results from an imbalance between the formation of bone and the
break down of bone. In osteopetrosis the cells that break down bone,
the osteoclasts, usually are fewer in number or are ineffective
in removing bone.
2. Q. Which bones are most commonly affected?
A. All bones are affected by osteopetrosis. They are
overly dense and the skeleton is extremely heavy.
What are the symptoms of osteopetrosis?
because the bones are weak.
- Less blood
cell production, because the bones have very little bone marrow
space. This can lead to frequent infections.
deafness, and strokes, because the holes in the bones are too
small for blood vessels and nerves to pass through.
Are there different types or forms of osteopetrosis?
A. There are three major types of osteopetrosis:
infantile form." This type is very severe (but not related to
cancer). Malignant infantile osteopetrosis is inherited as an
autosomal recessive disorder, where both parents have an abnormal
gene that is passed to the affected child. The disease is apparent
from birth and frequently ends in death.
- "Adult form."
This is a milder form. It becomes a major problem in 20 to 40
year olds. However, it rarely causes a significant reduction in
how long someone will live.
form." This is less severe than the malignant infantile form.
It is found in children under 10 years of age. Although this form
is more severe than the adult form, it usually does not lead to
an early death.
What do these three types have in common?
A. Common features of the three types are:
usually of the long bones in the adult form, and of the ribs and
long bones in the malignant infantile form.
- Loss of
cranial nerve function causing blindness, deafness, and facial
of teeth and the bone in the jaw.
Why is the malignant infantile form considered the most severe?
A. In addition to the common features of the other
forms, these children have:
- Anemia (and
frequently complete marrow failure). The anemia is often mistaken
for leukemia due to immature white cells seen on the blood smear.
infections. These are usually severe infections requiring antibiotics,
such as pneumonia, sepsis, and urinary tract infections. This
is due, in part, to a reduction in white blood cells (blood cells
which fight infection) and to inactive white cells.
- No or inadequate
- Failure to
- Delays in
psychomotor development-usually related to the heavy skeleton
and blindness. These will include delays in sitting, walking and
talking, in many cases, despite normal intelligence.
- The development
of blindness, deafness, and other cranial nerve problems.
- Death during
the first 10 years of life in 30% of these children.
7. Q. What causes osteopetrosis?
Q. How is the diagnosis usually made?
A. A specific genetic defect has been found in
only one type of osteopetrosis (carbonic anhydrase II deficiency).
These patients have a defect in the cellular production of acid,
with a defect in the enzyme carbonic anhydrase type II. This defect
usually causes a disease that is of moderate severity.
Q. Can osteopetrosis be passed from generation to generation?
A. The adult form of osteopetrosis is inherited
as an "autosomal dominant trait," meaning that it can be passed
from generation to generation. Offspring can inherit this even if
only one parent is affected. The chance of a child of someone with
adult osteopetrosis having the disease is 50%. Many cases, however,
occur without a known family history. It is likely that these are
new or spontaneous mutations. Thus, the risk to a sibling of someone
with osteopetrosis, whose parents have been examined and found not
to have the disease is closer to 1:10.
The severe malignant infantile form is inherited as an "autosomal
recessive disorder" where both parents have an abnormal gene that
is passed to the affected child. Each parent will be normal - that
is, will not have obvious disease. Usually, there is no history
of severe, congenital osteopetrosis in the family prior to the diagnosis
of the first child. If parents have one child with severe osteopetrosis,
there is a 1:4 chance (for each pregnancy) that a subsequent child
will be affected. A sibling of a parent known to carry the osteopetrotic
gene (the aunt or uncle of an affected child) has a 1:2 chance that
they carry the abnormal gene also. The frequency of the gene in
the normal population is low, with about 1:500 people carrying the
gene, so the risk of having an affected child is less than 1:500.
The odds are increased if there is a marriage to a close relative.
At present there is no means for prenatal diagnosis for osteopetrosis.
The intermediate form may be inherited in either an autosomal recessive
or an autosomal dominant fashion. However, most cases occur sporadically,
with no known inheritance pattern.
How common is osteopetrosis?
A.The adult form of osteopetrosis occurs
in about 1:20,000 people. There are about 1250 people with this
disease in the United States.
The malignant infantile form of osteopetrosis is seen in about 1:100,000
to 1:500,000 births. This means that only 8 to 40 children with
this severe form of osteopetrosis are born per year in the United
A. The diagnosis is made when dense bones
are found on x-rays. The diagnosis is usually confirmed by taking
a sample of the bone to determine the precise nature of the disease.
A variety of additional studies are done to look for any problems,
such as hearing and vision testing, x-rays, blood counts, and brain
How is osteopetrosis treated?
(Interferon gamma-1b). The U.S. Food and Drug Administration
(FDA) has approved ActimmuneŽ (Interferon gamma-1b) Injection
for delaying the time to disease progression in patients with
severe malignant osteopetrosis. ActimmuneŽ is the only therapy
approved specifically for the treatment of osteopetrosis. Adult
and pediatric patients may benefit. In addition to the approved
indication, there is also strong evidence to suggest that ActimmuneŽ
reduces the chance for serious infection in osteopetrosis.
Marrow Transplantation (BMT).
BMT is the only therapy which has resulted in a complete cure
of the severe malignant infantile form of osteopetrosis. BMT replaces
the abnormal osteoclasts with normal cells, curing the defect
if the transplantation, or engraftment, is successful. The survival
rate after BMT in children with osteopetrosis is 40 to 70 % depending
on how well matched the donor is to the patient. Young human leukocyte
antigen-matched siblings provide marrow with the best chance for
engraftment and cure of osteopetrosis. BMT is only used in severely
affected patients, because of the high risk of failure with the
potential of a fatal outcome.
- High Dose
is the active form of vitamin D and is a very potent stimulator
of osteoclastic function. When given in high oral doses, calcitriol
can reverse some of the problems of severe osteopetrosis and can
significantly improve the adult form. High dose calcitriol is
not FDA-approved for treating osteopetrosis at present.
Prednisone given orally has improved blood counts in patients
with anemia and low platelet counts. This therapy may slow blood
cell destruction. Prednisone treatment provides a short-term boost
to the blood system, allowing other therapies to continue. However,
if continued for long periods, prednisone may actually reduce
the growth velocity of children and predispose patients to infection.
Good nutrition is a must to ensure normal growth and development
of children with osteopetrosis.
and Occupational Therapy. Physical and occupational therapy
is extremely useful in helping children to reach their full developmental
potential. Even children with severe osteopetrosis frequently
(about 80% of the time) have a normal intellectual level. The
heavy skeleton results in gross motor delays. Blindness can delay
speech. The average severely affected child walks at about 2 years
and begins to speak at age 20 to 24 months.
Q. What is the prognosis for people with osteo-petrosis?
with the adult form of osteopetrosis have a normal life span. The
major complications are fractures and compression of the cranial
nerves leading to blindness, deafness, and facial nerve paralysis.
than 30% of all children with the severe malignant infantile form
survive to their tenth birthday, unless they are treated with BMT
or a combination of interferon gamma and calcitriol. Only 10% of
infants who have blindness and anemia before age six months survive
to beyond one year of life unless they are successfully treated.
Q. What types of physicians are specialists
in the diagnosis and treatment of osteopetrosis?
Most often, patients with osteopetrosis are seen by hematologists.
Endocrinologists are frequently asked to see patients due to their
metabolic bone disease and poor growth. Orthopedic surgeons care
for frequent fractures. Adults are usually diagnosed and treated
by orthopedic surgeons. Children with the severe congenital form
are most commonly treated by hematologists who are skilled in BMT.
Many of the specialists will work together to take care to people
Q. What research is being done to discover
treatment for osteopetrosis?
The gene defects that cause osteopetrosis are being searched for
in several species of animals who also develop this problem. Discovery
of similar genetic defects in man should help to devise new and
highly effective treatments for patients.
Having too few red blood cells. Symptoms include tiredness,
weakness, and shortness of breath.
A substance capable of stimulating an immune response.
One parent has an abnormal gene that is passed to the affected
recessive disorder Both parents have an abnormal gene that
is passed to the affected child.
The active form of vitamin D, which is generated by chemical alterations
in the liver and kidney. Calcitriol stimulates calcium absorption,
bone formation, and removal of calcium from bones.
Anhydrase An enzyme that aids in the break down of bicarbonate
into carbon dioxide and water. This enzyme is crucial to the ability
of cells to get rid of hydrogen ions and maintain the level of
Present at birth.
Pertaining to the bones of the head.
Physicians who specialize in hormonal and metabolism disorders.
Successful transplantation of cells from one individual to another.
A protein that aids a chemical reaction to take place. Enzymes
are responsible for controlling and facilitating the chemical
processes that allow cells to grow, develop, and function.
Human Leukocyte Antigen (HLA) These
antigens are present on the surface of white blood cells and are
used to determine if the body's immune system will detect a cell(s)
as foreign or self. Identity of these major histocompatability
antigens between cells being transplanted and the individual into
whom they are being transplanted is crucial to the success of
Physicians who study and treat diseases of the blood.
gamma A substance made by lymphocytes in the body, which stimulates
an immune response. Interferon gamma has been used to stimulate
improved immunity in patients with white cell defects. The U.S.
Food and Drug Administration (FDA) approved ActimmuneŽ (Interferon
gamma-1b) Injection in 2000 for delaying the time to disease progression
in patients with severe malignant osteopetrosis.
Cells that mediate the immune system.
Cells that break down bone.
A synthetic steroid hormone that is similar to, but more potent
than hydrocortisone. This type of steroid is known as a glucocorticoid
since it stimulates glucose (sugar) synthesis in and release from
the liver. Glucocorticoids also have a major effect on immune
cells, reducing their inflammatory activity.
Before the birth of the fetus.
The presence of disease-related microorganisms or their toxins
in the blood or other tissues.