Familial calcium pyrophosphate deposition (ORPHA:1416)
A rare inherited rheumatologic disease which causes calcification of articular fibrocartilage or hyaline cartilage, a process termed chondrocalcinosis (CC). It often associates with acute synovitis and osteoarthritis (OA).
Epidemiology
Familial calcium pyrophosphate deposition (CPPD) prevalence is unknown. It is rare: about 100 affected families have been identified to date.
Clinical description
Familial CPPD manifests in early adulthood (20-40 years old) and has a variable clinical phenotype. Generally, it is associated with acute CPP crystal arthritis involving the knees, the wrists, the shoulders, and/or a severe chronic inflammatory arthropathy, mimicking osteoarthritis (OA). In acute CPP crystal arthritis cases, acute episodes of pain, stiffness, swelling and sometimes ankylosis, can be observed in any joint, the knees or the wrist being the most affected. The attacks can last from hours (6-24) to days and can induce a limited range of motion. Chronic inflammatory arthropathy usually affects the knee, wrist, elbow, shoulder and hip, and can induce a severe OA-like arthropathy. Very rarely, familial CPPD can be associated with non rheumatological features, such as recurrent infantile seizures as was the case in a British family with CPPD and polyarticular chondrocalcinosis but without structural arthropathy.
Etiology
Mutations in the ANKH gene (human homologue of progressive ankylosis; 5p15.2), encoding a protein involved in cellular inorganic pyrophosphate transport, were identified in some cases of familial CPPD. Other familial cases have been linked to mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) Other causative genes are yet to be determined. Mutations in the collagen α-1(II) chain gene (COL2A1; 12q12-13.2), that codes for the major structural protein of cartilage, have been found to cause a particular form of chondrocalcinosis characterized by severe early onset OA, spondylo-epiphysial dysplasia and secondary CPPD.
Diagnostic methods
Diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by compensated polarized light. X-rays show calcium deposits within cartilage and fibro cartilage, mainly in knees, wrists and shoulders. X-ray findings support the diagnosis of CPPD, but the absence of radiographic CC does not exclude it. Ultrasonography allows for the detection of CC in peripheral joints, which typically appears as thin hyperechoic bands within hyaline cartilage and hyperechoic sparkling spots in fibrocartilage. Calcium deposits can be seen as well with Computed Tomography and DECT.
Differential diagnosis
Differential diagnosis includes other genetic conditions causing secondary CC such as chronic hypomagnesaemia (particularly the Gitelman syndrome), hereditary hemochromatosis and hypophosphatasia. In the large majority of cases, CPPD occur sporadically but it is a separate, much more common entity, with aging being the most important risk factor.
Antenatal diagnosis
Antenatal diagnosis could be possible when ANKH mutations in the family have already been found.
Genetic counseling
Familial CPPD has an autosomal dominant mode of inheritance with variable penetrance.
Management and treatment
Management is mainly symptomatic. To date, there are no effective treatments capable of dissolving calcium deposits. Acute CPP arthritis should be treated by non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroid injections. For difficult to treat patients, IL-1 blockers could be used Preliminary reports suggested Tocilizumab to be effective. CPPD with OA should be managed as primary OA, by a combination of non-pharmacological and pharmacological treatments (analgesics, NSAIDs).
Prognosis
Some forms may be severe and result in considerable pain and disability.

                            Last update: 
                            July 2020


                            - Expert reviewer(s): 
                            Dr Augustin LATOURTE  - Pr Pascal RICHETTE