Osteogenesis imperfecta

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Transcript Osteogenesis imperfecta

Osteogenesis imperfecta (literally means
"imperfectly formed bone." People with
osteogenesis imperfecta have a genetic defect
that impairs the body's ability to make strong
Some people have a more severe form of the
condition. Their bones break easily and they
may break hundreds of bones during their
lives. Many people, however, have a milder
form of OI, and go through life with few
In people with osteogenesis imperfecta, one of the •
genes that tells the body how to make a specific
protein does not function. This protein (type I
collagen) is a major component of the connective
tissues in bones. Type I collagen is also important
in forming ligaments, teeth, and the white outer
tissue of the eyeballs (sclera).
As a result of the defective gene, not enough type I •
collagen is produced, or the collagen that is
produced is of poor quality. In either case, the
result is fragile bones that break easily but can heal
at a normal rate.
In most cases of OI, children inherit the defective gene from one of their parents.
But, the child's symptoms and the degree of disability can be very different from
that of the parent.
In some children, neither parent has osteogenesis imperfecta. In these cases, the
genetic defect is a spontaneous mutation (change) in the gene, and it stops
functioning correctly.
There are different types of osteogenesis imperfecta with symptoms that range
from mild to severe. Each person with the condition may have a different
combination of symptoms. All people with OI, however, have weaker bones.
This 16-year-old boy has •
bone deformities in both
his shinbones that have
not yet been
straightened with
In many children with osteogenesis imperfecta, the number of times their bones
fracture decreases significantly as they mature. However, osteogenesis
imperfecta may become active again after menopause in women or after the age
of 60 in men.
Scoliosis, or curvature of the spine, is a problem for many children with
osteogenesis imperfecta.
There are several types of osteogenesis imperfecta and they vary in severity and
characteristics. As scientists have discovered new genetic problems causing OI,
new types of the disorder have been recognized. All types of the disorder,
however, have symptoms and severity that fall somewhere within the range of the
first four types recognized. These four types are described below
Type I Osteogenesis Imperfecta
Type I osteogenesis imperfecta is the most •
common and mildest type of this disease. While
the structure of the collagen is normal, there is
less collagen than there should be. There is little
or no bone deformity, although the bones are
fragile and easily broken. The effects of
osteogenesis imperfecta may extend to the
teeth, making them prone to cavities and
cracking. The whites of the eyes may have a
blue, purple, or gray tint.
Type II Osteogenesis Imperfecta
Type II osteogenesis imperfecta is the •
most severe form of the disease. The
collagen does not form properly. Bones
may break even while the fetus is in the
womb. Many infants with type II
osteogenesis imperfecta do not survive.
Type III Osteogenesis Imperfecta
Type III osteogenesis imperfecta also has •
improperly formed collagen and often severe
bone deformities, plus additional complications.
The infant is often born with fractures. The
whites of the eyes may be white, blue, purple, or
gray. People with type III osteogenesis
imperfecta are generally shorter than average.
They may have spinal deformities, respiratory
complications, and brittle teeth
Type IV Osteogenesis Imperfecta
Type IV osteogenesis imperfecta is moderately •
severe, with improperly formed collagen. Bones
fracture easily, but the whites of the eyes are
normal. Some people with type IV osteogenesis
imperfecta may be shorter than average and
may have brittle teeth. Bone deformities are mild
to moderate.
In many cases, broken bones that occur with •
little or no force are the first sign of osteogenesis
imperfecta, and will cause your doctor to suspect
the condition
Medical History and Physical
Because osteogenesis imperfecta is often •
inherited, your doctor will discuss family
medical history in addition to your child's
medical history. Your doctor will also
complete a thorough physical examination
that includes checking your child's eyes
and teeth.
X-rays will provide your doctor with clear images •
of your child's bones, showing fractures as well
as malformations of bone.
Your doctor may take blood or tissue samples •
for genetic testing. In many cases, these tests
are able to identify the mutation, particularly if
the parent's mutation is also known.
Ultrasound can often detect severe cases of •
osteogenesis imperfecta during pregnancy.
While there is no cure for osteogenesis •
imperfecta, there are ways to improve a child's
quality of life. Treatment is individualized and
depends on the severity of the disease and the
age of the patient. Care is provided by a team of
healthcare professionals, including several types
of doctors, a physical therapist, a nurse-clinician,
and a social worker. Support from a social
worker or psychologist is very helpful for both
the child and the family, and often becomes
even more important during adolescence
Nonsurgical Treatment
In most cases, treatment is nonsurgical.
Medication. Medical bisphosphonates, given to the child either by
mouth or intravenously, slow down bone resorption. In children with
more severe osteogenesis imperfecta, bisphosphonate treatment
often reduces the number of fractures and bone pain. These
medications must be administered by properly trained doctors and
require close monitoring.
Immobilization. Casting, bracing, or splinting fractures is necessary
to keep the bones still and in line so that healing can occur.
Exercise. After a fracture, movement and weight bearing are
encouraged as soon as the bone has healed. Specific exercises will
increase mobility and decrease the risk of future fractures.
Low-impact exercise, such as swimming and walking, can help
strengthen bones and the muscles that support them. Exercise is
part of a healthy lifestyle for every child.
Surgical Treatment
Surgery may be recommended in cases of:
Repeated fractures of the same bone
Fractures that do not heal properly
Bone deformity, such as scoliosis
This 14-year-old boy with osteogenesis imperfecta has
scoliosis. Scoliosis is a sideways curve of the spine.
Instead of a straight line down the middle of the back,
this spine has two curves.
Courtesy of Texas Scottish Rite Hospital for Children.
. Metal rods may be inserted in the long bones of •
the arms and legs to help reinforce the bone,
and subsequently lessen the number of
fractures. Some rods are a fixed length and must
be replaced as a child grows. Other rods are
designed like telescopes, and they expand as a
child's bones grow. There are,however, other
complications that may occur with telescoping
rods. Do not hesitate to ask your orthopaedic
surgeon about both rodding options
Spinal fusion for scoliosis.
Although bracing is the usual treatment for •
scoliosis, it is not often effective in children
with osteogenesis imperfecta because the
ribs will become deformed from the brace,
without preventing the scoliosis from
worsening. Spinal fusion, a surgery in
which the bones of the spine are realigned
and fused together, may be recommended
when the scoliosis becomes severe
Living with Ostogenesis Imperfecta
Below are some tips developed by the •
Osteogenesis Imperfecta Foundation for
taking care of children with osteogenesis
imperfecta. Most importantly, do not feel
guilty if your child breaks a bone. Children
must grow and develop, and fractures will
occur no matter
how careful you are
Do not be afraid to touch or hold an infant with osteogenesis imperfecta, but be
careful. To lift an infant with osteogenesis imperfecta, spread your fingers apart and
put one hand between the legs and under the buttocks, and place the other hand
behind the shoulders, neck, and head.
Never lift a child with osteogenesis imperfecta by holding him or her under the
Do not pull on arms or legs or, in those with severe osteogenesis imperfecta, lift the
legs by the ankles to change a diaper.
Select an infant car seat that reclines. It should be easy to place or remove your child
in the seat. Consider padding the seat with foam and using a layer of foam between
your child and the harness.
Be sure your stroller is large enough to accommodate casts. Do not use a sling- or
umbrella-type stroller.
Follow your doctor's instructions carefully, especially with regard to cast care and
mobility exercises. Swimming and walking are often recommended as safe
Adults with OI should avoid activities such as smoking, drinking, and taking steroids
because they have a negative impact on bone density.
Increasing awareness of child abuse and a lack of awareness about osteogenesis
imperfecta may lead to inaccurate conclusions about a family situation. Always have
a letter from your family doctor and a copy of your child's medical records handy.
What is osteopetrosis?
Osteopetrosis is a bone disease that makes •
bones abnormally dense and prone to breakage
(fracture). Researchers have described several
major types of osteopetrosis, which are usually
distinguished by their pattern of inheritance:
autosomal dominant, autosomal recessive, or Xlinked. The different types of the disorder can
also be distinguished by the severity of their
signs and symptoms
Autosomal dominant osteopetrosis (ADO), which is also called AlbersSchönberg disease, is typically the mildest type of the disorder. Some
affected individuals have no symptoms. In these people, the unusually
dense bones may be discovered by accident when an x-ray is done for
another reason. In affected individuals who develop signs and
symptoms, the major features of the condition include multiple bone
fractures, abnormal side-to-side curvature of the spine (scoliosis) or
other spinal abnormalities, arthritis in the hips, and a bone infection
called osteomyelitis. These problems usually become apparent in late
childhood or adolescence
Autosomal recessive osteopetrosis (ARO) is a more severe
form of the disorder that becomes apparent in early
infancy. Affected individuals have a high risk of bone
fracture resulting from seemingly minor bumps and falls.
Their abnormally dense skull bones pinch nerves in the
head and face (cranial nerves), often resulting in vision
loss, hearing loss, and paralysis of facial muscles. Dense
bones can also impair the function of bone marrow,
preventing it from producing new blood cells and immune
system cells. As a result, people with severe osteopetrosis
are at risk of abnormal bleeding, a shortage of red blood
cells (anemia), and recurrent infections. In the most severe
cases, these bone marrow abnormalities can be lifethreatening in infancy or early childhood.
Other features of autosomal recessive osteopetrosis can
include slow growth and short stature, dental abnormalities,
and an enlarged liver and spleen (hepatosplenomegaly).
Depending on the genetic changes involved, people with
severe osteopetrosis can also have brain abnormalities,
intellectual disability, or recurrent seizures (epilepsy).
A few individuals have been diagnosed with intermediate
autosomal osteopetrosis (IAO), a form of the disorder that can
have either an autosomal dominant or an autosomal recessive
pattern of inheritance. The signs and symptoms of this
condition become noticeable in childhood and include an
increased risk of bone fracture and anemia. People with this
form of the disorder typically do not have life-threatening bone
marrow abnormalities. However, some affected individuals
have had abnormal calcium deposits (calcifications) in the
brain, intellectual disability, and a form of kidney disease called
renal tubular acidosis.
Rarely, osteopetrosis can have an X-linked pattern of inheritance. In
addition to abnormally dense bones, the X-linked form of the disorder
is characterized by abnormal swelling caused by a buildup of fluid
(lymphedema) and a condition called anhydrotic ectodermal dysplasia
that affects the skin, hair, teeth, and sweat glands. Affected individuals
also have a malfunctioning immune system (immunodeficiency),
which allows severe, recurrent infections to develop. Researchers
often refer to this condition as OL-EDA-ID, an acronym derived from
each of the major features of the disorder.
How common is osteopetrosis?
Autosomal dominant osteopetrosis is the most •
common form of the disorder, affecting about 1
in 20,000 people. Autosomal recessive
osteopetrosis is rarer, occurring in an estimated
1 in 250,000 people.
Other forms of osteopetrosis are very rare. Only •
a few cases of intermediate autosomal
osteopetrosis and OL-EDA-ID have been
reported in the medical literature.
What genes are related to
Mutations in at least nine genes cause the various types •
of osteopetrosis. Mutations in the CLCN7 gene are
responsible for about 75 percent of cases of autosomal
dominant osteopetrosis, 10 to 15 percent of cases of
autosomal recessive osteopetrosis, and all known cases
of intermediate autosomal osteopetrosis. TCIRG1 gene
mutations cause about 50 percent of cases of autosomal
recessive osteopetrosis. Mutations in other genes are
less common causes of autosomal dominant and
autosomal recessive forms of the disorder. The X-linked
type of osteopetrosis, OL-EDA-ID, results from mutations
in the IKBKG gene. In about 30 percent of all cases of
osteopetrosis, the cause of the condition is unknown.
The genes associated with osteopetrosis are involved in the formation,
development, and function of specialized cells called osteoclasts. These
cells break down bone tissue during bone remodeling, a normal process in
which old bone is removed and new bone is created to replace it. Bones
are constantly being remodeled, and the process is carefully controlled to
ensure that bones stay strong and healthy.
Mutations in any of the genes associated with osteopetrosis lead to
abnormal or missing osteoclasts. Without functional osteoclasts, old bone
is not broken down as new bone is formed. As a result, bones throughout
the skeleton become unusually dense. The bones are also structurally
abnormal, making them prone to fracture. These problems with bone
remodeling underlie all of the major features of osteopetrosis
How do people inherit
disorder has an autosomal
dominant inheritance pattern, which means one copy of an altered gene in
each cell is sufficient to cause the disorder. Most people with autosomal
dominant osteopetrosis inherit the condition from an affected parent.
Osteopetrosis can also be inherited in an autosomal recessive pattern,
which means both copies of a gene in each cell have mutations. The
parents of an individual with an autosomal recessive condition each carry
one copy of the mutated gene, but they typically do not show signs and
symptoms of the condition.
OL-EDA-ID is inherited in an X-linked recessive pattern. The IKBKG gene is
located on the X chromosome, which is one of the two sex chromosomes.
In males (who have only one X chromosome), one altered copy of the gene
in each cell is sufficient to cause the condition. In females (who have two X
chromosomes), a mutation would have to occur in both copies of the gene
to cause the disorder. Because it is unlikely that females will have two
altered copies of this gene, males are affected by X-linked recessive
disorders much more frequently than females. A characteristic of X-linked
inheritance is that fathers cannot pass X-linked traits to their sons.
Osteopetrosis can have several different patterns of inheritance. Most commonly, the
Paget's disease of bone
bone is a localized disorder of bone remodeling. Increased number
s of larger than normal osteoclasts initiate the process at affected
skeletal sites, and the increase in bone resorption is followed by an
increase in new bone formation, altering bone architecture. The
signs and symptoms of Paget's disease are varied, depending in
part on the location of the involved sites and the degree of increased
bone turnover. Recent progress in Paget's disease research
includes new data regarding the etiology of this disorder and the
ongoing development of more effective therapies. Although the
cause of Paget's disease remains unproven, the creation of pagetic
osteoclasts seems ever more likely to result from both genetic and
environmental factors. Many studies indicate that in patients with
Paget's disease, both osteoclasts and their precursors harbor
evidence of a paramyxovirus infection, although not all studies
confirm this finding. Very recent genetic investigations hav
identified one candidate gene on chromosome 18q, although genetic
heterogeneity is almost certainly present. Advances in treatment have
resulted from the availability of several potent bisphosphonate
compounds (e.g., pamidronate, alendronate, and risedronate) that,
unlike earlier treatments, produce normal or near normal bone
turnover indices in a majority of patients. New bone formation after
such treatment has a more normal, lamellar pattern, and mineralization
abnormalities are rare to absent with the newer compounds. The
availability of such agents has prompted a more aggressive
management philosophy in which both symptomatic disease and also
asymptomatic disease at sites with a risk of progression and future
complications are viewed as clear indications for pharmacologic
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is a localized disorder of bone remodeling estimated to occur in 2–
3% of individuals in the U.S. over age 60. Increased numbers of
larger than normal and supernucleated osteoclasts initiate the
remodeling abnormality with increased bone resorption at affected
sites. Coupled to this initially osteolytic process is a secondary
increase in new bone formation, with the deposition of architecturally
disorganized new bone. As a consequence of this localized increase
in bone turnover, there is a characteristic radiographic appearance
of bone that may show areas of osteolysis juxtaposed to regions
with irregular cortical thickening, trabecular coarsening, and an
overall sclerotic appearance. Elevated biochemical markers of bone
turnover such as serum total (SAP) or bone-specific alkaline
phosphatase and urinary hydroxyproline or collagen cross-links and
associated peptides reflect the ongoing increased bone remodeling
that defines this disorder
On physical examination, pagetic bone may appear to be perfectly
normal if the changes are early or mild, or the bone may be enlarged
and obviously deformed with more advanced disease. Pagetic bone
and overlying skin may be warm to the touch in regions such as the
tibia or skull due to increased vascularity when turnover is high.
Pagetic bone deformity may include such findings as an enlarged skull,
kyphosis, and bowing of affected limbs.
Clinical symptoms and complications of Paget's disease include bone
pain; secondary osteoarthritis from deformity of bone near major joints
such as the hip, knee, or ankle; gait disturbances due to a shortened
bowed femur or tibia; fractures of long bones or vertebrae; headache or
hearing loss with extensive skull involvement; and lumbar spinal
stenosis or other syndromes of neural compression with attendant
sensory or motor deficits. A recent study has indicated that these
complications have a striking impact on the overall quality of life for
many patients