Osteopetrosis

The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts,^[4] cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.^[5]

• 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.^[5]

• 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.^[5] 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.

• 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.^[3]

Bone marrow transplantation (BMT) markedly improves some cases of severe, infantile osteopetrosis associated with bone marrow failure, and offers the best chance of longer-term survival for individuals with this type.^[3][1]

In pediatric (childhood) osteopetrosis, surgery is sometimes needed because of fractures.

Adult osteopetrosis typically does not require treatment, but complications of the condition may require intervention. Surgery may be needed for aesthetic or functional reasons (such as multiple fractures, deformity, and loss of function), or for severe degenerative joint disease.^[3]