Genotype–phenotype investigation of 35 patients from 11 unrelated families with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome

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.

Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Resembling Juvenile Idiopathic Arthritis: A Single-Center Experience from Southern Turkey

“…In the latter study, nearly half of the patients were earlier misdiagnosed as JIA. Age at diagnosis was between 3.5 and 53 years, while age at onset was 1-24 months [Yilmaz et al, 2018]. Therefore, we think that the physicians still underestimate the possibility of CACP diagnosis, a pseudo-JIA disease in the differential diagnosis of childhood arthropathies.…”

“…Bulutlar et al [1986] were the first to report this disorder in 4 sisters. Yilmaz et al [2018] followed, describing the clinical findings of CACP syndrome in 35 patients from 11 unrelated families, 10 of which were from the southeast region of Turkey. In the latter study, nearly half of the patients were earlier misdiagnosed as JIA.…”

Coexistence of a novel WISP3 pathogenic variant and an MEFV mutation in an Arabic family with progressive pseudorheumatoid dysplasia mimicking polyarticular juvenile idiopathic arthritis

“…Unfortunately, there is no known treatment for this condition; patients require supportive care for osteoarthritis-like pain due to joint degeneration and bony dysplasia. Although our initial suspicion was PPRD, we decided to proceed with WES rather than WISP3 single-gene analysis since a number of rare familial noninflammatory arthropathies should be considered in the differential diagnosis of PPRD [ 2 , 7 , 8 ]. Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CAPC), for example, is a rare autosomal inherited disorder caused by mutations in the proteoglycan 4 gene ( PRG4 ) gene.…”

“…Some patients may present with pericarditis, sometimes with effusion requiring pericardiocentesis. Synovial tissue biopsy shows proliferative synovium with hypercellularity by infiltrating macrophages with a contribution from proliferating fibroblastic synoviocytes [ 2 , 7 ].…”

“Lessons from Rare Forms of Osteoarthritis”

“…PRG4 deficient mice have been shown to exhibit synovial fluid protein deposition on cartilages, adhesion of synovial cells to the cartilage and show structural and biochemical alterations in the articular cartilage similar to osteoarthritic degeneration [28,29]. Whilst there is no data on CACP models, the PGR4 therapies trialled in more routine OA models demonstrate positive effects [30]. Intra-articular injections of PRG4 in a rat and minipig models of OA have been shown to reduce cartilage damage [31][32][33] by restoring normal cartilage boundary lubrication function.…”