Osteopetrosis is a bone disease that makes bone tissue abnormally compact and dense and also prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant or autosomal recessive. 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 Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In affected people with no symptoms, the unusually dense bones may be discovered by accident when an x-ray is done for another reason.

In individuals with ADO who develop signs and symptoms, the major features of the condition include multiple bone fractures after minor injury, 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 life-threatening 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.

The types of osteopetrosis are broken into categories based on inheritance pattern, age the disease develops, and the severity of the disease. The types include:

• Autosomal recessive osteopetrosis is the severe infantile form of the disorder. The symptoms of this type develop at or shortly after birth and shorten life expectancy.
• Autosomal dominant osteopetrosis is the noninfantile form of the disorder and is also known as Albers-Schönberg disease. The symptoms of this type develop later than the infantile form and have a wide range of disease severity. Even within the same family, some people have little or no impact from the disease, while others are severely affected by the disease and have significant disability and shortened life expectancy. People with this type of osteopetrosis may not be diagnosed until adolescence or adulthood.
• X-linked osteopetrosis is a rare form of the disease and can affect many areas of the body.

The severity of symptoms can vary depending on the type of osteopetrosis. They include:

• Bone fractures from brittle, dense bones.
• Nasal congestion from narrowing sinus cavities.
• Vision and hearing changes from enlarged bones pressing on nerves.
• Dental problems due to bone changes in the skull and jaw and because teeth come in later than normal.
• Low blood cell levels due to smaller amounts of bone marrow because of crowding in the center of bones can lead to anemia and infection.
• Infections in the bone (osteomyelitis).
• Chronic bone pain.

• Mutations in the CLCN7 gene cause most cases of autosomal dominant osteopetrosis, 10-15% of cases of autosomal recessive osteopetrosis (the most severe form), and all known cases of intermediate autosomal osteopetrosis.
• Mutations in the TCIRG1 gene cause about 50% of cases of autosomal recessive osteopetrosis.
• Mutations in the IKBKG gene cause X-linked osteopetrosis.
• Mutations in other genes are less common causes of osteopetrosis.
• In about 30% percent of affected people, the cause is unknown.

• In autosomal dominant inheritance, having a change (mutation) in only one copy of the responsible gene in each cell is enough to cause features of the condition. Most people with autosomal dominant osteopetrosis inherit the condition from an affected parent. Each child of a person with this form has a 1 in 2 (50%) chance of being affected.
• In autosomal recessive inheritance, in order to be affected a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:
  • 25% (1 in 4) chance to be affected
  • 50% (1 in 2) chance to be an unaffected carrier like each parent
  • 25% chance to be unaffected and not be a carrier
• X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome). Females have two X chromosomes, so if they have a gene mutation on one of them, they still have a normal copy on their other X chromosome. For this reason, females are typically unaffected. While females can have an X-linked recessive condition, it is very rare.
  
  If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child's sex.
  
  • Each male child has a 50% chance to be unaffected, and a 50% chance to be affected
  • Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier
  If a father has the condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be unaffected carriers.

• thoroughly evaluating the family history
• addressing questions and concerns
• assessing recurrence risks
• facilitating genetic testing if desired
• discussing reproductive options

• Vitamin D (calcitriol) appears to stimulate dormant osteoclasts, which stimulates bone resorption. Large doses of calcitriol with restricted calcium intake sometimes improves osteopetrosis dramatically, but the improvement seen with calcitrol is not sustained when therapy is stopped.
• Gamma interferon can have long-term benefits. It improves white blood cell function (leading to fewer infections), decreases bone volume, and increases bone marrow volume.
• Erythropoietin can be used for anemia, and corticosteroids can be used for anemia and to stimulate bone resorption.

There is little information in the medical literature about nutrition and dietary recommendations for people with osteopetrosis. We are not aware of any specific dietary guidelines that have been proposed.

Generally, nutritional support in childhood is important to improve growth. It also may enhance responsiveness to other treatments. A low-calcium and high-phosphate diet in conjunction with oral prednisone has led to improvement in anemia, thrombocytopenia, and bone density in a few patients. However, some people may need calcium if hypocalcemia or rickets becomes a problem. Vitamin D supplements may help by stimulating dormant osteoclasts, thus stimulating bone resorption.

A number of specialists may be needed to treat people with osteopetrosis. Medical management (aside from transplant) is usually done by an endocrinologist who is comfortable with, and knowledgeable of, metabolic bone disease. People with osteopetrosis who have scoliosis should see a spine specialist who is familiar with the condition. An orthopedic surgeon familiar with osteopetrosis should manage treatment for fractures and other problems with the bones and joints. It is also important to see an ophthalmologist (eye doctor) or neuro-ophthalmologist to follow or treat vision changes or vision loss.