1. What is osteopetrosis?
Osteopetrosis is a condition present at birth (congenital) in which the bones are overly dense. This results from an imbalance between the formation of bone and the breakdown of bone. In osteopetrosis the cells which break down bone, the osteoclasts, usually are fewer in number or are ineffective in removing bone.

2. Which bones are most commonly affected?
All bones are affected by osteopetrosis. They are overly dense and the skeleton is extremely heavy.

3. What are the symptoms of osteopetrosis?

a) Fractures because the bones are weak.

 b) Less blood cell production, because the bones have very little bone marrow space. This can lead to frequent infections.

 c) Blindness, deafness, and strokes, because the holes in the bones are too small for blood vessels and nerves to pass through.

4. Are there different types or forms of osteopetrosis?
There are three major types of osteopetrosis:

a) "Malignant infantile form." This type is very severe (but not related to cancer). It is apparent from birth and frequently ends in death.

b) "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.

c) "Intermediate 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.

5. What do these three types have in common?

 Common features of the three types are:

a) Fractures, usually of the long bones in the adult form, and of the ribs and long bones in the malignant infantile form.

b) Loss of cranial nerve function causing blindness, deafness, facial nerve paralysis.
c) Infections of teeth and the bone in the jaw.

6. Why is the malignant infantile form considered the most severe?
In addition to the common features of the other forms, these children have:

a) Anemia (and frequently complete marrow failure). The anemia is often mistaken for leukemia due to immature white cells seen on the blood smear.

b) Frequent 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.

c) No or inadequate tooth eruption.

d) Increased intracranial pressure.

e) Failure to thrive.

f) 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.

g) The development of blindness, deafness, and other cranial nerve problems.

h) Death during the first 10 years of life in 30% of these children.

7. What causes osteopetrosis?
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 which is of moderate severity.

8. If one person in a family has osteopetrosis, will other members of the family also have it?
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 which 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.

9. How common is osteopetrosis?
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 States.

10. How is the diagnosis usually made?
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 imaging.

11. How is osteopetrosis treated?
a) Bone 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.

b) High Dose Calcitriol:

Calcitriol 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.

c) Interferon Gamma:

Interferon gamma with calcitriol has been shown to improve osteopetrosis, but does not completely reverse the disease. Interferon gamma reduces the rate of infection, improves bone marrow function, and decreases the likelihood of cranial nerve compression.

Neither high dose calcitriol or interferon gamma are FDA-approved for treating osteopetrosis at present.

d) Prednisone

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.

e) Nutrition

Good nutrition is a must to ensure normal growth and development of children with osteopetrosis.

f) Physical 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.

12. What is the prognosis for people with osteopetrosis?
Patients 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.

Less 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.

13. 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 of people with osteopetrosis.

14. What research is being done to discover treatments 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.

Antigen- A substance capable of stimulating an immune response.

Calcitriol- 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.

Carbonic Anhydrase- An enzyme which 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 cell acidity.

Congenital- Present at birth.

Endocrinologists- Doctors who study and treat diseases of hormone production.

Engraftment- Successful transplantation of cells from one individual to another.

Enzyme- A protein which aids a chemical reaction to take place. Enzymes are responsible for controlling and facilitating the chemical processes which 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 the engraftment.

Hematologists- Doctors who study and treat diseases of the blood.

Interferon 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.

Lymphocytes- Cells that mediate the immune system.

Prednisone- A synthetic steroid hormone which 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.

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