Camptodactyly-arthropathy-coxa Vara-pericarditis Research Articles

Quadruped Gait and Regulation of Apoptotic Factors in Tibiofemoral Joints following Intra-Articular rhPRG4 Injection in Prg4 Null Mice.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome leads to diarthrodial joint arthropathy and is caused by the absence of lubricin (proteoglycan 4—PRG4), a surface-active mucinous glycoprotein responsible for lubricating articular cartilage. In this study, mice lacking the orthologous gene Prg4 served as a model that recapitulates the destructive arthrosis that involves biofouling of cartilage by serum proteins in lieu of Prg4. This study hypothesized that Prg4-deficient mice would demonstrate a quadruped gait change and decreased markers of mitochondrial dyscrasia, following intra-articular injection of both hindlimbs with recombinant human PRG4 (rhPRG4). Prg4−/− (N = 44) mice of both sexes were injected with rhPRG4 and gait alterations were studied at post-injection day 3 and 6, before joints were harvested for immunohistochemistry for caspase-3 activation. Increased stance and propulsion was shown at 3 days post-injection in male mice. There were significantly fewer caspase-3-positive chondrocytes in tibiofemoral cartilage from rhPRG4-injected mice. The mitochondrial gene Mt-tn, and myosin heavy (Myh7) and light chains (Myl2 and Myl3), known to play a cytoskeletal stabilizing role, were significantly upregulated in both sexes (RNA-Seq) following IA rhPRG4. Chondrocyte mitochondrial dyscrasias attributable to the arthrosis in CACP may be mitigated by IA rhPRG4. In a supporting in vitro crystal microbalance experiment, molecular fouling by albumin did not block the surface activity of rhPRG4.

Syndrome of progressive deforming non-inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare familial arthropathy of childhood, commonly misdiagnosed as juvenile idiopathic arthritis. It is characterized by non-inflammatory arthropathy, coxa vara deformity, and sterile pericarditis. We describe two children with CACP syndrome who were referred to the rheumatology clinic for the suspicion of inflammatory arthritis. A literature search was carried out using PubMed/ Medline and Embase databases. English language reports of mutation-proven cases of CACP syndrome reported until 31 March 2020 were retrieved and analysed. Both the children had a delay in diagnosis (age at diagnosis- 12 and 13years, respectively) and had received immunomodulatory therapy for suspected inflammatory arthritis. Presence of symmetrical arthropathy of large joints, camptodactyly, and normal inflammatory parameters are clues that indicated CACP syndrome. One child with a novel variant in PRG4 also had associated mitral valve prolapse and regurgitation. Both had severe constrictive pericarditis requiring pericardiectomy. On literature review, a total of 98 mutation-proven cases of CACP syndrome have been reported till date. Arthropathy in CACP syndrome mainly involves knees, wrists, ankles, and hips. Pericarditis is usually mild, however, can present rarely with severe symptoms requiring surgical intervention. CACP syndrome can closely mimic inflammatory arthritis and early clinical recognition is important to avoid misdiagnosis. Molecular confirmation is essential for early diagnosis and future genetic counselling for affected families.

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

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 CoxaVara Pericarditis Syndrome: Early diagnosis prevents unnecessary and harmful treatment

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a genetic disorder caused by mutation in the Proteoglyacn PRG4 gene on chromosome 1. The syndrome is characterized by congenital or early onset camptodactyly and childhood-onset of non-infl ammatory arthropathy, coxa vara deformity, or other dysplasia associated with progressive hip disease and non-infl ammatory pericardial effusion.

Camptodactyly Arthropathy CoxaVara Pericarditis Syndrome: Early diagnosis prevents unnecessary and harmful treatment

Camptodactyly Arthropathy CoxaVara Pericarditis Syndrome: Early diagnosis prevents unnecessary and harmful treatment

Spinal involvement in Camptodactyly Arthropathy Coxa-vara Pericarditis (CACP) syndrome in two Yemeni sisters

Aim of the workThe objective of this clinical report is to describe the detailed magnetic resonance imaging (MRI) findings of the spine, knee and hip joints in two young sisters with Camptodactyly Arthropathy Coxa-vara Pericarditis (CACP) syndrome. Cases reportIn two young sisters, both had normal levels of inflammatory markers and typical features of the CACP syndrome with camptodactyly, symmetric joint swelling of both hand joints, knees, ankles and both feet. The affected joints were not tender on palpation with no overlying redness or hotness. Coxa vara on plain X-ray and all cases have evidence of pericarditis. The MRI studies showed the typical rim pattern enhancement of the synovial membrane in the knee and hip joints in both, with no evidence of pannus formation, yet a sizable amount of joint effusion. Both had protrusio acetabuli and one had a unilateral synovial cyst of the hip. MRI studies of the lumbar spine showed evidence of facet joint arthropathy and facet joint effusion, a synovial cyst in both cases and synovial enhancement in post-contrast images with no associated facet joint ankylosis. ConclusionThe findings of the two cases confirm the possible axial affection in the CACP syndrome in the form of facet joint disease as a new finding in this rare syndrome. Spinal involvement should be screened in all cases, as it may have consequences for diagnosis and treatment.

Brothers with constrictive pericarditis – A novel mutation in a rare disease

Familial constrictive pericarditis is extremely rare. We report a case of two brothers both suffering constrictive pericarditis along with having multiple painless joint deformities. Genetic workup confirmed the clinical diagnosis of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome CACP syndrome and also revealed a rare mutation in the causative gene.

Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome: Important Differential for Juvenile Idiopathic Arthritis

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an inherited disorder characterized by congenital or early-onset flexion camptodactyly, childhood-onset of non-inflammatory arthropathy, often associated with non-inflammatory pericarditis or pericardial effusion and progressive coxa vara. The causative gene is located on chromosome band 1q25-31. This gene encodes for “proteoglycan-4” (PRG-4), which is a surface lubricant for joints and tendons. This syndrome has distinct radiological and histological features, which are important to recognize since it may clinically mimic juvenile idiopathic arthritis and mutation studies may not be easily available. We describe a case of a 3-year 3-month-old female with features of CACP syndrome.

CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort

Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1.

Utility of Ultrasonography in Children with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome

Background: Early recognition of Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is very important for counseling and avoiding unnecessary treatment with anti-rheumatic drugs including biologic agents. Objective: to evaluate utility of ultrasonography in CACP syndrome patients and to compare the findings of the wrist and matacarpophalangeal joints with those in JIA patients. Materials and Methods: The study cohort consisted of children with CACP syndrome and JIA with poly-articular course. Each patient completed the same assessment; clinical examination of 6 joints (wrist, 2nd and 3rd matacarpophalangeal joints bilaterally), laboratory assessment, conventional radiography and ultrasonography of the above-mentioned 6 joints. Ultrasonography assessment performed in the same day with clinical and laboratory assessment. Results: Total of 24 patients have completed the evaluation, 19 JIA and 5 CACP syndrome patients with total assessed joints were 144, each patient completed the same assessment. Most patients had synovial membrane thickening. However, synovial proliferation was more prominent in CACP syndrome (26/30) comparing to JIA patients (56/114) (P 0.0002). Interestingly all CACP syndrome patients showed normal vascularity of the synovium as by color Doppler while 25% of the assessed joints in JIA patients had increased synovial vascularity (P 0.0025). Joint effusion and bone erosion were more frequent in JIA patients comparing to CACP syndrome. However, the difference was not statistically significant. Conclusion: Our findings suggest that ultrasonography is probably beneficial in differentiating inflammatory arthritis from non-inflammatory arthropathy.

Total Hip Arthroplasty in Adolescents With Severe Hip Arthropathy and Dysplasia Associated With Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare disorder. Patients with this syndrome experience early symptomatic arthropathy of the hips. We report a case of adolescent siblings with bilateral arthropathy associated with CACP syndrome in which total hip arthroplasty was performed as treatment of severe associated disability. Postoperative Harris Hip Scores for patient 1 were 86 for the right at 18 months and 96 for the left at 12 months. Postoperative Harris Hip Score at 6 months for patient 2 was 53; however, he had good range of motion and lacked deformity. Based on our limited experience and the limited available clinical data, we feel that total hip arthroplasty is a reasonable treatment option for adolescents with debilitating hip arthropathy associated with CACP syndrome.

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4(-/-) mutant and Prg4(+/+) wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220(+) (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin(-)Sca-1(+)c-Kit(+) (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTH-stimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

Novel PRG4 mutations underlie CACP in Saudi families

The camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (Proteoglycan 4) gene. Manifestations vary across families as well as between affected individuals from the same family, with camptodactyly and arthropathy of the knees the most ubiquitous, while pericarditis is evident in only one-fifth of all reported cases. Thus far only eight pathogenic mutations have been described in this gene. We examined seven newly diagnosed childhood patients of this syndrome, hailing from four unrelated families of Saudi origin. Five novel mutations were uncovered, including four frameshift deletions and one nonsense mutation (c.923_924delAA, c.3125_3128delGAGT, c.3139_3140delAA, c.3276_3277delAA, c.4078A>T). No genotype/phenotype association was observed. Because all mutations reported in CACP patients thus far predict premature truncation, we hypothesize that missense mutations are either not physiologically relevant, or that they trigger a clinical phenotype that is distinct from classical CACP. This is only the second published communication on PRG4 mutations, and increases the number of reported mutations for all ethnicities from 8 to 13, and for the Arab population specifically from one to six.

Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Versus Juvenile Idiopathic Arthropathy

The objective of our article was to highlight the important clinical and radiographic features of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. In particular, we emphasize those features that allow differentiation of CACP syndrome from juvenile idiopathic arthropathy. CACP syndrome should be considered in all patients who present with a noninflammatory arthropathy or with "atypical juvenile idiopathic arthritis," particularly if radiographs reveal an absence of erosions. In the correct clinical setting, large acetabular cysts on pelvic radiographs may be considered pathognomonic of CACP syndrome.

Delineating biologic pathways involved in skeletal growth and homeostasis through the study of rare Mendelian diseases that affect bones and joints

We have found that the secreted glycoprotein, lubricin, is mutated in patients with the autosomal recessive disorder camptodactyly–arthropathy–coxa vara–pericarditis syndrome. To better define lubricin's role in articulating joints we have been studying lubricin knockout mice. Knockout mice recapitulate features observed in patients with camptodactyly–arthropathy–coxa vara–pericarditis, and therefore allow us to learn more about the protein's in vivo function. We find that synoviocytes from knockout mice have different growth characteristics than do wild-type synoviocytes. We also find that the articular cartilage surface in knockout mice loses superficial zone chondrocytes and becomes covered by proteinaceous material. These results indicate that lubricin protects cartilage surfaces and helps regulate synovial cell growth. We had found that Wnt-inducible-secreted protein 3 (WISP3) is mutated in patients with the autosomal recessive disorder progressive pseudorheumatoid dysplasia. Patients with progressive pseudo-rheumatoid dysplasia require joint replacement surgery for what resembles end-stage osteoarthritis by their second decade of life. WISP3 is in very low abundance since we have only been able to detect mRNA by reverse transcription-polymerase chain reaction, and not by northern blot or in situ hybridization. Furthermore, we have not been able to detect endogenous WISP3 protein using a sensitive polyclonal antibody. Therefore, to determine the role of WISP3 in maintaining joints we created Wisp3 knockout mice. Surprisingly these mice did not develop joint failure, but they did seem to have altered timing of their secondary centers of ossification. We are currently exploring whether this altered timing is relevant to the pathogenesis of cartilage failure in human patients. We have been searching for the gene responsible for autosomal recessive acromesomelic dysplasia. This is an interesting disorder because it primarily affects postnatal, rather than prenatal, growth. Also interesting is the fact that many carrier parents of affected individuals appear to have isolated short stature. Consequently, the discovery of the gene responsible for this disease may provide insights into pathways that effect growth.