NORD gratefully acknowledges Amada 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 2 (CCAL2) is a genetic type of calcium pyrophosphate deposition disease (CPDD), a metabolic disorder characterized by deposits of calcium pyrophosphate dihydrate crystals (CPPD) in joint cartilage and eventual damage to affected joints. The symptoms of CCAL2 include swelling, stiffness, pain, and loss of function of the affected joints. The knee is most commonly affected area. CCAL2 is an autosomal dominant genetic disorder that is 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 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 subside without treatment. Calcium pyrophosphate (CPP) crystal deposits may accumulate around the bones of the spine (vertebrae) and cause back or neck pain and/or loss of mobility. Many patients with CPDD develop chronic arthritis which can resemble osteoarthritis.
CCAL2 is caused by presumed gain-of-function mutations in the ANKH gene.
The protein produced by the ANKH gene seems to be involved in cellular transport of inorganic pyrophosphate (PPi), and mutations in ANKH have been shown to have a significant effect on the regulation of PPi levels within the cells (intracellular) and outside the cells (extracellular). When ANKH activity is increased, levels of PPi accumulate in cartilage, complex with calcium, and form calcium pyrophosphate (CPP) crystals.
In most cases, CCAL2 is inherited as an autosomal dominant genetic trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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 CCAL2 are thought to be more severe in those affected individuals who carry two abnormal genes for this disorder (homozygotes), one from each parent. Those who have only one abnormal gene (heterozygotes) are thought to experience less severe symptoms.
CCAL2 is a rare disorder. Eight families have been described in the medical literature. Some studies indicate a greater prevalence of non-genetic CPDD in females, but this is based on weak evidence. There is no known ethnic 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 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.
Treatment for 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 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 those 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 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 CCAL2 does not require treatment.
Genetic counseling may be of benefit for affected individuals and their families.
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