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FIBRODYSPLASIA OSSIFICANS PROGRESSIVA 1

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FOP FACT SHEET

What is Fibrodysplasia Ossificans Progressiva (FOP)?


One of the rarest, most disabling genetic conditions known to medicine, it
causes bone to form in muscles, tendons, ligaments and other connective
tissues. Bridges of extra bone develop across joints, progressively restricting
movement and forming a second skeleton that imprisons the body in bone.
There are no other known examples in medicine of one normal organ system
turning into another.

An example of the typical progression of FOP:


Spontaneous flare-ups of the disease arise in defined temporal and spatial
patterns, resulting in ribbons and sheets of bone that fuse the joints of the
axial and appendicular skeleton, entombing a patient in a skeleton of
heterotopic bone. These photos show an individual with FOP through his
lifetime.

How would understanding the cause of bone formation in FOP help


others?
The information obtained from studying this disease will have far reaching
implications for the treatment of common disorders such as fractures,
osteoporosis, hip replacement surgery, and other forms of heterotopic
ossification that occur in trauma and burn victims.

Demographics of FOP:

 Genetic disease affecting 1 in 2 million people


 No ethnic, racial, or gender patterns
 800 confirmed cases across the globe
 285 known cases in the United States
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Clinical Characteristics of FOP:

 Characteristic malformations of the great toe


 Flare-ups occur spontaneously or following bodily trauma such as: childhood
immunizations, falls while playing, viral illnesses
 Misdiagnosed in a majority of cases as cancer
 Surgery makes the condition worse
 There are no effective treatments

Finding a Cure and Treatment for FOP:

 Researchers at the University of Pennsylvania School of Medicine, the only


laboratory in the US dedicated to FOP research, announced the Discovery of
the FOP Gene in Nature Genetics in April 2006.
 10,000 sq. ft. of shared research space in the Department of Orthopaedic
Surgery
 3 principal investigators with 15 post-doctoral fellows, students, scientists,
and staff
 Funds spent on research - Approx. $1.5 million/year
 75% from FOP family fundraising and donations
 25% from institutional support (NIH/NIAMS, Orthopaedic Research and
Education Foundation)

History of FOP

FOP or fibrodysplasia ossificans progressiva (fibro-dis-play-sha os-sih-fih-cans


pro-gress-ev-a) means "soft connective tissue that progressively turns to
bone." The earliest documented cases date back to the 17th and 18th
centuries. In 1692, French physician Guy Patin met with a patient who had FOP
and mentioned the encounter in his writings. In 1736, British physician John
Freke described at length an adolescent whose diagnosis included swellings
throughout his back.

The disease became known as myositis ossificans progressiva, which means


"muscle turns progressively to bone." The name was officially modified to
fibrodysplasia ossificans progressiva in the 1970s by the late Dr. Victor
McKusick of Johns Hopkins University School of Medicine, who is considered
the father of Medical Genetics, in order to acknowledge that other soft (or
fibrous) tissues in addition to muscle (for example tendons and ligaments) are
replaced by bone.
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Symptoms

Fibrodysplasia ossificans progressiva (FOP) often begins in the neck and


shoulders and progresses along the back, trunk, and limbs of the body.

In addition, malformed big toes (short, bent, and sometimes curved inward)
are always associated with the condition and can be observed at birth. While
the toe malformations cause few problems, they serve as an important early
sign of FOP before the onset of extra bone.

Rather than crawl on their hands and knees, most kids with FOP scoot on their
buttocks; then get up and walk. The reason that most cannot crawl is because
the facet joints in the back of the neck have not formed properly or have
fused, thus limiting movement.

Although FOP is congenital, meaning that FOP starts before birth, the extra
bone does not form before birth.

Symptoms of FOP, including bone formation, usually begin during the first two
decades of life.

The majority of affected people learn that they have FOP before the age of ten.
Inflamed (sometimes painful) swellings, typically in the shoulder and back
areas and sometimes on the scalp or head, are usually the first sign of FOP.
The swellings eventually clear up, but they leave behind a new piece of mature
bone.

People who have FOP experience different rates of new bone formation. In
some the progress is rapid, while in others it is more gradual. In each case, the
exact rate of progression is unpredictable, although there appears to be a
pattern to the progression.

For example, extra bone formation tends to occur in the neck, shoulders, and
upper back early in life and in the hips and knees during adolescence or early
adulthood.
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Toes of infant with FOP:

More on FOP symptoms and misdiagnosis:

 Facts-In-Brief Sheet (PDF page 2 shows Flare-ups)


 FOP Misdiagnosis (webpage on IFOPA.org)
 Chapter 1 of "What is FOP? A Guidebook for Families" (PDF)
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MISDIAGNOSIS

FOP is one of the rarest diseases in the world. Few doctors encounter it in
medical school. Its symptoms are baffling and it is no wonder it is so
commonly misdiagnosed. Misdiagnosis rates for FOP have previously been
reported to be in the range of 80% or greater. Dr. Joseph Kitterman, Professor
of Pediatrics at UCSF, evaluated the misdiagnosis rates in FOP as well as the
most common causes for misdiagnosis. Suffice it to say, misdiagnosis of FOP
has caused a great deal of pain and suffering for FOP patients and families
worldwide.

For more information on this topic, please read Dr. Kitterman's


article, Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia
Ossificans Progressiva.

Three of the most common misdiagnoses for FOP have been reported to be:
cancer, aggressive juvenile fibromatosis, and fibrous dysplasia.

 FOP and Cancer


 FOP and Aggressive Juvenile Fibromatosis
 FOP and Fibrous Dysplasia

There are also many critical differences between FOP and the conditions listed
above. The key to diagnosing FOP is being aware of the condition,
understanding the association with the malformed toe, and also being aware of
the nature of how FOP progresses. An astute clinician knowledgeable about
FOP can diagnose the condition even before bone forms just from the presence
of the malformed great toes and the rapidly appearing soft tissue swellings
that form in characteristic anatomic locations.

One of the goals of the FOP community is to better educate physicians and
healthcare workers around the world about the proper diagnosis of FOP so that
dangerous misdiagnoses of FOP will not occur in the future.

FOP skeleton

The Skeleton of Harry Eastlack


The skeleton of Harry Eastlack, a man who lived with FOP until he died just six
days shy of his fortieth birthday, is on display at The Mutter Museum of The
College of Physicians in Philadelphia. Harry Eastlack's skeleton, one of the few
existing in the world, has become a valuable asset to physicians and scientists
studying the disease. Late in his life, Harry Eastlack made the decision to
bequeath his body to his physician who donated Harry's skeleton to The Mutter
Museum so that physicians and scientists in future generations could study and
learn about FOP.
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The glass case in which Harry Eastlack's skeleton dwells has become a window
into the medical mysteries and scientific challenges of FOP. It also exemplifies
the harsh reality of FOP more than any chart, slide, or clinical description could
accomplish.

Normal skeletons collapse into piles of loose bones when the connective tissues
that join bones together in life are removed. To be displayed in human form,
skeletons have to be re-articulated or pieced back together with fine wires and
glue. As a result of the bridges of bone that formed from FOP flare-ups, Harry
Eastlack's skeleton is almost completely fused into one piece, which proved
little challenge for the articulator's craft.

Sheets of bone cover Harry Eastlack's back. Ribbons, sheets, and plates of
bone lock his spine to his skull and his skull to his jaw. Additional ribbons and
cordons of bone span from the spine to the limbs and immobilize the
shoulders, elbows, hips, and knees. Thin stalagmites of bone launch
themselves from his pelvis and thighs. His upper arms are welded to his
breastbone by slender white bridges of bone that cross his immobilized rib
cage.

This FOP skeleton, which stands as Harry Eastlack stood in life, is a constant
reminder of how far scientists have come in the research of FOP, but it is also
a constant reminder of how much further they need to go. Harry Eastlack's
skeleton was graciously lent by The Mutter Museum to The International FOP
Association (IFOPA) for scientific and medical teaching at The Second and Third
International FOP Symposia held in Philadelphia in 1995 and 2000. Physicians
and scientists from around the world traveled to Philadelphia to learn about
FOP and to have the opportunity to view and study this now famous skeleton.

The Mutter Museum houses a collection of human specimens and models


depicting many diseases in various stages of development. This unique
museum is fitting for Harry's Eastlack's legacy, as Harry grew up in
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Philadelphia, and lived there his entire life with his mother, father, and sister.
In more recent times, Philadelphia has become the international center for FOP
research. The proximity of Harry Eastlack's skeleton to the FOP Center &
Laboratory and to its students, scientists, and visitors has added enormously
to its value in educating physicians, scientists, and patients alike across the
generations.

Although no member of the FOP research team at The University of


Pennsylvania in Philadelphia ever knew Harry Eastlack during his lifetime, they
have come to know Harry well posthumously through his remarkable bequest.
“Harry's skeleton is like The Sphinx. It stands silently and elegantly and
reveals its secrets if you ask the right questions,” said Dr. Frederick Kaplan
who leads the international FOP research team in Philadelphia. Dr. Kaplan and
members of his research team are frequent visitors to The Mutter Museum
where Harry's skeleton resides. ”When we discover something important about
FOP in the laboratory, we return to visit Harry's skeleton in order to confirm
the reality of the discovery. At other times, we may discover something about
Harry's skeleton that sends us running back to the laboratory to test a new
hypothesis about FOP,” Kaplan said. “The gift that Harry has given to the FOP
community is inestimable and his bequest has given additional meaning and
depth to medical and scientific research well beyond the confines of his mortal
existence. I never knew Harry in life,” added Kaplan, “But I bless his memory
every time I visit the museum where his legacy continues to educate and
inspire.”

FOP FAQ
Q - What does FOP stand for and when was it first documented?

A - FOP or Fibrodysplasia Ossificans Progressiva (Fibro-dis-playsha Os-sih-fih-


cans Pro-gress-eva) means "soft connective tissue that progressively turns to
bone." The earliest documented cases date back to the 17th and 18th
centuries.
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Q - How many people have FOP?

A - It is estimated that FOP affects about 3,300 people worldwide, or


approximately one in two million people. Such statistics may be better grasped
by the following example: if a large football stadium holds 100,000 fans, one
would need to fill nearly 20 football stadiums to find one person who has FOP.
At the present time, researchers are aware of approximately 700 people
throughout the world who have FOP.

Q - Can the extra bone be removed?

A - The technical answer is surprisingly "yes," but that does not tell the whole
story. Surgical intervention often results in a worsening of the condition. New
bone will grow back and further impair mobility.

Q - How is the extra bone in FOP different from normal bone?

A - The extra bone in FOP forms by a progressive transformation of soft tissue


into cartilage and bone. This is the same process by which bone regenerates
(heals) after a fracture (break) occurs and is nearly identical to the process by
which bone forms normally in an embryo. The abnormality in FOP occurs not in
the manner of bone formation but rather in its timing and location.

Q - What is a flare-up and is it painful?

A - A flare-up occurs when the body starts to generate new bone. No one
knows what initiates this process, but once it begins, it leads to tissue swelling
and much discomfort. Sometimes the individual will not feel well and may
develop a low-grade fever. While there is no medication or therapy that can
stop the process of bone formation once it has begun, a physician can
prescribe medicine to help relieve the pain. A single flare-up may continue for
as long as 6-8 weeks. Multiple flare-ups may also occur during an active period
of FOP. When a flare-up is in progress, joint stiffness may occur overnight. The
stiffness comes from swelling and pressure inside the muscle during the
earliest stages of new bone formation.

While flare-ups are usually painful, the degree of pain can vary. Most people
find that the pain subsides when a flare-up is over; it appears that it is the
process of extra bone formation, rather than the extra bone itself, that usually
leads to pain.

Q - Will FOP get worse? Does it ever stop or go away?

A - Unfortunately, FOP does not improve over time. The "P" in FOP stands for
"Progressiva." That means that FOP will progress, or get worse, as a person
ages. As FOP is part of a person's genetic make-up, people with FOP are born
with the condition, even though the extra bone may not have appeared at
birth. So people with FOP will not outgrow the condition. Nor can the extra
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bone that has been produced by FOP disappear. The body of a person with FOP
does not make extra bone all of the time; a person with FOP may go months or
years without a flare-up. Yet there is always a chance that extra bone can
form, either without any warning ("spontaneous flare-up") or following trauma,
such as a bump, fall, muscle overexertion, an injury, intramuscular injections,
surgery, or even some viruses. It is unclear why the disease is active some
times and quiet or dormant at other times.

Q - What parts of the body are involved in FOP? How does FOP affect
mobility?

A - FOP affects the neck, spine, chest, shoulders, elbows, wrists, hips, knees,
ankles, jaw, and many areas in between. The progression of ossification
follows a characteristic pattern. Usually extra bone forms in the neck, spine,
and shoulders before developing in the elbows, hips and knees. The muscles of
the diaphragm, tongue, eyes, face, and heart are characteristically spared. The
well-documented and characteristic progression of FOP, as well as the regions
not affected, likely hold important clues to the cause and development of the
disease.

FOP affects mobility because the body's joints, such as the knees or the
elbows, connect the bones and aid in movement. In FOP, extra bone replaces
the ligaments (which cover the joints), as well as muscles and tendons (which
move the joints). Consequently, movement in areas affected by FOP becomes
difficult or impossible.

Q - What physical variations are seen from person to person?

A - The largest variation seen is the timing and rate of extra bone formation.
Another common variation includes the severity of movement restriction. For
example, an elbow could be fixed in a closed position, putting the hand
permanently across the chest, or the elbow may be left with some range of
motion.

Q - Is there any treatment for FOP?

A - At this time, there is no treatment for FOP. For now, medication is only
helpful to manage the symptoms of FOP (pain, inflammation, etc.) For more
information, please read the The Medical Management of Fibrodysplasia
Ossificans Progressiva: Current Treatment Considerations.

Q - How does FOP affect a child's school life?

A - FOP does not affect a person's intelligence or cognitive abilities. It does,


however, negatively impact the child's ability to safely access the school
premises, use and manipulate the school's materials, and function
academically in a typical way. For a detailed discussion of the various issues
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that may arise in school and the ways others have dealt with them, please click
on one of the following resources:

 FOP and School article


 What is FOP? A Guidebook for Families, Chapters 23 and 24