Years published: 1986, 1988, 1989, 1995, 2003, 2018, 2023
NORD gratefully acknowledges Amanda Wong, NORD Editorial Intern from the Keck Graduate Institute and Ann K. Rosenthal, MD, FACP, Will and Cava Ross Professor of Medicine and Chief of Rheumatology, Medical College of Wisconsin, for assistance in the preparation of this report.
Chondrocalcinosis 1 and 2 (CCAL1 and CCAL2) are genetic forms of calcium pyrophosphate deposition disease (CPPD), a metabolic disorder characterized by deposits of calcium pyrophosphate crystals (CPP) in joint cartilage and eventual damage to affected joints. The symptoms of CCAL1 and CCAL2 include swelling, stiffness, pain and loss of function of the affected joints. The knee is the most affected area. CCAL1 and CCAL2 are autosomal dominant genetic disorders that are usually diagnosed in early adulthood.
The non-genetic forms of CPDD are much more common, and typically cause arthritis in patients over the age of 60.
The symptoms of CCAL1 and CCAL2 usually begin as acute, recurring attacks of pain, swelling, warmth and redness in one or more joints. Other affected people have swelling, stiffness, and pain with little or no inflammation in the joints. A knee, wrist, hip, or shoulder is most frequently affected, although any joint of the body may be involved. Acute episodes can last for days to weeks, and symptoms may go away without treatment. CPP deposits may accumulate around the bones of the spine (vertebrae) and cause back or neck pain and/or loss of mobility. Many patients with CPPD develop chronic arthritis which can resemble osteoarthritis or rheumatoid arthritis.
CCAL2 is caused by changes (variants or mutations) in the ANKH gene that lead to an increased amount of the ANKH protein produced.
The protein produced by the ANKH gene seems to be involved in cellular transport of ATP. ATP is an important energy-containing compound. In cartilage, when it is transported outside the cell, it is metabolized by enzymes into inorganic pyrophosphate (PPi). Variants in ANKH have been shown to have a significant effect on the regulation of extracellular ATP and PPi levels (outside chondrocytes). When ANKH activity is increased, levels of PPi accumulate in cartilage, complex with calcium and form calcium pyrophosphate (CPP) crystals.
CCAL1 is caused by variants in the TNFSRF11B gene that lead to a reduced amount of the osteoprotegerin protein produced.
Osteoprotegerin is made by both bone and cartilage and regulates the activity of cells known as osteoclasts which cause bone loss. When osteoprotegerin is not fully functional, osteoclasts increase in number and activity. Exactly how and why this causes CPPD is not yet known.
In most cases, CCAL1 and CCAL2 follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
The symptoms of CCAL1 and CCAL2 are thought to be more severe in people who carry two gene variants for the disorder (homozygotes), one from each parent. People who have only one abnormal gene (heterozygotes) are thought to experience less severe symptoms.
CCAL1 and CCAL2 are rare disorders. Eight families have been described in the medical literature with CCAL2. Four families with TNFSRF11B gene variants associated with CCAL1 have been identified. There is no known ethnic or sex predilection.
Few or no symptoms may be apparent in the first several decades of life. X-rays of joints, especially the knees and wrists, may detect calcifications before symptoms occur. The diagnosis of CCAL1 and CCAL2 is based on a clinical evaluation that includes a thorough patient history and specialized laboratory tests. In one test, fluid is removed from an affected joint (synovial fluid). The presence of calcium pyrophosphate crystals in this fluid confirms the diagnosis of articular chondrocalcinosis. Radiographic (x-ray) studies typically demonstrate calcium pyrophosphate deposits in the cartilage in joints (articular).
Joint ultrasonography is well tolerated by patients and is another method of observing calcified deposits in soft tissues.
Molecular genetic testing for mutations in the ANKH gene is available to confirm the diagnosis of CCAL2.
Treatment for CCAL1 and CCAL2 is symptomatic. There is no way to prevent the formation of calcium pyrophosphate crystals or to satisfactorily remove existing crystals from the joints.
Acute attacks of CCAL1 and CCAL2 are treated in several ways. Excess fluid may be drained from the affected joint using a needle and syringe. If only one joint is involved, a corticosteroid drug may be injected directly into the affected joint (intra-articular). For individuals with frequent, recurring acute attacks, colchicine or oral corticosteroids such as prednisone may be effective. These medications are also used to treat gout. Other drugs that are frequently used include nonsteroidal anti-inflammatory drugs (e.g., ibuprofen and naproxen sodium) which are commonly prescribed for many types of arthritic conditions.
When corticosteroids, nonsteroidal anti-inflammatory drugs and colchicine are ineffective, contraindicated or not well-tolerated, drugs that inhibit the cytokine interleukin 1 alpha might be helpful. There is some evidence that methotrexate and hydroxychloroquine may also be useful, but the effectiveness of these drugs is not well studied.
During an acute attack of arthritis, the affected joint may require rest. Splints, canes and other devices that protect and support the joint may be prescribed and may require special fitting. Once the episode subsides, rest should be balanced with appropriate exercise that is carefully monitored by a physician or physical therapist.
In some people with CCAL1 or CCAL2, surgery may be necessary to repair a joint that is badly damaged. Surgery may be an effective means for reducing pain and enhancing mobility in some people.
Asymptomatic CCAL1 and CCAL2 do not require treatment.
Genetic counseling may be helpful for affected individuals and their families.
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