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

ABSTRACT: BACKGROUND:The 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. METHODS:In 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. RESULTS:We 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. CONCLUSION:With 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.

SUBMITTER: Yilmaz S

PROVIDER: S-EPMC5902402 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Yilmaz Saliha S Uludağ Alkaya Dilek D Kasapçopur Özgür Ö Barut Kenan K Akdemir Ekin S ES Celen Cemre C Youngblood Mark W MW Yasuno Katsuhito K Bilguvar Kaya K Günel Murat M Tüysüz Beyhan B

Molecular genetics & genomic medicine 20180204 2

<h4>Background</h4>The 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.<h4>Methods</h4>In the present study, we compared the clinical and molecular findings of CACP syndrome in ...[more]

PMID: 29397575

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Project description:BackgroundCamptodactyly-arthropathy-coxa vara-pericarditis (CACP, OMIM: #208250) syndrome is a rare autosomal recessive disease that can be difficult to recognise not only because of its wide clinical variability but also because of its clinical resemblance to juvenile idiopathic arthritis (JIA). PRG4 is the only gene so far known to be associated with CACP syndrome. Children with CACP syndrome lack the glycoprotein lubricin due to recessive mutations in PRG4. Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation. Children with CACP syndrome suffer from congenital camptodactyly, arthropathy, coxa vara and sometimes pericarditis. This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis and so contributes to knowledge of the presentation of CACP syndrome.Case presentationA 10- year-old girl with consanguineous parents suffered from congenital camptodactyly and progressive swollen and painful joints. Her father and his sister had similar childhood-onset joint complaints. Laboratory tests showed no signs of inflammation but showed persistent low protein- and IgG- levels, indicating a secondary immunodeficiency. Increased alpha antitrypsin clearance confirmed PLE. Abdominal ultrasound with Doppler showed hepatomegaly and portal hypertension. Echocardiography suggested constrictive pericarditis. However, heart catheterization could not confirm this. Ultrasound and X-ray examination of the joints combined with a puncture of the synovial fluid were performed. These results, combined with the clinical presentation and the consanguinity, suggested CACP syndrome. Due to excessive enteral protein losses, the patient was treated with Cotrimoxazol prophylaxis and immunoglobulin supplements. These supplements were inadequate to achieve normal IgG values. As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results. Genetic testing in our patient was complicated but revealed a pathogenic mutation within the repeat sequence in exon 7 of the PRG4 gene.ConclusionPLE resulting from constrictive pericarditis can be a complication of CACP syndrome. As serious complications can arise from the resulting secondary immunodeficiency, we recommend regular evaluation of clinical symptoms of constrictive pericarditis and PLE in children with CACP syndrome.

Project description:ObjectiveWe aimed to investigate whether and how corticosteroid use was associated with serious hip arthropathy.Methods and materialsThis population-based cohort study analyzed the Taiwan National Health Insurance Research Database and screened the one-million random sample from the entire population for eligibility. The steroid cohort consisted of 21,995 individuals who had used systemic corticosteroid for a minimum of 6 months between January 1, 1997 and December 31, 2006. They were matched 1:1 in propensity score on the index calendar date with controls who never used steroid. All participants were followed up until occurrence of serious hip arthropathy that required arthroplasty, withdrawal from the national health insurance, or the end of 2011. Surgical indication was classified as fracture-related and -unrelated. The cumulative incidence of hip arthroplasty was estimated by the Kaplan Meier method. The association with steroid exposure was explored by the Cox proportional hazard model.ResultsCumulative incidences of hip arthroplasty after 12 years of follow-up were 2.96% (95% confidence interval [CI], 2.73-3.2%) and 1.34% (95% CI, 1.2-1.51%) in the steroid users and non-users, respectively (P<0.0001). The difference was evident in fracture-related arthroplasty with 1.89% (95% CI, 1.71-2.09%) versus 1.10% (95% CI, 0.97-1.25%), but more pronounced in fracture-unrelated surgery, 1.09% (95% CI, 0.95-1.24%) versus 0.24% (95% CI, 0.19-0.32%). Multivariate-adjusted Cox regression analysis confirmed steroid use was independently associated with both fracture-related (adjusted hazard ratio [HR], 1.65; 95% CI, 1.43-1.91) and unrelated arthroplasty (adjusted HR, 4.21; 95% CI, 3.2-5.53). Moreover, the risk for fracture-unrelated arthropathy rose with steroid dosage, as the adjusted HR increased from 3.30 (95% CI, 2.44-4.46) in the low-dose subgroup, 4.54 (95% CI, 3.05-6.77) in intermediate-dose users, to 6.54 (95% CI, 4.74-9.02) in the high-dose counterpart (Ptrend<0.0001).ConclusionsCorticosteroid use is associated with long-term risk of hip arthroplasty, particularly for fracture-unrelated arthropathy.

Project description:Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome is a rare genetic skeletal dysplasia. Its diagnosis can be deceptively similar to childhood-onset genetic skeletal dysplasias and juvenile idiopathic arthritis. We aimed to report the syndrome's clinical and radiologic features with emphasis on skeletal manifestations. And establish relevant phenotype-genotype correlations. We evaluated two boys, 4-and-7-years-old with MONA syndrome. Both patients had consanguineous parents. We verified the diagnosis by correlating the outcomes of clinical, radiologic and molecular analysis. We specifically evaluated the craniofacial morphology and clinical and radiographic skeletal abnormalities. We contextualized the resultant phenotype-genotype correlations to publications on MONA and its differential diagnosis. Skeletal manifestations were the presenting symptoms and mostly restricted to hands and feet in terms of fixed extension deformity of the metacarpophalangeal and flexion deformity of the interphalangeal joints with extension deformity of big toes. There were arthritic symptoms in the older patient especially of the wrists and minute pathologic fractures. The skeletal radiographs showed osteopenia/dysplastic changes of hands and feet. Both patients had variants in the matrix metalloproteinase2 gene which conformed to phenotype of previously reported literature in one patient while the other had a novel variant which conformed to MONA phenotype. Craniofacial abnormalities were present. However, minimal extra-skeletal manifestations. Overall, there is an emerging distinctive skeletal pattern of involvement in terms of both clinical and radiographic features. This includes age of onset and location of presenting skeletal manifestations, chronological order of joint affection, longitudinal disease progression, specifics of skeletal radiographic pathology and craniofacial features. Nevertheless, physicians are cautioned against differential diagnosis of similar genetic skeletal dysplasias and juvenile idiopathic arthritis.

Dataset Information

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

Publications

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

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