Alternative titles; symbols
ORPHA: 1416; DO: 1156;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.2 | Chondrocalcinosis 2 | 118600 | Autosomal dominant | 3 | ANKH | 605145 |
A number sign (#) is used with this entry because chondrocalcinosis-2 (CCAL2) is caused by heterozygous mutation in the ANKH gene (605145) on chromosome 5p15.
Chondrocalcinosis, or cartilage calcification, is a common condition that usually results from deposition of crystals of calcium pyrophosphate dihydrate (CPPD) in articular hyaline and fibro-cartilage. CPPD crystal deposition may be asymptomatic or associated with characteristic acute attacks ('pseudogout') or chronic arthritis. It can be detected radiographically. Chondrocalcinosis occurs in 3 forms: a primary hereditary form (e.g., CCAL2); a form associated with metabolic disorders (e.g., hyperparathyroidism, hemochromatosis, and hypomagnesemia); and a sporadic form, which may in some cases represent the hereditary form (summary by Hughes et al., 1995 and Richette et al., 2009).
Genetic Heterogeneity of Chondrocalcinosis
Another form of chondrocalcinosis (CCAL1; 600668) has been mapped to chromosome 8q.
Under the designation of chondrocalcinosis articularis, Asshoff et al. (1966) described a family with 4 affected persons in 2 generations. The disorder was manifested clinically by episodic inflammatory involvement, acute or subacute, of one or more joints. Calcified hyaline and fibrous cartilage is demonstrable by x-ray, particularly in large joints. In articular cartilage a dense narrow band follows the contour of the epiphysis.
Reginato et al. (1970) observed an unusually high frequency among natives of the Chiloe Island group. Twenty-eight patients were observed of whom 19 were aggregated in 6 kindreds. Parent-child involvement with no male-to-male transmission was observed in 3 of the families. In the other 3 families one or both parents were not screened. Since the Chiloe group lives in an isolated area and is presumably inbred, recessive inheritance remains a possibility. In these cases involvement was polyarticular. Ankylosing of joints was a new feature observed in this study.
Rodriguez-Valverde et al. (1980) studied the first-degree relatives of 46 cases in northern Spain and found that 5 cases were familial. In these 5 families, a total of 17 persons showed calcified cartilage radiographically. All were in the same generation, although not always in the same sibship. Inbreeding (type unspecified) was stated for 4 of the 5 kindreds. In a further study, Rodriguez-Valverde et al. (1988) identified 13 pedigrees through a systematic radiologic survey of the first-degree relatives of 76 probands. Thirty women and 11 men in 25 sibships were affected. The disease was of early onset in only 4 pedigrees. The clinical manifestations in these 4 pedigrees were similar to those found in the kindreds with late onset. Autosomal dominant inheritance was supported.
In Spain, Fernandez Dapica and Gomez-Reino (1986) found a 28.1% prevalence of chondrocalcinosis in 149 relatives of 32 patients with calcium pyrophosphate dihydrate deposition disease. No clinical or radiologic differences between sporadic and familial cases were found. The features were similar to those of the Chiloe islanders with familial chondrocalcinosis as reported by Reginato (1976). Fernandez Dapica and Gomez-Reino (1986) concluded that the findings support the idea that the disorder was carried to Chile by Spanish immigrants.
Depressed activity of synovial pyrophosphohydrolase was suggested by the findings of Good and Starkweather (1969). This was not pursued further (Good, 1974).
Van der Korst et al. (1974) reported a family with chondrocalcinosis in which father-to-son transmission was noted, supporting autosomal dominant inheritance. Twenty-two cases in 2 generations were observed. Acute attacks occurred in only 14 of the 22 and 6 of the 14 had not yet sought medical care.
Gaudreau et al. (1981) described articular chondrocalcinosis in 9 persons in 3 generations of a Quebec family (presumably French Canadian). Extensive calcification of the cartilage of the pinnae and of intervertebral discs was demonstrated.
In 12 affected members of a single kindred (Gaucher et al., 1977), Lust et al. (1981) found that cultured fibroblasts and lymphocytes had a concentration of intracellular inorganic pyrophosphate 2 times greater than that in cells from unaffected family members and normal, unrelated volunteers.
Bjelle et al. (1982) studied 2 extensive, affected Swedish kindreds that supported autosomal dominant inheritance. Of persons over 50 years of age, 47% had experienced acute attacks of arthritis and/or had joint calcifications. Back pain was frequent, but no ankylosis or deformity was observed. As compared with 50 sporadic cases observed in the same area of Sweden, the familial cases had an earlier onset, a greater number of involved joints, and more frequent peripheral joint involvement. Back pain was more frequent, and calcification of intervertebral discs was found only in the hereditary cases. Bjelle et al. (1982) demonstrated a genealogic link between 3 Swedish families, thus showing probable founder effect similar to that found in Slovakia, France, and Chile. No connection to other European families was found.
In an Ashkenazi Jewish kindred, Eshel et al. (1990) found 7 members with a medical history of this disorder and in the most recent generations 5 members with direct evidence of the disorder. Symptoms started in the third decade and radiologic evidence developed by the fourth decade. The joints commonly affected were knees, wrists, and elbows. The course was chronic with acute, exercise-induced exacerbations.
Doherty et al. (1991) reported 5 unrelated English kindreds with familial chondrocalcinosis due to CPPD crystal deposition. The largest pedigree was unique in that affected family members also suffered recurrent benign fits in childhood, permitting clear delineation of phenotype at a young age--a major advantage in a condition that usually shows late onset. The pattern of inheritance in this extended pedigree was consistent with autosomal dominant transmission with 100% penetrance. Hughes et al. (1995) described the clinical phenotype in this large English family, which included recurrent benign seizures that developed in the second half of the first year of life, occurred with a frequency of 3-9 per year, ceased around age 6 years, and were not associated with physical or mental retardation. Acute attacks of pseudogout associated with radiographic polyarticular chondrocalcinosis developed in the late third and early fourth decades. These attacks continued against a subsequent background of chronic or intermittent arthralgia. Chronic inflammatory arthritis or deformity did not develop and functional outcome was good in general.
An autosomal dominant mode of inheritance of chondrocalcinosis was suggested in several reports (e.g., van der Korst et al., 1974; Bjelle et al., 1982; Rodriguez-Valverde et al., 1988).
In a study of 35 patients with chondrocalcinosis in Spain, Balsa et al. (1990) found a prevalence of familial disease of 26%. They suggested autosomal dominant inheritance with incomplete penetrance and more severe involvement in homozygotes.
Autosomal dominant inheritance was demonstrated by Hughes et al. (1995).
By a genomewide screen using highly informative microsatellite polymorphisms in a large English family with affected members with chondrocalcinosis in 4 generations, Hughes et al. (1995) mapped the mutant gene in this kindred to chromosome 5p. A maximum multipoint lod score of 4.6 was obtained for the region between D5S810 and D5S416.
In a study of 2 families, an Argentinian kindred of northern Italian ancestry and a French kindred from the Alsace region, Andrew et al. (1999) found evidence of linkage consistent with the mapping to 5p15 previously reported by Hughes et al. (1995). Andrew et al. (1999) stated that recombinants in the Argentinian kindred enabled them to designate a region of less than 1 cM between markers D5D416 and D5S2114 for the CPPDD locus. Hughes (2001) pointed out that these 2 regions do not overlap. They stated that the likely reason for the discrepancy is misdiagnosis or mistyping in a family studied by Andrew et al. (1999) since phenocopies and nonpenetrant individuals had been shown in early versions of one of their pedigrees.
Pendleton et al. (2002) showed that affected members of the families with chondrocalcinosis-2 reported by Hughes et al. (1995) and Andrew et al. (1999) had mutations in the ANKH gene; see 605145.0006-605145.0007.
Williams et al. (2003) screened for mutations in the ANKH gene in 2 U.S. families with autosomal dominant CPPDD and found that all affected members were heterozygous for a pro5-to-thr mutation (605145.0010). The 2 families displayed distinct haplotypes. Williams et al. (2003) noted that the family described by Williams et al. (2002) had a different mutation at the same codon (see 605145.0009) and also displayed a distinct haplotype. They concluded that the evolutionarily conserved pro5 position of ANKH may represent a hotspot for mutation in families with autosomal dominant CCAL2.
Baynam et al. (2009) restudied a large 4-generation Australian family with craniometaphyseal dysplasia (CMDD; 123000), originally described by Taylor and Sprague (1989) and in which affected individuals were found to have a heterozygous missense mutation in the ANKH gene (G389R; 605145.0002) by Nurnberg et al. (2001). A 57-year-old female family member with CMDD also reported episodic unilateral shoulder pain beginning in her twenties, with radiographically confirmed ectopic calcification treated by surgical excision at 22 years of age. In addition, she had episodic pain of the small joints of her hands and feet (second and third metacarpals and metatarsals, respectively) and of her knees, and underwent excision of an exostosis of the left knee in her thirties. Technetium bone scan was consistent with marked focal arthropathy and mild synovitis of the affected small joints. A sister and half sister, both mutation-positive and aged 53 and 68 years, respectively, similarly reported episodic excruciating joint pain typically lasting 48 hours, with onset in their twenties; 1 of the sisters had calcium hydroxyapatite crystals identified in synovial fluid from an affected joint. Their affected mother was described as having episodic joint pain that was occasionally debilitating, predominantly affecting the hands and feet. The 57-year-old woman had 3 mutation-positive sons, 2 of whom were asymptomatic; the third, who was 30 years old, manifested a slowly progressive unilateral facial palsy but no discrete episodes of pain, and he had a 22-month-old son with choanal stenosis and radiographic evidence of CMDD. Although a chance association of chondrocalcinosis with CMDD could not be excluded, Baynam et al. (2009) suggested that the lack of joint symptoms in affected male family members might be due to involvement of sex-dependent mechanisms or to the fact that only mutation-positive women in the pedigree had reached the age at which the chondrocalcinosis phenotype typically expresses.
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