Nora Holmes's List: fibrousdysplasia ossificans progressiva

• How Fibrodysplasia Ossificans Progressiva (FOP) Works
• muscles, tendons and ligaments turned to bone
• formed a second skeleto
• 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
• skeleton is almost one solid piece
• sheets of bone exist where they should not.
• malformed big toes
• most common sign of FOP
• aren't sure why
• initial signs of FOP usually show up in the first two decades
• large lump
• rapidly
• neck or back area
• red and painfu
• gets smaller, and turns to bone
• normal bone, but in the wrong place -- where the body neither needs it nor wants it.
• appear all through the life
• lumps are called flare-ups
• any kind of injury,
• bruises of daily life are a major threat to the mobility and independence
• extra bone formation almost always starts at the neck, spine and shoulders
• Eventually, people with FOP will probably lose most of their mobility.
• Joints lock, and bones can twist
• scoliosis,
• jaw fuses
• skeleton will fuse into one position,
• eating and brushing teeth extremely difficult
• Any attempt to remove the extra (or heterotopic) bone only leads to extra bone formation
• 700 people worldwide

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• FOP Bone versus Normal Bone
• FOP Bone versus Normal Bone
• FOP Bone versus Normal Bone
• FOP Bone versus Normal Bone
• FOP Bone versus Normal Bone
• French doctor Guy Patin
• 1692,
• thorough documentation
• 1740,
• osteogenesis
• Ossification
• endochondral
• intramembranous
• how FOP bone grows
• Most bones in the body grow and heal after a break through endochondral bone formation
• • how the body maintains homeostasis -->
• process of endochondral bone formation
• endochondral bone formation finishes with the epiphyses
• • more maintaining of homeostasis (and mutation) -->
• Secondary ossification centers develop to form bone,
• With FOP, ligaments and tendons and other connective tissues all go through this process of bone formation
• cells that can grow into any type of cell, to make bones
• process uses undifferentiated cells
• body convinces undifferentiated cells in tendons, ligaments and muscles to turn into something completely different.
• heterotopic ossification.
• extra bone formation almost always starts at the neck, spine and shoulders. Only then does it move to the other joints.
• • "how does a disruption in homeostasis result in the disease" THIS ANSWERS IT METHINKS
• So what happens with FOP?
• mutation in the gene encoding activin receptor IA (ACVR1) tells the body to make an extra skeleton.
• gene helps control bone morphogenetic proteins
• BMPs are present, the faucet explodes
• gene is active without BMPs -- operating like a leaky faucet

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• FOP Treatment
• FOP bone can be removed.
• but that actually makes things worse
• bone will simply grow back, possibly with even more
• Any kind of trauma to the body can cause a flare-up,
• Even injections into the muscle
• isn't any real proven treatment for FOP, so doctors use medications
• Reports are anecdotal -- they rely on the unscientific observations of people using
• Eventually, it should be possible to design new medications to block the overactive receptor that triggers bone formation in FOP.
• medicines that have been reported to be helpful
• Corticosteroid
• NSAIDs
• Advil or aspirin
• COX-2 inhibitors
• prevent the formation of blood vessels
• anti-angiogenic
• Aminobiphosphonates
• keep too much bone resorption from happening by shortening the life span of osteoclasts
• Doctors aren't sure why.
• appears to modify immune system responses and functions in a way that might help with flare-ups.
• Thalidomide
• wheelchair-friendly,
• caregiver.
• IFOPA
• organization for families dealing with FOP

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• Abstract
• most catastrophic disorder of HO in humans
• mutation in activin receptor
• one of the most highly specific disease-causing mutations in the human genome.
• Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups
• block ACVR1/ALK2 signalling
• Two clinical features define classic FOP
• alformation of the great toes
• ogressive HO in specific spatial patterns
• Minor trauma such as intramuscular immunizations, mandibular blocks for dental work, muscle fatigue and blunt muscle trauma from bumps, bruises, falls or influenza-like illnesses can trigger painful new flare-ups of FOP leading to progressive HO
• characteristic anatomical and temporal patterns that mimic the patterns of normal embryonic skeletal formation
• Several skeletal muscles including the diaphragm, tongue and extra-ocular muscles are enigmatically spared
• Cardiac muscle and smooth muscle are not involved
• early lesional involvement in the axial regions
• very rapidly
• swelling
• regional differences
• Bone formation in FOP is episodic, but disability is cumulative
• confined to a wheelchair by the third decade
• require lifelong assistance
• Severe weight loss may result following ankylosis of the jaw
• pneumonia or right-sided heart failure
• low reproductive fitness
• median age of survival is approximately 45 years, and death often results from complications of thoracic insufficiency syndrome
• malformed thumbs, clinodactyly, short broad femoral neck and proximal medial tibial osteochondromas.
• Other skeletal anomalies often associated with FOP include
• Hearing impairment is a common feature of FOP and occurs in approximately 50%
• approximately one in two million
• no ethnic, racial, gender or geographic predisposition
• spontaneous new mutation
• can be inherited from either mothers or fathers
• genetic determinants strongly influence disease phenotype during prenatal
• environmental factors strongly influence postnatal progression
• ACVR1/ALK2
• prevention and treatment of HO in FOP
• will be based on at least one of four principles: disrupting the relevant inductive signalling pathways; suppressing the immunological and/or inflammatory triggers; altering the relevant osteoprogenitor cells in the target tissues; and/or modifying the tissue environment conducive to heterotopic osteogenesis.
• ACVR1/ALK2 as a specific druggable target
• Surgical release of joint contractures is generally unsuccessful
• additional HO develops at the operative site
• Spinal bracing is ineffective
• useful anecdotally in managing chronic discomfort and ongoing flare-ups, but to date there is no proven efficacy with any therapy in altering the natural history of the disease
• range of motion is progressively lost leading to near-complete immobility
• rehabilitation approaches should be focused on enhancing activities of daily living
• While the mutation that causes classic FOP has been discovered, much work remains to elucidate the molecular mechanism by which this mutation leads to the complex disease phenotype of skeletal malformations and episodic progression of HO.

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• rarest, most disabling genetic conditions
• causes bone to form in muscles, tendons, ligaments and other connective tissues
• no other known examples in medicine of one normal organ system turning into another.
• Spontaneous flare-ups
• defined temporal and spatial patterns,
• ribbons and sheets of bone that fuse the joints
• heterotopic bone
• • use this photo
• How would understanding the cause of bone formation in FOP help others?
• • hmmm...
• 1 in 2 million people
• No ethnic, racial, or religious patterns
• 700 confirmed
• 185 known
• Clinical Characteristics of FOP:
• great toe
• Flare-ups occur spontaneously
• following bodily trauma
• • "tumors" are actually flare-ups
• Misdiagnosed in a majority of cases as cancer
• Surgery
• no effective treatments
• Discovery of the FOP Gene

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• begins in the neck and shoulders and progresses along the back, trunk, and limbs
• malformed big toes
• few problems, they serve as an important early sign
• kids with FOP scoot on their buttocks; then get up and wal
• facet joints in the back of the neck have not formed properly or have fused
• • notes
    
• FOP is congenital, meaning that FOP starts before birth, the extra bone does not form before birth.
• • notes
    
• begin during the first two decades
• majority of affected people learn that they have FOP before the age of ten
• swellings
• different rates of new bone formation
• gradual.
• rapid,
• pattern to the progression.
• • NOTES
• 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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• Misdiagnosis rates for FOP have previously been reported to be in the range of 80% or greater
• most common misdiagnoses for FOP have been reported to be: cancer, aggressive juvenile fibromatosis, and fibrous dysplasia.

• malnutrition
• breathing difficulties
• extra bone formation around the rib cag
• Flare-ups may also be caused by viral illnesses
• What genes are related to fibrodysplasia ossificans progressiva?
• ACVR1
• provides instructions for producing a member of a protein family called bone morphogenetic protein
• ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage
• helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone
• Researchers believe that a mutation in the ACVR1 gene may change the shape of the receptor
• and disrupt mechanisms that control the receptor's activity.
• the receptor may be constantly turned on
• causes overgrowth of bone and cartilage and fusion of joints
• How do people inherit fibrodysplasia ossificans progressiva?
• one copy of the altered gene in each cell is sufficient to cause the disorder.
• Most cases of fibrodysplasia ossificans progressiva result from new mutations
• no history of the disorder
• small number of cases, an affected person has inherited

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