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
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
presents in one of three forms:
Dominant (also known as Benign Osteopetrosis)
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.
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.
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.
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.
disease should be excluded in every child with osteopetrosis by measuring CAII
Symptoms Common to Osteopetrosis
remaining three forms have some common symptoms. They include:
fractures, especially of the long bones which are difficult to heal
compression which leads to headaches, blindness and deafness
difficulties including anemia, thrombocytopenia and leukopenia
bossing of the skull
dentition, including malformed and unerrupted teeth
Autosomal Dominant or Benign osteopetrosis
can be noted that patients with this form of osteopetrosis suffer from many
difficulties and thus the term benign is quite misleading.
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.
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
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
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
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
Treatment and Intervention
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
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
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
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
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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