Osteopetrosis

Osteopetrosis, also referred to as marble bone disease and Albers-Schönberg disease, is a rare hereditary bone disorder that causes the bones to harden and thicken. The disease causes malfunctioning of cells called osteoclasts. These cells are responsible for breaking down and reabsorbing bone tissue. Malfunctions in the osteoclasts result in the thickening and excess formation of bones, which affects a person's growth.

Osteopetrosis can manifest in one of three forms: osteopetrosis tarda (benign adult type, autosomal dominant), osteopetrosis congenita (malignant infantile type, autosomal recessive), or intermediate osteopetrosis (autosomal recessive and intermediate between the malignant infantile type and the benign adult type).

A fourth very rare form is the severe X-linked osteopetrosis (recessive). Osteopetrosis tarda, also known as Albers-Schönberg disease, occurs in adolescence and adulthood, while the other two types form in infancy and childhood. Autosomal dominant forms are estimated to affect about 1 in 20,000 people, while autosomal recessive forms affect about 1 in 250,000. Problems associated with osteopetrosis include growth deformities, brittle bones, liver and spleen enlargement, blindness, and deafness.

Causes and Symptoms

Two types of cells work together to make and break down bone tissue: osteoblasts and osteoclasts. Osteoblasts build bone tissue while osteoclasts dissolve bone tissue. These cells allow the bones to take different shapes as a person ages and grows over their lifespan. The formation and reabsorption of bones and bone tissue are continuous processes throughout a person's development.

Osteoclasts absorb bone tissue during growth and healing and play an important role in the normal development of bones. Osteoclasts make enzymes that dissolve bone tissue. The osteoclast cells absorb this dissolved bone tissue and break it down into its component parts of amino acids, calcium, and phosphate, which are released and used in different parts of the body. This allows osteoblasts to make new bone tissue that reshapes the bone. When osteoclasts malfunction, which may occur due to a genetic defect, bone tissue is not dissolved properly and builds up on the bone, making it difficult for the bone to reform. If severe infantile osteopetrosis develops at an early age, it can stunt a person's growth and cause physical deformities and bone marrow failure. Infants born with osteopetrosis usually die within two years.

The major symptoms of osteopetrosis include bone marrow failure and brittle bones. Bone marrow failure is caused when defective bone tissue replaces bone marrow in the cavities of the bone. Bone marrow is needed to produce red blood cells and other immune system cells. If bone marrow fails to develop properly, a blood cell deficiency results, which can negatively affect the immune system. A compromised immune system leads an individual to be more susceptible to disease, especially certain blood diseases such as anemia. Blood cell deficiency can also impair the clotting process, causing excessive bleeding in affected individuals.

Despite the thickening of the bones, osteopetrosis makes the bones fragile and easily fractured. The disorder also causes bone deformities, which include an increase in bone density and abnormal curvature of the spine. Some patients with osteopetrosis suffer from breathing difficulties due to cranial malformations. Other bone displacements may occur in the skull that can cause nerve damage and lead to blindness, deafness, and fluid accumulation in the brain. Brain fluid accumulation often results in brain damage.

Three Types

The three types of osteopetrosis develop during different stages of the lifespan. Osteopetrosis tarda, the benign form, presents itself in adulthood and shows no symptoms in fifty percent of patients. This form is often discovered accidentally during routine X-ray examinations. The most common symptom of this type of osteopetrosis is brittle bones. The affected individual’s bones are more sensitive to fractures and breakage. Bone healing is normal for patients with osteopetrosis tarda, however. Some patients experience degenerative joint disease as well. Bone marrow failure can occur, but it is rare. Other adult symptoms include chronic pain, arthritis, and a bone infection known as osteomyelitis.

Osteopetrosis congenita (autosomal recessive osteopetrosis or severe infantile form) is a malignant (deadly) form of osteopetrosis. This type manifests in infancy and causes severe bone marrow failure, growth failure and deformity, and accumulation of brain fluid. Blindness and deafness are common. Bone marrow failure normally leads to pancytopenia, a medical condition that results in a low number of red cells, white cells, and platelets. Low blood cell counts lead to a weak immune system, leaving the child vulnerable to disease. Most infants with this type of osteopetrosis do not live past the age of two and die as a result of severe bleeding or infection, but early transplantation can improve survival in eligible patients.

The third form of osteopetrosis is referred to as intermediate osteopetrosis (autosomal recessive). This type has milder or absent bone marrow failure, and survival rates are higher. Other symptoms caused by the disease can shorten a patient's lifespan, however. This form can lead to chronic kidney problems, which can have fatal consequences. Patients have increased bone density, often resulting in brittle bones and frequent fractures, and are usually short in stature, with calcium buildup in their skulls. Anemia, dental caries, poor dentition, hearing loss, and a slowing of physical and emotional reactions (developmental delay, intellectual disability, or specific neurologic complications) are also common.

The extremely rare form of osteopetrosis is referred to as X-linked osteopetrosis. This type is recessive and can cause immunodeficiency, lymphedema, and other complications.

Prevention and Treatment

Osteopetrosis is a hereditary disorder and cannot be prevented. Few medical treatments are available for the disease. Infants are often given high doses of vitamin D to help activate inactive osteoclasts. Some patients with severe osteopetrosis are also administered a drug known as Interferon Gamma-1b (Actimmune) to delay the disease's progression. Doctors also recommend that patients with osteopetrosis engage in physical therapy and maintain a well-balanced diet. A 2024 guideline from the European Society for Immunodeficiencies/European Society for Blood and Marrow Transplantation states that stem cell transplantation is the preferred treatment for many severe infantile cases but is not effective in all genetic forms.

Couples with a family history of osteopetrosis or related bone disorders who are considering pregnancy should consider a visit to a genetic counselor for assistance.

Bibliography

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