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Familial calcium pyrophosphate deposition

Orpha number ORPHA1416
Synonym(s) Calcium pyrophosphate dihydrate crystal deposition disease
Familial CC
Familial CPPD
Familial articular chondrocalcinosis
Hereditary CC
Hereditary articular chondrocalcinosis
Hereditary calcium pyrophosphate deposition
Prevalence Unknown
Inheritance
  • Autosomal dominant
  • Sporadic
Age of onset Adulthood
ICD-10
  • M11.1
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 239832006

Summary

Familial calcium pyrophosphate deposition (CPPD) is a chronic inherited arthropathy characterized by chondrocalcinosis (CC; i.e. cartilage calcification), often associated with recurrent acute calcium pyrophosphate (CPP) crystal arthritis and polyarticular osteoarthritis (OA).

Its prevalence is unknown. About 100 affected families have been identified to date.

Familial CPPD manifests in early adulthood (20-40 years old) and has a variable clinical phenotype. Although it can be asymptomatic, it can manifest as isolated CC with pain at the sites of calcification or can be associated with acute CPP crystal arthritis 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.

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 chromosome 8 but CC in those patients seems to be secondary to cartilage matrix degradation, rather than being the primary cause of the arthropathy. 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.

Diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid, usually by compensated polarized light or phase contrast microscopy. 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 is a promising tool as it 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.

Differential diagnosis includes other genetic conditions causing secondary CC such as chronic hypomagnesaemia, Gitelman syndrome, hereditary hemochromatosis and hypophosphatasia (see these terms). CPPD can also occur sporadically but it is a separate, much more common entity, with aging being the most important risk factor.

Antenatal diagnosis could be possible when ANKH mutations in the family have already been found.

Familial CPPD has an autosomal dominant mode of inheritance with variable penetrance.

Management is mainly symptomatic. Acute CPP arthritis should be treated by non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroid injections. Recent reports have shown that IL-1 blockers are effective in patients who cannot tolerate or have contraindications to NSAIDs. CPPD with OA should be managed as primary OA, by a combination of non-pharmacological and pharmacological treatments (analgesics, NSAIDs). To date, there are no effective treatments capable of dissolving calcium deposits.

Some forms may be severe and result in considerable pain and disability.

Expert reviewer(s)

  • Pr Thomas BARDIN
  • Pr Pascal RICHETTE

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