of this disease in the body, and

2

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

instigates the further growth of the abnormal, mature bone

formations outside of the skeleton. The muscle damage can be

something such as a muscle tear, which can occur from

something as simple as a fall. In the average person, when

there is damage done to the muscle tissue, a signal is sent to

the brain, and the tissue repairs itself. In FOP the damaged

gene increases a certain type of signal to greater than

average levels. This improper signalling is what causes the

growth of a second skeleton (Kaplan, Kaplan & Shore, 2011).

As with most bones in the body, bones formed in an FOP

patient are formed through endochondral bone formation. This

is how bones such as femurs will grow. In this type of bone

growth, cartilage is first formed, and then is slowly replaced

by the mature bone tissue. Bone formation in those with FOP

occurs in exactly the same way as it would occur in the

average person, albeit with a few key differences. These key

differences lie in the location of the growth, the cells which

create the bone tissue, and what causes the bone growth.

The formation of the abnormal bone growth then begins

with an inflammation, or ‘myositis’ (Harmon, 2009) / oedema.

There is also an initial destructive stage where the damaged

soft tissue is infiltrated with lymphocytes, macrophages, and

mast cells. The process of inflammation tends to lead to

muscle cell injury and death (Kaplan, Pignolo & Shore, 2012)

after which the ossification begins with a congregation of

mesenchyme cells.

3

Mesenchyme cells are cells that differentiate to form all

types of connective tissue. This is where the chondroblasts

come from. Chondroblasts form cartilage tissue, performing

with cartilage what osteoblasts perform with bone ("What is

the," ). This initial tissue formation grows into the shape of

what will later become the bone. This process instigates the

occurence of chondrocytes, which cause calcification, a

hardening the cartilage. At this point, the osteoblasts take

over, creating a matrix of bone to replace the cartilage. This

tissue mass then becomes the periosteum, the outside of the

bone. Blood vessels begin to grow through the matrix and begin

a primary ossification centre. The cartilage within the

periosteum is then replaced by bone tissue, as the osteoblasts

cover the cartilage with bone matrix. Secondary ossification

centres then form at the ends of the bone, which then will

leave way for mature bone.

This entire process of bone formation is from cells that

can become any other type of cell. These cells are called

undifferentiated. In FOP the undifferentiated cells in

tendons, ligaments, and muscles start to form bone. This is

the basis of what happens in FOP patients. This creates a

second skeleton on top of, and around, the original one. This

abnormal growth can happen without any particular reason, or

can happen wherever there has been tissue damage. This unusual

bone growth is called heterotopic ossification (Lambert) .

4

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

Heterotopic ossification is not specific to FOP.

Heterotopic ossification is any bone formation in soft tissue

where bone does not generally form. This appears most often in

certain injuries, such as musculoskeletal trauma, spinal cord

injury, or CNS injury. A common example is patients who have

undergone an invasive hip replacement surgery (Shehab,

Elgazzar & Collier, 2002).

Progression

With FOP, although the heterotopic bone growth can be

stimulated by muscle damage, there is also a general

progression to the disease. The growths begin with swelling,

and inflammation, which can be quite painful for those

affected with FOP. The growths normally begins in the neck,

shoulders, and upper back progressing downwards and outwards,

affecting the axial skeleton first. This will generally happen

in the earlier years of life, often appearing between ages two

and five (St-Amant & Gaillard). Later on, the appendicular

skeleton is affected, with bone growth around the hips first,

and then along knees and other appendages. This tends to

happen around adolescence, or early adulthood. The joints of

the axial and appendicular skeletons become fused over time as

sheets and ribbons of bone tissue form all over the body.

Although most people with the condition are aware early on,

5

the progression of the ossification varies from case to case,

and can not be predicted.

This condition is congenital, which means that it is

present since before even birth. However, the actual

heterotopic bone growth does not begin until after birth. The

extra bone growth generally begins with in the first twenty

years of a person’s life, and most of those affected with this

condition are aware of it’s presence within their first decade

of life (Fop fact sheet).

Although obvious once the condition has progressed to a

certain stage, there are some indicators early in life that

can signal the presence of FOP in a child. One key symptom

that is evident since birth is a valgus deviation of the

distal phalanx (Barnett, 1962). This is essentially when the

big toe is malformed, turning inwards. The toe is generally

also shorter than average. The shortening of digits can also

affect the sufferer’s thumbs (Weiss, 2010).

As well as the valgus deviation of the distal phalanx,

there is certain behaviour in children that can be indicative

of FOP. For instance, the bones in the neck of infants may

have already fused, making it difficult for them to move their

neck, thus limiting their ability to crawl the way a normal

infant would. Therefore many infants with FOP tend to scoot

around instead of crawling. More obvious indications of this

condition are inflamed areas around the upper back, neck, and

shoulder area, where the abnormal bone growth tends to begin.

6

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

This inflammation does end up in bone formation, and is

generally one of the first signs of the heterotopic bone

growth in these patients (Fibrodysplasia ossificans progressiva).

For the condition itself, there are certain key features

that are characteristic of this

specific condition. FOP can be evaluated only with non-

invasive procedures, and some radiographic procedures used are

plain films, CT-scans, and MRI’s. The key features which a

radiologist would look for in identifying FOP in a patient are

hallux valgus, monophalangic first toe, shortened matacarpals,

pseudoexostoses, macrodactyly of the first

metacarpal/metatarsal, and neck muscles oedema (St-Amant &

Gaillard) .The hallux valgus, or bunion, the monophalangic

first toe, shortened metacarpals, pseudoexostoses, and

macrodactyly of the first metacarpal/metatarsal all allude to

the abnormalities associated with the thumbs and first toes of

FOP patients. The neck muscles oedema alludes to the initial

growth pattern that the heterotopic bone growth tends to

follow.

Hallux valgus affects the joint at the base of the first

toe. An increase in size, or a bump on the side, causes that

part of the foot to jut out abnormally (Bunions hallux valgus,

2006). This hard bony structure at the base of the first toe

is called a pseudoexostosis ("Hallux valgus," ). The

monophalangic first toe is basically what the valgus

deformation of the first toe/ distal phalanx describes. The

7

shortened metacarpals refers to the shortened length of the

thumbs and first toes of FOP patients, and is similar to

macrodactyly. Macrodactyly is a congenital condition where all

parts of the patients digits increase in size, except for the

metacarpal/metatarsal. Macrodactyly causes the shortened

metacarpals. These factors in combination result in the

characteristic shortened, deformed digits of FOP patients

(Farooque & Kotwal, 1998). It is not known why these symptoms

occur in those with FOP.

The last key characteristic which doctors will look for in

scans is neck muscles oedema. Oedema is a term which

essentially means fluid retention ("Oedema," ). The reason

this is a defining characteristic is because the growth tends

to start in this area of the body. The bone growth will start

with myositis (inflammation), and oedema (fluid retention)

before any bone growth even begins, which makes it a good

marker in the early stages of this condition’s progression.

Especially as this genetic condition is extremely rare,

as rare as only one person in every two million people being

born with it, (Weiss, 2010) it isn’t surprisingly that it can

be improperly diagnosed initially. There are only 700

documented cases of this illness worldwide. This lends to a

tendency of misdiagnosis for FOP, which occurs in

approximately 80% or more cases (Fibrodysplasia ossificans progressive).

Common misdiagnoses include scleroderma, CREST syndrome,

8

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

juvenile fibromatosis, dermatomyositis, and cancer (St-Amant &

Gaillard) .

Scleroderma is a type of disease that affects the skin

and connective tissue. With this condition, the skin as well

as internal organs can be affected, and the tissues become

hardened. It’s easy to see how FOP may become confused with

scleroderma, especially in the initial stages ("Scleroderma,"

2010). CREST syndrome is a limited form of scleroderma, and a

subtype.

Juvenile fibromatosis is different from scleroderma,

affecting the skin, but also affecting the bones and joints.

This condition, like FOP, is congenital, rare, and begins

within the first few years of life. With this condition, skin

bumps frequently will appear on the hands, neck, scalp, ears

and nose. These areas are also very similar to where FOP

symptoms first begin to take place as well (Juvenile hyaline

fibromatosis, 2013).

The last commonly confused condition is dermatomyositis.

This condition involves muscle inflammation, which is easily

confused, as myositis/oedema are key characteristics of the

first stages of FOP as well (Dermatomyositis, 2011). Cancer is

also a common misdiagnosis as the hard growths can sometimes

be misdiagnosed as tumours (Weiss, 2010).

Treatment

9

Once a proper diagnosis has been made for fibrodysplasia

ossificans progressiva, there are a limited number of options

for the patient. A patient generally requires full time

nursing care (Wzietek & Franczuk), and needs to be treated

extremely gently. The way the disease progresses, the growth

of a heterotopic skeleton continues throughout the person’s

life, with any injuries to the soft tissue initiating further

flare ups. The disease progresses at different rates in

different patients, leaving some more mobile longer than

others.

One of the common issues that can be seen in the

progression of this condition is when there is bone growth

around the neck and jaw, as this can make it difficult for a

person to eat, or speak. Something as simple as a dental

injection can trigger a flare-up that results in a fused jaw.

In these cases the front teeth of patients sometimes have to

be removed to allow the patients to be fed. The difficulties

in eating can still sometimes lead to malnutrition in some

patients. Some patients also develop scoliosis due to the

fusion of vertebrae in the spine. Bone growth around in muscle

tissue around the rib cage can also result in difficulties

breathing ("Fibrodysplasia ossificans progressiva," 2011). Due

to the extreme nature of this disease, and the lack of a true

cure, most patients will die before the age of 40

("Fibrodysplasia ossificans progressiva," ). However, there

are people who suffer from FOP that have been know to live

10

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

even into their 70’s ("Fibrodysplasia-ossificans-progressiva,"

).

The focus of treatment for FOP patients revolves around

medication taken orally, and anything non-invasive, as any

injections, or invasive surgeries would trigger more bone

growth. The bone growth can be removed surgically, but as the

invasive procedure would damage the soft tissue, it would

instigate yet another flare-up and end up exacerbating the

original problem ("Frequently asked questions," ).

Currently, patients are treated with corticosteroids, an

anti-inflammatory, which alleviate some of the symptoms such

as the myostisis and oedema flare-ups. Corticosteroids are

currently the best option, and can stop a flare-up if used

early enough.

As for a future cure, although there is no true cure for

this disease as of now, there is a lot of promise in the area.

FOP is a congenital condition, meaning the problems that cause

the conditions arise from a person’s genes, and can be

inherited. FOP is an autosomal dominant condition. This means

that a parent with the gene has a 50-50 chance of passing it

on to their offspring ("Fibrodysplasia-ossificans-

progressiva," ).

In 2006, the responsible gene for this disease was found.

The gene mutation is in the gene encoding Activin receptor

1A / Activin-like kinase 2 (ACVR1/ALK2). Each person has two

copies of this gene. In those with FOP, one of those genes is

11

mutated (Kaplan, Kaplan & Shore, 2011). This mutation is

recurrent and active. The mutation in ACVR1 / ALK2 that causes

FOP turned out to also be extremely specific to a bone

morphogenetic protein (BMP) receptor. The receptor is part of

a certain pathway whose disruption is critical in FOP. With

this knowledge, scientists began predicting possible molecules

that could be used to block this BMP pathway.

In the research of possible blocking of the BMP pathway

is a certain signal transduction inhibitor. In zebrafish

embryos it was found to be able to inhibit BMP signalling.

This compound, named Dorsomorphin, specifically inhibited the

section of the BMP pathway without affecting transforming

growth factor-beta (TGF-beta) activity or p38 MAPK activity

(Frederick & Shore, 2008). The TGF-beta activity is important

because it’s a group comprised of multifunctional peptides

that control proliferation, differentiation, adhesion,

migration, and many other important cell functions (Tgfb1

transforming growth, 2013). The MAPK, or mitogen-activated protein

kinase, p38 pathway is equally important as it plays a role by

creating a signals which are activated by pro-inflammatory

stimuli and other types of cellular stresses ("p38 mapk

activity," ). Although inflammatory issues are involved in the

unwanted heterotopic bone growth, cancellation of the body’s

reactivity to inflammatory stimuli is not ideal, which is why

Dorsomorphin was so promising (Frederick & Shore, 2008).

12

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

In regards to the future of Dorsomorphin, it is not

currently capable of being harnessed for human use. However,

there are newer iterations of the compound that are more

specific. Still, long-term safety concerns, tolerance,

rebound, and off-target effects prevail (Kaplan, 2013). One of

the issues that arises with Dorsomorphin is that the treatment

of the condition with the compound would likely be intensive,

and the doses needed forn effectiveness would be toxic to the

patient.

For instance, in a study with zebrafish, Dorsomorphin

caused severe and lethal embropathy, which is when there is a

morbid condition of abnormal embryonic development

(Embryopathy). In post-natal studies on mice, the compound

caused seizure activity. Furthermore, the studies conducted,

are conducted on different versions and different mutations

than those existing in current patients. So even where

Dorsomorphin is shown to work, it’s effectiveness may be

overstated (Frederick & Shore, 2008). Much work is being done

in several labs and pharmaceutical companies on Dorsamorphin

and its derivatives. All compounds also still need to be

tested on the classical model of FOP. Thus far, none of these

compounds have been tested on the classical model (Kaplan,

2013).

As for treatments not involving Dorsomorphin, there are

new possible paths for treatment such as blocking monoclonal

13

antibodies, BMP antagonists, inhibitory RNA, and agents that

alter the intracellular microenvironment of early flare-ups.

With blocking monoclonal antibodies, a monoclonal

antibody is a synthesized molecule that attaches to specific

cells. Monoclonal antibodies mimic your body’s natural

antibodies. These monoclonal antibodies are used to help block

the BMP pathways that allow over-activation of the ACVR1/ALK2

gene (Bronner, Farach-Carson & Helmtrud, 2010), in turn

causing heterotopic ossification to take place.

BMP antagonists, another possible path for treatment,

regulate BMP activity. Antagonists include noggin, gremlin,

and follistatin, and these antagonists create a feedback loop

in the BMP pathway. A defect in this pathway can lead to FOP,

which is why these antagonists have been brought more into

focus in terms of treatment for this condition (Ahn, Serrano

de la Pena, Shore & Kaplan, 2003). Regulating and monitoring

these antagonists could allow for a correction in the BMP

pathway, establishing a normalized BMP pathway, and BMP

response, which could result in the creation of a workable

solution for FOP patients.

Inhibitory RNA is yet another possible approach being

researched. Small sequences of RNA can be used to block the

damaged copy of the ACVR1/ALK2 gene, while leaving the un-

mutated version alone. By doing this, the cellular function

can be restored to normal. All of the ACVR1 / ALK2 mutations

can be rid from the cells with this approach. Researchers

14

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

pinpoint the difference in the genes, and target the mutated

one on the slight difference. The cells used in this approach

were adult stem cells, taken from the discarded baby teeth of

FOP patients. This approach has still yet to be tested on

classic models of FOP in mice, let alone humans (Kaplan,

Kaplan & Shore, 2011).

Agents which alter the intracellular microenvironment of

the early flare-up’s include, but are not limited to,

corticosteroids as well as other anti- inflammatory

medications. Which treatment, or which combination of

treatments will turn out to be best is still yet to be

determined.

Cases

As a rare disease, there are only a few extremely well

documented case studies to draw from. One of the few well-

documented and well-known examples is Harry Eastlack’s case.

Harry Eastlack was born in the early 1930’s, and discovered

his condition when he was five, while playing with his sister.

While playing, he broke his leg. The fracture never properly

set, and his leg, and then hip, stiffened. This was due to

strange bone growths appearing in his thighs.

Taking the path that FOP generally takes, the

heterotopic growths soon also began on his back, neck, and

chest, and later, buttocks. The doctors dealing with his

15

condition never knew what the disease was, and tried to solve

the excess growth by surgically removing it. However, with

FOP, surgically removing the growths only makes the growths

worse, with the bone plates growing back thicker and larger

than before (Angier, 2009).

By his mid-20’s, his back muscles were completely

replaced by bone.

Eastlack died in

1973 of pneumonia.

Shortly before he

died, he decided to

donate his body to

science. His

skeleton was

preserved and is

kept at the Mutter

Museum in

Philadelphia to this

day.

This is the skeleton of Harry Eastlack, one of the

original documented cases of FOP. The bone covering his

original skeleton, is the heterotopic bone growth, or ‘second

skeleton’ that is seen in FOP patients.

Another documented case is Peter Cluckey. Born in 1882,

and living until 1925, he began experiencing joint pain and

stiffness in his early 20’s, which is uncharacteristically

16

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

late for FOP. Initially diagnosed with chronic rheumatism, it

later become evident that he was suffering from FOP. Over the

next 20 years, all the joints in his body became fused. At

this point in a person’s diagnosis they have to decide what

position they want to spend the rest of their life in, as

their joints fuse together and lock them into a position.

Cluckey was moved into a sitting position so that he could be

placed in a chair. As with some other people who suffer from

FOP, he had to have his front teeth removed so that he could

be fed soft foods. His body, like Eastlack’s, was also donated

to science when he died in his early 40’s (Solomon).

A more recent case of FOP is Rachel Winnard, 26, from the

United Kingdom. At 26 she decided to marry her boyfriend while

she could still walk down the aisle. For people with FOP, as

already mentioned, they have to make the choice, at some

point, of what position they want to spend the rest of their

life in. Generally people choose to sit, and are able to be

move around in a wheelchair. This can sometimes casse the

problem of sores from sitting in the same position for such

extended periods of time.

In Rachel’s case, she has decided she wants a daughter.

With this condition, a child has a 50% chance of also ending

up with the condition, and a pregnancy can be extremely risky.

Pregnancy can actually accelerate the progression of the

growths as well ("Marry me before," 2011).

17

Support

For these people, it often takes years before they are

properly diagnosed, due to the rarity of the illness. But once

they are diagnosed, there are groups for the few that suffer

from the condition. MDJunction has an online support group,

and there are conferences and forums on the topic that people

with fibrodysplasia ossificans progressiva can attend to learn

more about their disease. IFOPA is another organization that

reaches out to support those dealing with FOP. IFOPA has

awards, holds benefits, fundraisers such as marathons, and

provides information on FOP, as well the contact information

of an array professionals.

Many specialist doctors are listed on the website, with

their contact information, as well as a few researchers from

the University of Pennsylvania. Among others, one of the

researchers listed is Frederick S. Kaplan. Kaplan is a

Professor of Orthopaedic Molecular Medicine and Chief of the

Division of Molecular Orthopaedic Medicine at the Perelman

School of Medicine of the University of Pennsylvania, and a

key researcher in this field. Another researcher listed on the

website, also a key researcher in this area, is Eileen M.

Shore, a Professor in the Departments of Orthopaedics and

Genetics in the Perelman School of Medicine at the same

university as Dr. Kaplan. She is also the co-Director of the

Centre for Research in FOP and Related Disorders.

18

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

One of the programs run through the University of

Pennsylvania is the tooth fairy program. This unique program

aims to help the university further it’s research in

inhibitory RNA in regards to FOP treatment. The RNA research

being done uses adult stem cells from the baby teeth of FOP

patients, and this program simply requests that children with

FOP who are losing their teeth send in their baby teeth. With,

of course, no cost to the child or family ("Ifopa," ).

Few labs are dedicated to research on FOP, but one of the

primary research centres is at Pennsylvania University. A

surprising amount of information has been uncovered about FOP,

which is surprising for a condition so rare. For such uncommon

conditions, it is less likely that a cure can be expected, but

since the finding of the specific mutated gene, research on a

cure for FOP has greatly expanded. There are many promising

avenues at this point, but of course, only time will tell.

19

References

1. Genetic Home Reference, (2013). Fibrodysplasia ossificans progressiva.

Retrieved from website:

20

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-

progressiva

2. The john hopkins myositis center and a current list of forms of myositis. (n.d.).

Retrieved from

http://www.hopkinsmedicine.org/myositis/myositis/

3. Kaplan, F. S., Kaplan, J., & Shore, E. M. (2011). Genetic

technology restores normal bmp signaling and suppresses bone

cell differentiation in a human stem cell model of fop: Proof-

of-principle for the treatment of fop.

4. Harmon, K. (2009). How can a genetic mutation cause muscle to

turn into bone?. Scientific American, Retrieved from

http://www.scientificamerican.com/article.cfm?id=genetic-

mutation-muscle-bone&page=2

5. Kaplan, F. S., Pignolo, R. J., & Shore, E. M. (2012). The

twenty-first annual report of the fibrodysplasia ossificans

progressiva (fop) collaborative research project.

6. What is the difference between chondroblasts and osteoblasts?. (n.d.).

Retrieved from

http://wiki.answers.com/Q/What_is_the_difference_between_chond

roblasts_and_osteoblasts

7. Lambert, K. (n.d.). How fibrodysplasia ossificans progressiva (fop) works.

Retrieved from http://science.howstuffworks.com/life/human-

biology/fop1.htm

8. Shehab, D., Elgazzar, A. H., & Collier, B. D. (2002).

Heterotopic ossification. J Nucl Med., 43(3), 346-353. Retrieved

from http://www.ncbi.nlm.nih.gov/pubmed/11884494

21

9. St-Amant, M., & Gaillard, F. (n.d.). Fibrodysplasia ossificans

progressiva. Retrieved from

http://radiopaedia.org/articles/fibrodysplasia-ossificans-

progressiva

10. Fop fact sheet. In IFOPA. Retrieved from

http://www.ifopa.org/what-is-fop/overview.html

11. Weiss, T. C. (2010). Fibrodysplasia ossificans progressiva

(fop) - facts and information. In Disabled World. Retrieved

from http://www.disabled-world.com/disability/types/fop.php

12. Fibrodysplasia ossificans progressiva. In UCSF Benioff

Children's Hospital. Retrieved from

http://www.ucsfbenioffchildrens.org/conditions/fibrodysplasia_

ossificans_progressiva/

13. Hallux valgus. (n.d.). Retrieved from http://www.schoen-

kliniken.com/ptp/medizin/mobilitaet/hand-fuss/hallux-valgus/

14. Farooque, M., & Kotwal, P. P. (1998). Macrodactyly. The

Journal of Bone & Joint Surgery, 80, 651-653. Retrieved from

http://www.bjj.boneandjoint.org.uk/content/80-B/4/651.full.pdf

15. Oedema. (n.d.). Retrieved from

http://www.nhs.uk/conditions/Oedema/Pages/Introduction.aspx

16. Scleroderma. (2010). Retrieved from

http://www.mayoclinic.com/health/scleroderma/DS00362

17. Juvenile hyaline fibromatosis. In (2013). Genetics Home

References. Retrieved from

http://ghr.nlm.nih.gov/condition/juvenile-hyaline-fibromatosis

22

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

18. Dermatomyositis. In (2011). MedlinePlus. Retrieved from

http://www.nlm.nih.gov/medlineplus/ency/article/000839.htm

19. Wzietek, B., & Franczuk, B. (n.d.). Surgical outcome in

fibrodysplasia ossificans progressiva: A case study. 6(5),

658-664. Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/17618217

20. Fibrodysplasia ossificans progressiva (fop). (n.d.). Retrieved from

http://www.wellness.com/reference/conditions/fibrodysplasia-

ossificans-progressiva-fop

21. Frequently asked questions. (n.d.). Retrieved from

http://www.cfopn.org/FAQ.htm

22. Frederick, S. K., & Shore, E. M. (2008). What should be

done to cure him: Lightning bug for fibrodysplasia ossificans

progressiva (fop) ?.

23. Kaplan, F. (2013). Personal Correspondence by Basa M.

[Personal Interview].

24. (n.d.). p38 mapk activity assay kit. Sigma, Retrieved from

http://www.sigmaaldrich.com/etc/medialib/docs/Sigma/Bulletin/c

s0250bul.Par.0001.File.tmp/cs0250bul.pdf

25. Bronner, F., Farach-Carson, M. C., & Helmtrud, I. R.

(2010). Bone and development. Springer. Retrieved from

http://books.google.ca/books?

id=VtkOUeD6A5sC&pg=PA245&lpg=PA245&dq=blocking monoclonal

antibodies

FOP&source=bl&ots=XMr6syWerf&sig=6ZxQycYC3HVoMla86Iawmp4qP4s&h

l=en&sa=X&ei=RotPUYi5N_GxygGPpIH4Bg&ved=0CDQQ6AEwAA

23

26. Ahn, J., Serrano de la Pena, L., Shore, E. M., & Kaplan,

F. S. (2003). Paresis of a bone morphogenetic protein-

antagonist response in a genetic disorder of heterotopic

skeletogenesis. Journal of Bone and Joint Surgery, 85(4), 667-674.

Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12672843

27. Embryopathy. In The Free Dictionary. Retrieved from

http://medical-dictionary.thefreedictionary.com/embryopathy

28. Fibrodysplasia-ossificans-progressiva. (n.d.). Retrieved from

http://runkle-science.wikispaces.com/Fibrodysplasia-

Ossificans-Progressiva

29. Fibrodysplasia ossificans progressiva. (2011). Retrieved from

http://www.livingnaturally.com/ns/DisplayMonograph.asp?

StoreID=9F623QASQBSR2L1C0G03N0ET9MQD62W2&DocID=condition-

fibrodysplasiaossificans

30. Angier, N. (2009, april 27). Bone, a masterpiece of

elastic strength. The New York Times. Retrieved from

http://www.nytimes.com/2009/04/28/science/28angi.html?_r=0

31. Solomon, S. (n.d.). The stone people - living statues. Retrieved

from http://thehumanmarvels.com/114/the-stone-people-living-

statues/other

32. Marry me before i turn into 'stone' : Woman rushes down

the aisle before rare disease leaves her unable to move.

(2011, march 22). Daily Mail, Retrieved from

http://www.dailymail.co.uk/health/article-1368763/Fibrodysplas

ia-Ossificans-Progressiva--Woman-rushes-aisle-rare-disease-

turns-statue.html

24

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

33. Ifopa. (n.d.). Retrieved from https://www.ifopa.org/

25