FOP Skeleton....

The Skeleton of Harry Eastlack

The skeleton of Harry Eastlack (1933 – 1973), a man who lived with FOP until he died just six days short of his fortieth birthday, is on display at The Mutter Museum of The College of Physicians in Philadelphia.

At age 5, he broke his left leg while playing with his sister. There were complications with the fracture, which did not set properly. The hip and knee stiffened and bone growths began to develop on the muscles of his thigh. Within some years the condition spread to other parts of his body, ossifying his tendons and muscle and fusing his joints. By his mid-20s his vertebrae had fused together. He died from pneumonia in November 1973, six days before his 40th birthday. At the time of his death his body had completely ossified; even his jaw locked up, leaving him able to move only his lips.

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. Unfortunately, when Harry was alive, he never met another person with FOP. Harry Eastlack's skeleton, one of the few existing in the world, has become a valuable asset to physicians and scientists studying Fibrodysplasia Ossificans Progressiva (FOP). 

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.

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. Dr. Frederick Kaplan said that “Harry's skeleton is like The Sphinx. It stands silently and elegantly and reveals its secrets if you ask the right questions,”….“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 added. “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.”

Source: ifopa

What Discovery says......

Inheritance

How do people inherit Fibrodysplasia Ossificans Progressiva (FOP)?

FOP is inherited in an autosomal dominant pattern, which means one copy of the mutated gene in each cell is sufficient to cause the disorder.

Most cases of Fibrodysplasia Ossificans Progressiva (FOP) result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. In a small number of cases, an affected person has inherited the mutation from one affected parent.

How it is possible....

How are changes in the ACVR1 gene related to health conditions?

Now we all know that Fibrodysplasia Ossificans Progressiva (FOP) is caused by mutations in the ACVR1 gene. All individuals with a definite diagnosis of FOP have a mutation in which the protein building block (amino acid) ‘histidine’ is substituted for the amino acid ‘arginine’ at position 206 of the ACVR1 protein (written as Arg206His or R206H). Researchers believe that under certain conditions this mutation may change the shape of the receptor. This shape change may disrupt the binding of an inhibitor protein such as FKBP12 or interfere with other mechanisms that control activation. As a result, the receptor may be constantly activated (constitutive activation) even in the absence of ligands. Constitutive activation of the receptor causes overgrowth of bone and cartilage and fusion of joints, resulting in the signs and symptoms of Fibrodysplasia Ossificans Progressiva (FOP).

Source: www.ghr.nlm.nih.gov

Function of ACVR1 Gene....

What is the normal function of the ACVR1 gene?

The ACVR1 gene provides instructions for making the activin receptor type I protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors. BMP receptors span the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This arrangement allows receptors to receive signals from outside the cell and transmit them inside to affect cell development and function.

Activin receptor type I is found in many tissues of the body including skeletal muscle and cartilage. It helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone (ossification). This process occurs in normal skeletal maturation from birth to young adulthood.

Activin receptor type I is normally activated at appropriate times by molecules called ligands. Activation may occur when these ligands, such as BMPs, bind to the receptor or to other proteins with which it forms a complex. A protein called FKBP12 can inhibit activin receptor type I by binding to the receptor and preventing inappropriate (leaky) activation in the absence of ligand.

ACVR1 gene.....

The official name of the ACVR1 gene...

The official name of this gene is “activin A receptor, type I.”

ACVR1 is the gene's official symbol.

Where the ACVR1 gene located...

Cytogenetic Location:  2q23-q24

Molecular Location  : base pairs 158,592,957 to 158,732,373 on chromosome 2

The ACVR1 gene is located on the long (q) arm of chromosome 2 between positions 23 and 24.

More precisely, the ACVR1 gene is located from base pair 158,592,957 to base pair 158,732,373 on chromosome 2.

Source: www.ghr.nlm.nih.gov

The Gene....

Which gene is related to Fibrodysplasia Ossificans Progressiva (FOP)?

Mutation in ACVR1 gene cause Fibrodysplasia Ossificans Progressiva (FOP).

The ACVR1 gene provides instructions for producing a member of a protein family called bone morphogenetic protein (BMP) type I receptors. The ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage. It helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone (ossification) that occurs in normal skeletal maturation from birth to young adulthood.

Researchers believe that a mutation in the ACVR1 gene may change the shape of the receptor under certain conditions and disrupt mechanisms that control the receptor's activity. As a result, the receptor may be constantly turned on (constitutive activation). Constitutive activation of the receptor causes overgrowth of bone and cartilage and fusion of joints, resulting in the signs and symptoms of Fibrodysplasia Ossificans Progressiva (FOP).

Source: www.ghr.nlm.nih.gov

The Discovery.....

The Gene Discovery

On 23^rd April, 2006, after 15 years of painstaking research, the FOP research team at the University of Pennsylvania, School of Medicine and their international collaborators, pinpointed a single gene mutation—one out of 6 billion human genome—which is the culprit of such devastating bone growth in Fibrodysplasia Ossificans Progressiva (FOP).

Senior authors Eileen M.Shore, Ph.D. and Frederick S. Kaplan, MD, both from the Penn Department of Orthopaedic surgery and their international consortium of colleagues report their findings on April 23^rd, 2006 in advance online edition of “Nature Genetics”.

As per Kaplan “This discovery of the FOP gene is relevant to every condition that affects the formation of bone and every condition that affects the formation of the skeleton”.

Eileen Shore, a research associate professor of orthopaedic surgery at the University of Pennsylvania, has been studying the disease since 1991~ "I always had been interested in development on a cellular level" she says— "What changes a cell, or what regulates a cell to follow certain cell fate decisions? We usually think about development on an organism level, but it was more a question of what determines the personality of the cell?". 

In 2009, Shore and her team found some of the key biochemical steps that lead soft tissue cells to turn to bone—the results were published in the ''Journal of Clinical Investigation'' in November’09. 

Diagnosis

In most cases, an accurate diagnosis of Fibrodysplasia Ossificans Progressiva (FOP) can be made based on the patient's characteristic signs and symptoms of the disorder. Young children typically have malformed big toes and painful, tumour-like swellings on the head, neck, and/or back.

However, researchers believe that FOP is often misdiagnosed because it is a rare disease, affecting about one out of every two million people worldwide. Three most common misdiagnoses of FOP are Cancer, aggressive juvenile fibromatosis and progressive osseous heteroplasia. Experts estimate that the rate of misdiagnosis of FOP is arround 80% or higher.

Complications

General: There are many complications associated with Fibrodysplasia Ossificans Progressiva (FOP) because the condition leads to progressive loss of mobility as more and more parts of the body become affected. Frequent illnesses or trauma to the body may speed up the disease progression.

Breathing problems: If extra bone replaces the tissues over the rib cage, the patient may not be able to expand their lungs normally. As a result, breathing may be difficult.

Difficulty speaking or eating: If extra bone develops in the jaw joints, a person may have difficulty speaking or eating. In some cases, difficulty eating may lead to malnutrition.

Limited mobility: As bone replaces muscles and connective tissues, the person with FOP typically experience limited mobility in the affected parts of their bodies. As a result day-to-day activities such as walking and getting dressed, may be challenging. Most FOP patients are bedridden by the time they reach 30 years of age.

Skin sores: People with FOP especially adults often develop pressure sores on their skin. Sore and broken skin may develop if extra bone puts pressure on the skin. Therefore, people with FOP should wear protective padding over bony bumps on their bodies and they are encouraged to change sitting positions frequently. People who sit for many hours during the day are encouraged to use well-padded seat cushions.

Skin sores may also develop if the skin becomes moist or sweaty in difficult-to-reach areas. Because people with FOP often have limited mobility of their joints, they may be unable to properly clean the skin. As a result, bacterial or fungal infections may develop on the skin.

Complications vary among patients with FOP, depending on which part of the body is affected.

Source: www.wellnwss.com

Cause

Genetic mutation

People with Fibrodysplasia Ossificans Progressiva (FOP) are born with mutations in the activin A receptor, type I (ACVR1) gene. Normally, this gene provides the body with instructions on how to produce the activin receptor type I protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors. The ACVR1 protein is present in many body tissues, including the skeletal muscles and cartilage. The protein helps regulate the growth and development of muscles and bones. It also helps control the gradual replacement of cartilage by bone that occurs when a person grows into an adult.

Random occurrence

Nearly all cases of FOP occur randomly and are not inherited. Instead, the genetic mutation randomly occurs during the development of the egg, sperm or embryo.

Inheritance

When FOP is inherited, it is passed down as an autosomal dominant trait— i.e. one copy of the mutated gene (from any of one parent) is enough for a child to develop the disorder. However, FOP is rarely inherited because most people with the disorder are unable to have children.

Source: wellness 

But the problem lies.......

The gene which causes ossification is normally deactivated after a fetus’ bones are formed in the womb—but in patients with FOP, the gene keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during apoptosis (self-regulated cell death), resulting in lymphocytes containing excess bone morphogenetic protein 4 (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements. These elements, however, can fuse with normal skeletal bone. 

Interestingly, the diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and smooth muscle. Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes—BMP4 is a protein which contributes to the development of the skeleton in the normal embryo.

Because the disease is so rare, the symptoms are often misdiagnosed as cancer or fibrosis—leads doctors to order biopsies, which can actually exacerbate the growth of these lumps.

Symptoms

FOP 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 decades of life.

The majority of affected people learn that they have FOP before the age of ten. Inflamed (and 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.

Source : www.ifopa.org

Epidemiology

Frequency

Demographics of FOP

ü The prevalence of Fibrodysplasia Ossificans Progressiva (FOP) has been estimated at 1 case per 2 million persons.

ü 700 confirmed cases across the globe, from an estimated 2500.

ü  285 known cases in the United States and 45 in the UK.

Mortality/Morbidity

In most cases FOP (Fibrodysplasia Ossificans Progressiva) usually starts in early infancy with episodes of soft tissue swelling, although skeletal deformations are present at birth. The prognosis is poor because of the involvement of thoracic muscles, leading to restrictive lung disease. Most of the patients become bedridden by time they are in their 30’s.

Race

FOP mainly occurs in whites, but it is also reported in blacks.

Sex

FOP is more common in females than in males. The observed male-to-male transmission of the disorder excludes X-linked inheritance. Because few individuals who are affected choose to have children, most patients are considered to have new mutations.

Age

FOP usually starts in early infancy; however, reports exist of in utero involvement and skeletal deformations are present at birth.

FOP starts at....

So when does FOP start?

When someone with FOP is born, there is no evidence that there is any of the extra-skeletal bone which has started. The child’s embryonic development is pretty normal—except for a bent great toe. The bone formation typically starts by the age of 5. There have been some cases where it starts in the 1^st month and others where someone is 10 or little greater.

History

The 1^st case of Fibrodysplasia Ossificans Progressiva (FOP)

In 1692, French doctor Guy Patin was the first physician to record a case. The first thorough documentation of the disease was in 1740, when a London physician described an adolescent with large swellings of bone on his body in a letter to the Royal College of Physicians [source: IFOPA].

The best known FOP case is that of Harry Eastlack (1933–1973). His condition began to develop at the age of 10 and by the time of his death from pneumonia in November 1973, six days before his 40th birthday, his body had completely ossified, leaving him able to move only his lips.

Shortly before Eastlack's death, he made it known that he wanted to donate his body to science, in the hope that in death, he would be able to help find a cure for this little-understood and particularly devastating disease. Pursuant to his wishes, his preserved skeleton is now kept at the Mütter Museum in Philadelphia, and has proven to be an invaluable source of information in the study of FOP. There have approximately been 700 confirmed cases across the globe from an estimated 2500.

FOP Bone Vs. Normal Bone

Before moving to the FOP related facts and figures let’s try to understand FOP bones versus Normal bone.

FOP Bone versus Normal Bone

Bone is a living tissue. Each bone in our body is like an organ, made up of tissues and cartilage. FOP bone is just like normal bone — but in the wrong place.

Ossification (osteogenesis) is the process of new bone formation. There are two methods of bone formation:

ü Intramembranous 

ü Endochondral

Intramembranous bone formation is the simpler process, and it's responsible for forming a person's skull and lower jawbone. It's also determine how long bones like the ‘humerus’ and ‘femur’ grow in width.

Most bones in the body grow and heal after a break through endochondral bone formation. It's also controls how FOP bone grows. First, cartilage forms and then bone gradually takes the place of the cartilage.

Both kinds of ossification begin with mesenchyme. Mesenchyme is a connective tissue from which all other connective tissues come from. Mesenchymal cells can turn into different kinds of specialized cells which form tissues. The process of endochondral bone formation is as follows:

1.    Mesenchymal cells come together in the shape of the bone they will form. They turn into chondroblasts — cells that secrete cartilage matrix. A membrane called the perichondrium surrounds this cartilage.

2.    After the chondroblasts cover themselves in cartilage matrix, they turn into chondrocytes. The chondrocytes keep dividing while new chondroblasts continue to make cartilage matrix, causing the cartilage to grow.

3.    Some of the chondrocytes burst and others die. The bursting of the cells causes calcification or hardening of the cartilage. The dying cells make small spaces in the cartilage.

4.    A nutrient artery enters the cartilage, triggering cells in the perichondrium to turn into osteoblasts. Osteoblasts are just like chondroblasts, but they secrete bone matrix instead of cartilage matrix. The osteoblasts start to secrete compact bone, and the perichondrium becomes the periosteum — the cover of the outside of the bone.

5.    Blood vessels grow into the cartilage and bring red bone marrow cells and other bone cells with them. The blood vessels stimulate a primary ossification center to grow — this is the place where bone tissue will begin to take the place of cartilage. Osteoblasts start covering the broken-down cartilage with bone matrix.

6.    Osteoclasts follow behind the osteoblasts and break down the spongy bone, making a cavity for red bone marrow to fill.

So, at this point, the long part of the bone, which started as cartilage, is compact bone with red bone marrow in the center. The endochondral bone formation finishes with the epiphyses, the ends of the bones. 

Secondary ossification centers develop to form bone, although unlike with the primary ossification center, spongy bone stays at the center of epiphyses instead of marrow.

This process uses undifferentiated cells or cells that can grow into any type of cell to make bones. The amazing thing about FOP is that the body convinces undifferentiated cells in tendons, ligaments and muscles to turn into something completely different. The body doesn't normally work this way. With FOP, ligaments and tendons and other connective tissues all go through this process of bone formation. It is normal bone, but in the wrong place at the wrong time — this is called heterotopic ossification.

So what happens with FOP?

A mutation in the gene encoding Activin receptor IA (ACVR1) tells the body to make an extra skeleton. This gene is responsible I controlling helps ‘bone morphogenetic proteins’ — BMPs. In FOP, the gene is active without BMPs — operating like a leaky faucet. When BMPs are present, the faucet explodes with activity. This clue might someday help scientists figure out how to make extra bone for people who need it, like people with osteoporosis.

Source: www.science.howstuffworks.com

What is Fibrodysplasia Ossificans Progressiva (FOP)?

FOP !!! What is it?

Fibrodysplasia Ossificans Progressiva (FOP) is a rar autosomal dominant disorder with complete penetrance involving progressive ossification (where muscle tissue and connective tissue such as tendons and ligaments are gradually turned into bone) of  skeletal muscle, fascia, tendons and ligaments.

Any trauma to the muscles of an individual with fibrodysplasia ossificans progressive (FOP), such as a fall or invasive medical procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification in the injured area. Flare-ups may also be caused by viral illnesses such as influenza.

The Nomenclature

FOP or Fibrodysplasia Ossificans Progressiva ~ fibro-dis-play-sha os-sih-fih-cans pro-gress-ev-a ~ means “Soft connective tissue that progressively turns into bone”

The Mystery of Growth

We might not think about our bones very often unless we break one. When we break a bone, the bone heals itself and begins to regrow.

But, wait a minute!!!

What if our muscles, tendons and ligaments turned to bone?

What if we formed a second skeleton on top of the one we already have? 

That's what exactly happens with Fibrodysplasia Ossificans Progressiva (FOP).

An FOP skeleton doesn't look like the ones we see at Halloween or the kind that hangs in an anatomy classroom. Instead of having lots of bones linked to one another with functioning joints, an FOP skeleton's bones fuse together, essentially forming a second skeleton out of the tendons, ligaments and muscles ~ a true metamorphosis. The skeleton is almost one solid piece, and sheets of bone exist where they should not.

The most common sign of FOP can be seen at birth: malformed big toes. Doctors aren't sure why this happens — it just appears as an early indicator of FOP. Aside from the malformed big toes, other initial signs of FOP usually show up in the early stage of life. One day, a large ‘lump’ suddenly begins to form on a child's body, usually in the ‘neck’ or ‘back area’. It can appear rapidly, often overnight and grows much faster than most tumours. It's warm to the touch, red and painful. A person's first reaction is often to assume it must be some sort of tumour — what if it's cancer? — but then the lump stops being painful, eventually gets smaller, and turns to bone — Normal Bone!!, but in the wrong place — where the body neither needs it nor wants it.

These lumps are called Flare-Ups (a sudden burst of fire/light; here, a symptom of a disease) and they appear all through the life of a person with FOP. Doctors aren't always sure what triggers them, but they do know that any kind of injury, even a small one, can cause a flare-up. For someone with FOP, a fall is not just a fall and the typical bumps & bruises of daily life are a major threat to the mobility and independence. If a person with FOP bumps his elbow or knee, bone could begin to grow there and lock the arm or leg for the rest of the life.

In general, for FOP patients, extra bone formation almost always starts at the neck, spine and shoulders. Only then does it move to the other joints. Eventually, people with FOP will probably lose most of their mobility. Joints lock and bones can twist into odd positions. Some people with FOP develop ‘scoliosis’— their spine twists. Often, the jaw fuses together either spontaneously or as a result of an injection for dental work, which makes eating and brushing teeth extremely difficult.

The skeleton will fuse into one position and in that posture the person with FOP will stay in for the rest of his or her life.

Any attempt to remove the extra (heterotopic) bone only leads to extra bone formation.

Only 700 people worldwide are known to have FOP, which makes this disorder extremely rare [source: IFOPA].

The skeleton of Harry Eastlack, (1933 – 1973), suffered from FOP [from the collections of the Mütter Museum, College of Physicians of Philadelphia] © A.B. Shafritz et al., New Eng. J. Med. 1996, Massachusetts Medical Society.