Abstract
BackgroundThe camptodactyly–arthropathy–coxa vara–pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.MethodsIn the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.ResultsWe found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.ConclusionWith this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense‐mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.
Highlights
The camptodactyly–arthropathy–coxa vara–pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by early onset camptodactyly, noninflammatory arthropathy with synovial hyperplasia, and progressive coxa vara deformity (MIM # 208250)
CACP syndrome may initially be confused with juvenile idiopathic arthritis (JIA), causing a delay in diagnosis and unnecessary treatment with antirheumatic drugs
proteoglycan 4 (PRG4) is known to be implicated in CACP, and all five affected cases carried the homozygous deletion while the parents carried the heterozygous variant (Figure 2c)
Summary
The camptodactyly–arthropathy–coxa vara–pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by early onset camptodactyly, noninflammatory arthropathy with synovial hyperplasia, and progressive coxa vara deformity (MIM # 208250). The PRG4 gene, located on chr 1q25-q31, contains 12 exons spanning 18 kb (Ikegawa, Sano, Koshizuka, & Nakamura, 2000) The product of this gene, lubricin, is the lubricating component in the final lubricating fraction of human synovial fluid. Since the molecular basis of CACP was revealed in 1999, seven additional studies have reported more than 13 CACP families with more than 22 unique PRG4 deleterious mutations. All of these alterations are predicted to lead to a premature stop codon (PTC), except for one case (Marcelino et al, 1999). We aimed to explore the detailed clinical and molecular data for 35 patients with CACP in 11 unrelated families in order to look for possible phenotype– genotype correlations and discuss for the intra- and interfamilial clinical variability reported in CACP population
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