Osteogenesis Imperfecta

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Osteogenesis Imperfecta

• Kaitlin
• Ali
• Michael

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What is Osteogenesis Imperfecta?

• Osteo-bone Genesis- creation Imperfecta-
  imperfect.
• A disease most commonly caused by a mutation to
  the COL1A1 and COL1A2 genes.
• It is both a dominant and recessive disorder,
  however between 85 and 90 percent of O.I. cases
  are dominant.

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What were your favorite Childhood Activities?
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How common is OI?

• Between twenty and forty thousand cases are found
  nationwide, that means 6-7 in every 100,000
  individuals.
• Half of the worlds OI cases are found in the
  United States.

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Diagnosis of OI

• Fractures occurring with little or no trauma
• Short stature or stature shorter than predicted
• Bone Deformity
• Blue Schlera
• Progressive, post-pubertal hearing loss.
• Family History

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Symptoms of Osteogenesis Imperfecta

• Muscle Fatigue.
• Scoliosis (Curvature of the Spine).
• Curved Limbs.
• Blue or Gray Tint in the Whites (sclera) of the
  Eye.
• May develop hearing loss later in adulthood (Can
  be as early as 20s or 30s). This is linked to
  deformities in the inner ear and three small
  bones in the middle ear.
• Brittle and underdeveloped teeth.
• OI patients often bruise easily.
• Constipation.
• Heart Defects.
• Delays in motor development.

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Treatment Options

• There are medicines such as Bisphosphonates
  (BPs), particularly those containing nitrogen,
  that are being increasingly administered to
  increase bone mass and reduce the incidence of
  fracture.
• Proper vitamin intake such as Calcium, Vitamin C,
  and Vitamin D are essential for bone growth and
  repair.
• Growth hormones and gene, cell, and drug
  therapies are also being studied.

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Recent Advances in OI Care

• They are testing different bisphospates
  pamidronate is one. I was part of an
  international study comparing Vometa to
  pamidronate, to see if it was as good or better.
  Thats about it. Eventually people would like to
  do gene therapy, but that will probably be
  decades away! Some people have done bone marrow
  transplants, but that hasnt been successful. The
  hope was that stemcells would be used to make
  normal bone. This was done at St. Jude.
• -- Dr. Charles McKay M.D.

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Surgeries

• Rods are added in order to strengthen bones.
• These rods are either non-expandable or
  expandable. Non-expandable rods are very
  versatile but must be changed as the child grows.
  Expandable rods grow with the bone, but are only
  suitable for larger bones such as the femur.
• Spinal rodding is used in severe cases of
  Scoliosis.
• Surgery is also used in order to mend the broken
  bones.

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Casts

• Normal casts would actually harm patients with
  OI.
• Instead specialized casts are used due to the
  brittle nature of the bones.
• Fiberglass offers a lighter and more comfortable
  solution for OI patients.
• The main purpose of casts is to immobilize the
  broken limbs. However immobilization should be
  limited in order to prevent bone loss.
• For less serious breaks, parents are also taught
  to wrap bones for their children.

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What do parents use to wrap the limbs of children
with OI?

• They use bandages similar to Ace Bandages, they
  have special bandages for children with OI.
• -- Dr. Charles McKay M.D.

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Traction

• Traction is used to regain alignment of a
  fracture by applying force to the body part. It
  also can relieve muscle spasms while the bone is
  healing. Skeletal traction is applied directly to
  the bones using pins, wires, or screws.

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Exercise and Physical Therapy

• Regular exercise helps the patients to become
  stronger and more independent.
• Swimming and water exercise is the best way for
  OI patients to become more fit because it causes
  less stress on bones than any other sport.

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How can children get exercise and stay healthy
with such weak bones?

• A lot of these kids get physical therapy, and one
  of the most valuable therapies is aqua therapy.
  Their legs cannot support them, but if they get
  into the pools they can exercise their muscles
  without putting stress on their broken bones.
• -- Dr. Charles McKay M.D.

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Types of O I

• There are 8 types of Osteogenesis Imperfecta.
• Types 1-5 caused by Dominant Mutation
• Type 1 is the mildest form of the disease and is
  also the most common.
• Type 2 is fatal and usually leads to death in the
  first year of life.
• Type 3 is the most severe form of OI found in the
  living. Those affected have a shortened life
  expectancy and necessity for a wheelchair.
• Type 4 is moderately severe and leads to normal
  life expectancy and causes a necessity for
  crutches or braces.
• Types 6-8 are due to recessive mutations.

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What causes a child to die of type II OI?

• The bones are just too fragile, the lungs just
  cant develop, and the child cannot breathe.
  This is due to small thorax and fractured ribs or
  flayl chest (when the child breathes, they have
  negative pressure in their chests and the chest
  collapses). A child who survives the first day
  of life may not be able to take in sufficient
  calories to survive any longer.
• --Dr. Charles McKay M.D.

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Fig 1--Life expectancy in osteogenesis imperfecta
() in comparison with that in the general
population (O). Vertical ratios determined with
the GLIM statistical package5 bars represent 95
confidence intervals for mortality
Paterson, C. R et al. BMJ 1996312351
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How many patients have you seen that have died
from their Osteogenesis Imperfecta?

• None, I have never had someone die of the
  disease. However, I have had children die of
  complications. The most common cause of death is
  from severe scholosis, the childs chest cant
  expand anymore and they may have pneumonia and
  their heart and lungs just cant expand properly.
  Another cause of death is Basilar invagination,
  which is, as the head fits on the spinal chord,
  it pushes up into the base of the brain because
  the skull is so soft.

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General Health Concerns

• Maintaining a healthy weight reduces stress on
  bones.
• Proper nutrition can be figured for OI patients
  small frames.
• Avoiding smoking, caffine, and alcohol intake, is
  beneficial for OI patients because these lead to
  depleted bones. Taking medicinal steroids can
  also be beneficial.

This sling helps families with children who have
OI to lift and move their children. It is
specialized with those who have brittle bones.
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Living With Osteogenesis Imperfecta

• Patients must make frequent trips to the hospital
  to get casts for their multiple broken bones.
• Braces, walkers and wheelchair use is common.
• A balanced healthy diet and exercise is important
  to keep the fragile body as healthy as possible.
• Specialized dental care may be necessary to
  protect fragile teeth.

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Broken Bones

• Fractured bones are a result of a gene defect
  which affects the creation of collagen, a protein
  which is needed for proper bone growth.
• In the more mild cases of OI bone fracture
  incidence decreases after puberty.
• However, even for the mildest form of OI (Type
  1), an average of 40 bones break prior to puberty.

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Testing Options

• 5 mL of blood in an anticoagulated tube or 5 mL
  of amniotic fluid are required for testing.
• Skin Tests measure the collagen levels in skin
  (This technique identifies 90 of OI patients)
• It can identify 87 of nonfatal OI and 98 of
  fatal OI.
• Chronic Villus sampling can be used to detect
  abnormal collagen and genetic mutations.
• Amniocentesis can also analyze for genetic
  mutation.
• Prenatal testing is suggested for families that
  have a member who has already been diagnosed.

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Cost of Testing

• Collagen TestingResults in 6-8 weeks770.00 -
  1,178.50
• DNA SequencingResults in 6 months2,363.00 for
  both genes

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Testing Ethics

• Testing in Parents can help determine the
  prognosis of having another child affected by OI.
  This is most commonly done in mothers who have
  lost a child to OI.
• Tests are not 100 percent effective due to the
  fact that over 800 mutations have been identified
  so far in the COL genes
• Genetic counseling should be used along with
  testing in order to help parents understand the
  disease, the risks, and the test.

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How is genetic testing performed for patients
with OI?

• A test would be sent to Peter Byers in Seattle,
  WA, and for genetic testing. There is another
  site in New Orleans. They used to do collagen
  testing, growing fibroblasts,(makes connective
  tissue in skin) and would be tested to see if it
  makes normal collagen. Genetic testing is new.
  COL1A1 genetic mutations cause OI. From this
  gene you are looking for abnormalities. Because
  its such a long protein, its hard to find all
  the abnormalities. Most types of OI are found in
  this gene.
• -- Dr. Charles McKay M.D.

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Why do you do genetic testing?

• I dont do genetic testing on everyone. If Im
  sure of the diagnosis, like if the mother has OI
  or if the child has classic blue sclera or teeth.
  Genetic testing can be used to confirm a case or
  to confirm the diagnosis of a new mutation within
  a family. Its not necessarily necessary. I
  know Peter Byers, a geneticist who specializes in
  the OI genetic tests. Eventually what they would
  like to do is correlate what the defect is and
  what the clinical course would be. They want to
  see if certain courses would be more effective
  for certain defects.
• -- Dr. Charles McKay M.D.

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What does the COL1A1 Gene do?

• The normal COL1A1 gene functions as a
  collagen-producing gene.
• The COL1A1 gene codes for proa1(1) and proa(2)
  which both are necessary to create type I
  procollagen
• When mutated, the COL1A1 gene causes the victim
  to have a reduced amount of collagen or weak,
  less effective collagen.

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Gene Defects

• Of your gene defects, if you have mild OI, you
  dont make enough collagen. If you have two gene
  defects perhaps one doesnt make enough protein.
  Typically you make two strands, and they have to
  wrap together. If you dont make enough of one
  protein, its hard to have enough collagen. In
  the more severe form, you have one normal
  collagen and one abnormal collagen, and what
  happens is the abnormal collagen will keep the
  normal collagen from functioning properly, this
  is in your type II or type III OI.
• -- Dr. Charles McKay M.D.

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COL1A1 and COL1A2 Genes

• The COL1A1 gene is found on the seventh
  chromosome, while the COL1A2 gene is found on the
  seventeenth chromosome and are responsible for
  the creation of Type One Collagen.
• Type 1 collagen is a peptide chain composed of 2
  alpha-1(COL1A1) chains and 1 alpha-2 (COL1A2)
  chains to be functional.

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Type 1 Collagen

• Type 1 collagen is the most abundant type of
  collagen in the human body.
• It is found in scar tissue, tendons and the
  myofibirils (muscle cell), and in bones.

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Why do we need Collagen?

• Collagen is a fiberous protein that connects and
  supports tissues within the body.
• Collagen is found in eyes, hair, teeth, bone,
  skin, cartledge and tendons, connective tissue,
  capillaries, the kidneys and the placenta.

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Genetics of Dominant Cases of O I

• It is not a sex-linked disorder
• Caused by a spontaneous mutation that occurs
  prior to conception in the egg or sperm.
• 35 of diagnosis occur in families without any
  history of the disease.

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Common types of Mutationto the COL1A1 Gene

• Point Mutation- is a type of mutation where the
  replacement of a single base nucleotide with
  another nucleotide.
• Deletion- a type of genetic mutation occurring
  when part of a chromosome or a sequence of DNA is
  missing.
• Insertion- a genetic mutation that occurs when
  one or more nucleotide base pairs is added into a
  genetic sequence.

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De Novo Mutation

• An alteration in a gene that is present for the
  first time in one family member as a result of a
  mutation in a germ cell (egg or sperm) of one of
  the parents or in the fertilized egg itself.
• 60 percent of patients with mild OI have this
  type of mutation
• Almost 100 percent of babies with fatal OI have
  de novo mutation.

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Life With OI

• His world has been hospitals, labs, clinics,
  specialist and doctors offices. He takes a large
  assortment of medications, he is hooked up to the
  VNA and other support systems us, we are it and
  he has taught us so much through this.
• James is a high functioning adult, loves people
  and we are blessed for having him, he has taught
  us not to take anything for granted, look at
  things with simplicity and love. He has an
  apartment in our building, to help him maintain
  as much independence as he can, he does quite
  well. He has days that are very difficult because
  the O.I. has affected his respiratory system and
  his heart, he has CHF. His attitude is great and
  through this the medical field has learned a lot
  about O.I. especially his primary doctor, who has
  kept on top of his situation, they have gained a
  sense of humor and this has helped James cope
  with his health.
• They never thought he would live beyond 14,
  well he has beaten those odds. We love James and
  will always fight to make life better for him, he
  has given us more then he will ever know. He has
  such an innocence about him, he becomes
  contagious.

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Interview with Dr. Charles McKay

• Dr. McKay is a local Osteogenesis Imperfecta
  specialist who works at Carolinas Medical Center
  in Charlotte, NC. He began his OI clinic there
  in 2006, after joining the CMC faculty as a
  Nephrologist. He started this clinic because he
  saw a need for a OI specialist in the Southern
  United States. He had a clinic at his previous
  job at A.I. duPont Hospital for Children in
  Wilmington, Delaware.

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I know Osteogenesis Imperfecta is a rare disease.
How did you learn about it?

• Initially I learned about it reading about bones
  and pediatrics. Then about osteoporosis. At
  duPont, they needed someone to treat children
  with pamidronate.

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Why did you chose to learn more and eventually
care for children with osteogenesis imperfecta?

• I read about it. I read the facts and I
  understood it. Then I suddenly started seeing
  patients and needed to know much more. What I
  needed to know to care for patients was a great
  deal more. It went from a casual knowledge to
  being an expert in order to care for patients. I
  learned a lot reading and from parents taking
  care of their children each day, the problems
  they had and what works and what doesnt. Some
  of the parents have O.I. as well.

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What is it like to take care of children with OI?

• Its very rewarding because you have to remember
  some have a very mild disease and some have a
  very severe disease, so its a very different
  experience. Some children just have fractures
  and need medication, but some children are
  remarkable, being able to live a relatively
  normal life and being able to do what ever child
  wants to do. As the OI foundations says, these
  children have unbrakeable spirits. There are
  also children who will never walk, will always be
  in a wheelchair, but still can have a wonderful
  sense of self. And they have their own
  aspirations. Many want to do something with
  computers because it is something they can do
  still being crippled.

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What is it like to take care of children with OI?

• Its very rewarding because you have to remember
  some have a very mild disease and some have a
  very severe disease, so its a very different
  experience. Some children just have fractures
  and need medication, but some children are
  remarkable, being able to live a relatively
  normal life and being able to do what ever child
  wants to do. As the OI foundations says, these
  children have unbrakeable spirits. There are
  also children who will never walk, will always be
  in a wheelchair, but still can have a wonderful
  sense of self. And they have their own
  aspirations. Many want to do something with
  computers because it is something they can do
  still being crippled.

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What special considerations do you have to take
to properly care for children with OI?

• They are at risk for fractures, so you have to be
  careful handling the child. I once even
  accidentally broke a childs arm. I picked her
  up to move her, and put too much pressure on her.
  You have to be careful not to put pressure on
  them. You cant pick them up by their arms, like
  you would a normal child, because their bones are
  fragile. That was a pretty terrible experience.
  I dont know if I actually broke her arm, but she
  developed pain. These children may need special
  dental care or have constipation. They may need
  special aids to exercise. For some kids, they
  start fracturing when they start walking. This
  is when you often need to rod their bones. They
  can develop deafness, so they may need to be
  checked for that. They can also get
  hydrocephilis (swelling of the ventricles in the
  brain). Just because the child has fractures and
  maybe wheelchair bound, doesnt mean they dont
  have dignity. To treat them like real people is
  very important.

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Do you have an recommendations to give to
parents with affected children?

• When I see them for the first time, I try to
  first figure out how severe the OI is and how
  likely they are to get fractures. Some have
  already had many fractures, and may need to or
  may be seen by an orthopedic specialist. After I
  treat them with pamidronate, we encourage parents
  to allow them to be children, knowing that they
  may get a broken bone, but we still want them to
  play and be children. When they do get a broken
  bone, parents are taught not to bring their
  children to an emergency room to get a cast, but
  to wrap it, putting it in a splint. This allows
  it to heal. Casts are more likely to break
  bones.

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Do you have and special anecdotes that you would
like to share about a patient?

• Well, Ive had patients in wheelchairs that were
  able to walk. One thing about patients with OI is
  that they may have different forms of getting
  around due to distance and how many people will
  be around. Some patients use special wheelchairs
  that can even lift them up. Its miraculous to
  have children with parents who have severe OI and
  have been able to have children. Some people
  with OI are only about sixty pounds.

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But, there is hope!

• Doctors, including endocrinologist Dr. Orwoll, is
  experimenting with a medicine called Forteo,
  meant to treat patients with osteoporosis."In
  osteoporosis, Forteo does work by forming new
  bone and strengthens the bone and reduces
  fracture," Dr. Orwoll says. This medicine has
  also been used to help strengthen the bones of
  patients with mild Osteogenesis Imperfecta, and
  has given patients hope for a more normal life!
• Life With OI