Osteopetrosis is a rare congenital bone disorder. In osteopetrosis, bones are abnormally dense and brittle.  This results from an imbalance between the formation of bone and the breakdown of the bone.  There are several types of osteopetrosis of varying severity.  Symptoms can include fractures, frequent infections, blindness, deafness and stroke.

Osteopetrosis is also known as Albers-Schonberg Disease, Generalized Congenital Osteosclerosis, Ivory Bones, Marble Bones, Osteosclerosis Fragilis Generalisata

Normal bone is live tissue in a continuous state of remodeling.  As new bone grows, old bone is resorbed or taken away.  In osteopetrosis, the interplay between bone growth and breakdown is disturbed.  New bone continues to be formed but breakdown of old bone tissue is impaired. As a result, the bones overgrow.  The condition is quite rare; incidences have been reported at 1 in 250,000 for the dominant form and 1 in 200,000 for the recessive form.

Osteopetrosis is generally diagnosed through skeletal x-rays.  X-rays of osteopetrosis patients will have an unusual density with chalky white appearance.  Bone density tests and bone biopsies can confirm the diagnosis while other tests such as CAT scans or MRI can be performed to evaluate any potential complications.

Types of Osteopetrosis

Osteopetrosis presents in one of three forms:

Autosomal Dominant (also known as Benign Osteopetrosis)

Malignant Infantile Osteopetrosis

Intermediate Osteopetrosis


There are subcategories of osteopetrosis with different genetic backgrounds.  However, all types of osteopetrosis are characterized by hardened bones that become very brittle and break easily.  Two additional types of osteopetrosis have been discussed in the literature:  Transient Infantile Osteopetrosis and Osteopetrosis with Renal Tubular Acidosis.


Neonates may present with abnormally high bone density in the Transient form of Osteopetrosis but the condition resolves itself in the first year of life and does not require medical treatment.


Osteopetrosis with Renal Tubular Acidosis is caused by an enzyme deficiency, carbon anhydrase type II.  This enzyme is active in bones, kidneys and the brain.  These organs, therefore, are affected.  The gene responsible for producing CAII is found on chromosome 8 at 8q22.  Symptoms in this type of osteopetrosis include increased bone density, a tendency to fracture easily and change in body chemistry. Other symptoms may include intracranial calcifications, sensorineural hearing loss and developmental delays.  The blood is slightly acidic and has a high chloride concentration (hyperchloraemic acidosis.)  The blood acidity is caused by excessive leakage of bicarbonate from the kidney tubules (renal tubular acidosis.)  CAII must also have an important role in brain development aand children who are affected often develop cerebral calcidixcation and experience developmental delays.


This form of the disease usually causes symptoms in the first few years of life although x-rays are normal at birth.  X-ray appearances often improve again in later life.  Unlike malignant osteopetrosis, blood problems tend to be minor or absent.


This disease should be excluded in every child with osteopetrosis by measuring CAII activity.

Symptoms Common to Osteopetrosis

The remaining three forms have some common symptoms.  They include:


       -Frequent fractures, especially of the long bones which are difficult to heal

       -Nerve compression which leads to headaches, blindness and deafness

       -Hematological difficulties including anemia, thrombocytopenia and leukopenia

       -Enlarged spleen


       -Frontal bossing of the skull

       -Unusual dentition, including malformed and unerrupted teeth




Autosomal Dominant or Benign osteopetrosis

*It can be noted that patients with this form of osteopetrosis suffer from many difficulties and thus the term benign is quite misleading.


Benign osteopetrosis is genetically dominant.  Generally individuals are diagnosed in their late teens or in early adulthood.   People with Adult Dominant Osteopetrosis (ADO) suffer from frequent fractures that have difficulty healing.  Diagnosis is often discovered by chance in an x-ray performed for another medical reason.  The images reveal abnormally calcified bone.  X-rays of the spine and the cranial bones are particularly helpful in making the diagnosis.  Management of ADO involves treating fractures as with the general population.  Other symptoms associated with Adult Dominant Osteopetrosis include osteomyelitis, pain, degenerative arthritis and headache.  Life expectancy is not altered.

Intermediate osteopetrosis

Because there are individuals with symptoms that do not fit clearly into the two more recognizable categories, some publications will present a third type of osteopetrosis known as Intermediate Osteopetrosis.  These individuals will generally have a diagnosis in the first decade of life and symptoms more severe than those described as Benign Osteopetrosis.  This variant resembles malignant osteopetrosis although symptoms are less pronounced.  These diffuse signs often delay diagnosis and treatment.  Severity of the symptoms varies. 

Some children have limited vision, while others become completely blind in their first year of life.  The head shape is abnormal and nasal congestion – an early sign of malignant osteopetrosis- is not typical with this variant.  As in malignant form, the bone marrow is affected in most children and the spleen and liver attempt to compensate for decreased cell production. 

Spleen enlargement can be seen, markedly distending the abdomen and may disturb gastrointestinal function.  The prognosis varies from case to case, but most children reach adulthood.

Malignant or infantile osteopetrosis

Infants are diagnosed with this form of osteopetrosis immediately or shortly after birth.  In this type of osteopetrosis bone marrow is severely affected.  Blood production is affected resulting in anemia and other hematological difficulties. Compression of the cranial nerves affects vision and hearing.  Enlarged cranial bones give the head a characteristic appearance with a large, rounded forehead.  The nose can be flat, decreasing the size of the nasal cavity and leading to frequent congestion.  Children with MIOP tend to have a heavy head and body.  Balance problems may result.  Sitting can be difficult and ambulation may be delayed.  A side effect of restricted mobility is that bone fractures are less common than expected.  Bones of severely involved infants may fracture during delivery.

Since teeth develop from bone tissue, both primary and permanent dentition is affected.  It is common that several teeth fail to erupt and tooth enamel may be of poor quality and vulnerable to caries.

Blood calcium levels may be abnormally low due to increased bone calcification.  Very low serum calcium concentrations may cause muscle cramps.

Children with MIOP have poor vision and/or varying degrees of blindness because of compression to the optic nerve which passes through the cranial bone.  In addition, compression of the auditory and balance nerves may impair hearing and balance.  Other cranial nerves may be involved affecting, for example, the facial muscles and pharynx resulting in poor control over facial expressions and swallowing difficulties.

The production of blood cells takes place in the bone marrow (the tissue comprising the center of the long bones).  When abnormal bone growth compresses the marrow, blood cell production is affected and blood count decrease.  The thrombocyte count may drop dramatically, increasing the risk of spontaneous bleeding or bleeding from trivial injuries.  If the concentration of white blood cells also decreases, the child will have recurrent infections, particularly bacterial respiratory tract infections.  There is a high risk of developing severe infections such as sepsis and especially osteomyelitis (an infection of the bone).  The latter condition typically presents in the lower jaw, probably as a result of increased vulnerability to tooth decay and bacteria.

The body to some extent compensates for bone marrow failure by switching blood production to the spleen and liver, resulting in organ enlargement and a severely distended abdomen. 

Diagnosis of Osteopetrosis

A routine x-ray will reveal abnormally dense bones.  In the infantile malignant form, typical radiological findings also include abnormalities in the growth zones of the long bones and the facial bones have a mask-like appearance, called “sign du masque” or “batman sign.”

A bone marrow examination is performed to check the number of osteoclasts which is normal or increased in all forms of osteopetrosis except the one caused by a mutation of the NFSF11 gene.  When there is a TNFSF11 mutation and a deficiency of RANKL there are very few, if any, osteoclasts.

In approximately three quarters of all malignant cases, the diagnosis can be confirmed by DNA analysis of the four genes known to cause the disease.

Prenatal diagnosis is possible if the specific mutation underlying the condition in a particular family has been identified.

The diagnosis of the Intermediate variety is often delayed.  One reason is that the appearance of these children is less distinct than in the malignant variant and frequently remains inconspicuous.  The parents often express concern about minor abnormalities, but their worries are often dismissed.

Treatment and Intervention

Malignant Osteopetrosis

The only curative treatment for malignant infantile osteopetrosis and the Intermediate variant is hematopoietic stem cell transplantation.  The intervention must be carried out at a very early stage, before nerve damage has occurred.  If a suitable donor is found and the transplantation is carried out early, the results are usually excellent.  It is important to observe that the rare form of malignant osteopetrosis caused by a TNFSF11 mutation cannot be cured by stem cell transplantation and this variant therefore must be excluded before transplantation is considered.

While waiting for transplantation or if transplantation is not a viable option for some reason, gamma interferon treatment may provide an alternative.  Interferon is a substance naturally produced by the immune system (the white blood cells).  It stimulates white cell (including osteoclast) production of hydrogen peroxide, a substance required for bone degradation.  Stimulating bone degradation sometimes delays the progression of the disease.  However, treatment results remain inconsistent and controversial. 

All signs of infections must be taken seriously and treatment should begin early.  All bacterial infections should be treated with antibiotics.  It is particularly important to observe the risk of osteomyelitis.

Iron supplements are given to treat anemia.  In rare cases with severe thrombocytopenia, thrombocytes are administered.  Since the effect of thrombocyte transfusions is very sort-lived, the method is used only in cases of serious bleeding or before surgery.  Surgical removal of the spleen can improve quality of life dramatically, particularly in patients with the Intermediate form of the disease.  However, relief may be only temporary if liver enlargement arises as a consequence of the liver taking over blood production.  A child whose spleen has been removed therefore requires careful monitoring.  Special care must be taken to ensure that all vaccines normally administered plus pneumococcal vaccination have been given before surgery is performed.

Physical therapy is essential for supporting the development of motor skills.  Abnormal bone mass and a large head may prevent or delay the child’s ability to balance the head or to sit and stand upright.

Parents of children with malignant osteopetrosis or the intermediate variant should be offered psychological and social support.  Parents should also be offered contact with other families in the same situation who are willing to share their experience.

Hematopoietic Stem Cell Transplantation

The only treatment known to cure osteopetrosis is stem cell transplantation.  Stem cells have the potential to differentiate into various cells of the human body.  They can be harvested from bone marrow, found in bone cavities.  Blood-forming stem cells (hematopoietic stem cells) have the specific ability to produce all our different types of blood cells including osteoclasts.  Transplantation makes it possible to use bone marrow from a healthy donor to replace the affected individual’s stem cells.

To optimize the chances of successful transplantation the recipient of the stem cells should be as free from infection as possible and in good physical condition.  For this reason, it is important to carry out the transplantation early, preferably before the age of six months, as this will increase the chances that the child has not developed any serious infections.  The intervention itself is fairly simple, but the preparations, aftercare and major risks involved make it a highly demanding procedure.

In order to carry out a stem cell transplant, a donor must be found whose tissue type (HLA antigen) matches that of the recipient.  Ideally they should be identical.  The HLA type is inherited from both parents and each child has a 25 percent chance of having the same tissue type as an ill sibling.  It is optimal to transplant bone marrow from a healthy sibling but if this is impossible there are both national and international bone marrow donor programs where a suitable donor may be located.

If no suitable bone marrow donor can be found, it is possible to search for a match using cord blood banks where they store stem cells from the umbilical cord after delivery.  Blood from the umbilical cord is particularly rich in stem cells and the small amount that is left after the umbilical cord has been cut is normally sufficient for a transplant.  The advantage of umbilical cord blood is that the HLA match does not have to be perfect which means that a suitable door can be found in most cases.  Stem cells from umbilical cord blood do, however, take slightly longer to begin the production of new blood cells.

For the new bone marrow to engraft and to avoid a situation in which the donor’s and the recipients blood cells attempt to attack and destroy each other, thorough preparations are required.  The recipient is treated with chemotherapy so that the bone marrow is cleared from all disease carrying stem cells.  This is important because the immune system will otherwise react to the transplanted stem cells as foreign tissue that should be rejected.

Preparations may in these cases be highly demanding.  When the immune system of the recipient is essentially wiped out, there is a great risk of serious infection.  For this reason the patient needs to be kept in isolation for a period of six to eight weeks before and after the transplantation in anticipation of the production of new, healthy blood cells by the transplanted stem cells.

Most blood stem cells are in the bone marrow, but a few are also found in the bloodstream.  The concentration can be increased by using special medications that induce the stem cells to move from the bone marrow to the blood.  Accordingly there are three available methods for retrieval of stem cells.  Either bone marrow is removed from the hipbone of the donor by suction, after which it is collected in a container or blood can be machine-filtered for stem cells which are then skimmed off.  The filtered blood can then be returned to the donor.  The third alternative is to use stem cells from umbilical cord blood.

The stem cells are administered as IV drip directly into the recipient’s blood vessels in much the same way as a blood transfusion.  The stem cells then find their way to the recipient’s marrow cavities (in the bones in various parts of the body) and grow there to supply the recipient with a new immune system.  However, it may take up to one year for bone marrow function to be fully restored.

Treatment for Adult Dominant Osteopetrosis

Adult Dominant Osteopetrosis is primarily managed by informing individuals with the condition about the risk of bone fractures, even in minor incidents.  Although leisure and work activities involving high risk should be avoided individuals with ADO can live essentially normal lives.  Standard orthopedic and arthritis interventions are used.


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