Osteopetrosis

Osteopetrosis is a rare bone disease characterized by abnormally compact, dense bones that are prone to breakage, with severity ranging from asymptomatic to life-threatening depending on the genetic inheritance pattern.

Overview

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.

Types and Symptoms

Autosomal Dominant Osteopetrosis (ADO)

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 or other spinal abnormalities
• Arthritis in the hips
• A bone infection called osteomyelitis

These problems usually become apparent in late childhood or adolescence.

Autosomal Recessive Osteopetrosis (ARO)

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. Other major features include:

• Vision loss, hearing loss, and paralysis of facial muscles caused by abnormally dense skull bones pinching nerves in the head and face
• Impaired bone marrow function, preventing the production of new blood cells and immune system cells
• Risk of abnormal bleeding, a shortage of red blood cells, and recurrent infections
• Slow growth and short stature
• Dental abnormalities
• An enlarged liver and spleen (hepatosplenomegaly)
• Brain abnormalities, intellectual disability, or recurrent seizures (epilepsy), depending on the genetic changes involved

In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.

Intermediate Autosomal Osteopetrosis (IAO)

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
• Anemia
• Abnormal calcium deposits (calcifications) in the brain
• Intellectual disability
• A form of kidney disease called renal tubular acidosis

People with this form of the disorder typically do not have life-threatening bone marrow abnormalities.

Frequency

Autosomal dominant osteopetrosis is the most common form of the disorder, affecting about 1 in 20,000 people. Autosomal recessive osteopetrosis is rarer, occurring in an estimated 1 in 250,000 people.

Causes & Genetic Factors

Variants (also called mutations) in at least eight genes cause the various types of osteopetrosis. Variants in the CLCN7 gene are responsible for about 75 percent of cases of autosomal dominant osteopetrosis, 10 to 15 percent of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis. TCIRG1 gene variants cause about 50 percent of cases of autosomal recessive osteopetrosis. Variants in other genes are less common causes of autosomal dominant and autosomal recessive forms of the disorder. In about 30 percent of all cases of osteopetrosis, the cause of the condition is unknown.

The genes associated with osteopetrosis are involved in the formation, development, and function of specialized cells called osteoclasts. These cells break down bone tissue during bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.

Variants in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis.

Genes Associated with Osteopetrosis

• CLCN7
• ITGB3
• TCIRG1
• TNFRSF11A
• CA2
• OSTM1
• PLEKHM1
• TNFSF11

Inheritance Pattern

Osteopetrosis can have several different patterns of inheritance:

• Autosomal dominant pattern: One copy of an altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant osteopetrosis inherit the condition from an affected parent.
• Autosomal recessive pattern: Both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Congenital osteopetrosis
• Marble bone disease
• Osteopetroses