When juvenile idiopathic arthritis is not inflammatory: a case-based review of camptodactyly–arthropathy–coxa vara–pericarditis syndrome in early childhood

When juvenile idiopathic arthritis is not inflammatory: a case-based review of camptodactyly–arthropathy–coxa vara–pericarditis syndrome in early childhood | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report When juvenile idiopathic arthritis is not inflammatory: a case-based review of camptodactyly–arthropathy–coxa vara–pericarditis syndrome in early childhood Nataliya Tkachenko¹˒², Cláudia Castelo Branco¹ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8788802/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood; however, not all early-onset arthropathies are inflammatory. We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate and subsequently with a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers. Clinical reassessment raised suspicion of a non-inflammatory arthropathy, supported by characteristic radiographic findings, including metaphyseal flaring of the distal femora and proximal tibiae. Genetic evaluation identified compound heterozygous pathogenic and likely pathogenic variants in the PRG4 gene, confirming the diagnosis of camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome (OMIM #208250). This case highlights common diagnostic pitfalls in pediatric practice and emphasizes the importance of considering genetic, non-inflammatory causes of chronic arthropathy when clinical, laboratory, and therapeutic features are atypical for JIA. Early recognition of CACP syndrome prevents unnecessary immunosuppression and allows appropriate multidisciplinary management. juvenile idiopathic arthritis CACP syndrome PRG4 pediatric arthropathy misdiagnosis Figures Figure 1 What is know – What is new Not all chronic arthropathies presenting in early childhood are inflammatory in origin. Persistently normal inflammatory markers and a poor or absent response to immunosuppressive therapy represent important diagnostic red flags. Imaging findings, particularly metaphyseal flaring and absence of erosive changes, are critical in differentiating non-inflammatory conditions from juvenile idiopathic arthritis. Molecular confirmation of PRG4 variants establishes the diagnosis, prevents unnecessary exposure to immunosuppressive therapies, and guides appropriate long-term management and genetic counselling. Introduction Juvenile idiopathic arthritis (JIA) represents the most frequent cause of chronic arthritis in children and is primarily defined by clinical and laboratory features of inflammation. In routine pediatric practice, persistent joint swelling in early childhood is often presumed to be inflammatory in origin, leading to early initiation of immunosuppressive therapy [ 1 , 2 ]. Although genetic susceptibility plays a role in certain JIA subtypes, most notably systemic JIA, in which associations with HLA-DRB1* 11 and other MHC class II variants have been described [ 3 ], the presence of arthritis alone does not equate to immune-mediated disease. However, a subset of pediatric arthropathies is non-inflammatory and genetically determined. Among these, camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome is a rare autosomal recessive condition caused by pathogenic variants in the PRG4 gene, encoding lubricin, a critical glycoprotein for joint lubrication and cartilage protection [ 4 , 5 , 6 ]. The clinical presentation of CACP syndrome often overlaps with JIA, particularly in early childhood, resulting in frequent misdiagnosis [ 1 , 7 ]. Here, we present a case-based review illustrating how CACP syndrome can mimic juvenile idiopathic arthritis and highlight key clinical and radiological features that should prompt diagnostic reconsideration in pediatric practice [ 2 , 8 ]. In addition, this work underscores the growing importance of a multidisciplinary clinical approach in the evaluation and management of children with atypical or treatment-refractory arthropathies. Case Description A 4-year-old girl, the second child of young, healthy, non-consanguineous parents, was referred to the genetics consultation for further evaluation of chronic joint swelling. Pregnancy and perinatal history were unremarkable. Growth, head circumference, and global psychomotor development were appropriate for age. Her medical history was notable for plagiocephaly treated with physiotherapy, recurrent episodes of painful radial head subluxation since the first year of life, and trigger fingers, surgically corrected at 2 years of age, with residual flexion contracture of the third finger of the right hand. From approximately 2–3 years of age, she developed progressive bilateral knee swelling, later involving the ankles. Importantly, this occurred without pain, morning stiffness, functional limitation, fever, or systemic symptoms. There was no history of trauma. She was initially followed in Pediatric Rheumatology and diagnosed with oligoarticular JIA. Antinuclear antibodies were negative, and uveitis was excluded. Treatment with methotrexate (10 mg/week; 15 mg/m²) was initiated, followed by adalimumab (20 mg every two weeks) due to poor response. Despite therapy, there was no meaningful clinical improvement, and she developed recurrent respiratory infections and hepatic steatosis as treatment-related adverse effects. Serial laboratory investigations consistently demonstrated normal or minimally elevated inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), negative autoimmunity (ANA, rheumatoid factor, anti-CCP antibodies, HLA-B*27 and -DRB1*11), and negative infectious workup. Synovial fluid analysis revealed low cellularity (330 cells/mm³) with mononuclear predominance, normal glucose and protein levels, and no evidence of a frankly inflammatory process. Imaging studies showed bilateral joint effusion and synovial hypertrophy. Plain radiographs of the knees demonstrated metaphyseal widening with an Erlenmeyer flask–like deformity of the distal femora and proximal tibiae, with preserved joint alignment and absence of erosions (Fig. 1 ). Gaucher disease and mucopolysaccharidosis type I were excluded. Given the absence of systemic inflammation, lack of response to immunosuppression, history of trigger fingers and flat feet, and characteristic radiographic findings, a non-inflammatory genetic arthropathy was suspected. Clinical exome sequencing identified compound heterozygosity for a pathogenic variant (c.2806_2810del; p.(Lys936AspfsTer40)) and a likely pathogenic variant (c.3787_3788del; p.(Lys1263GlufsTer11)) in the PRG4 gene, confirming the diagnosis of CACP syndrome. Following diagnosis, the initial diagnosis of JIA was revised and immunosuppressive therapy was discontinued. The patient was referred for multidisciplinary follow-up focused on orthopedic and rehabilitative management. Discussion CACP syndrome as a mimicker of juvenile idiopathic arthritis CACP syndrome is a well-documented mimicker of juvenile idiopathic arthritis (JIA), particularly the oligoarticular form, as both conditions may present with joint swelling in early childhood accompanied by preserved joint function and minimal pain [ 1 , 2 ]. This clinical overlap frequently leads to initial misclassification as JIA. However, in contrast to inflammatory arthritis, patients with CACP syndrome typically exhibit normal inflammatory markers and lack systemic features, key elements that should raise suspicion of an alternative, non-inflammatory diagnosis [ 1 , 7 ]. Diagnostic pitfalls in pediatric practice The clinical resemblance between CACP syndrome and JIA contributes to a major diagnostic pitfall in pediatric rheumatology: the assumption that persistent joint effusion necessarily reflects inflammatory arthritis. This assumption may delay accurate diagnosis and expose patients to unnecessary immunosuppressive therapies. In particular, persistence of joint swelling despite normal inflammatory parameters and absence of clinical response to methotrexate or biologic agents should prompt careful diagnostic reassessment and consideration of CACP syndrome [ 1 , 2 ]. Role of imaging In this context, imaging becomes a critical tool for refining the differential diagnosis. Radiological findings play a central role in distinguishing CACP syndrome from inflammatory arthropathies. The absence of erosive changes, together with metaphyseal widening and the characteristic Erlenmeyer flask–like deformity, strongly supports a non-inflammatory etiology [ 2 ]. Complementary imaging with ultrasound typically reveals joint effusion without Doppler signal or other features of active synovitis, further helping to differentiate CACP syndrome from JIA [ 8 ]. Synovial fluid and pathology When diagnostic uncertainty persists, synovial fluid analysis and histopathological evaluation provide additional supportive evidence. Synovial fluid in CACP syndrome usually demonstrates low cellularity with mononuclear predominance, in contrast to the inflammatory profiles seen in JIA [ 9 ]. Histopathological studies further corroborate this distinction, revealing synovial hyperplasia in the absence of inflammatory infiltrates, findings that are consistent with lubricin deficiency rather than immune-mediated synovitis [ 9 ]. Genotype–phenotype considerations Finally, integration of clinical, imaging, and pathological findings underscores the importance of genetic confirmation. Genetic studies have demonstrated marked phenotypic variability among patients with CACP syndrome, even within the same family, highlighting the limitations of clinical criteria alone [ 5 , 6 , 10 ]. Identification of pathogenic variants in PRG4 establishes a definitive diagnosis and provides essential information for prognosis, family screening, and genetic counseling. Conclusion Early recognition of CACP syndrome is critical to avoid misdiagnosis as juvenile idiopathic arthritis and to prevent unnecessary and potentially harmful exposure to immunosuppressive therapies. A comprehensive, integrated assessment incorporating clinical presentation, laboratory results, imaging findings, and genetic analysis enables accurate diagnosis and supports appropriate, individualized patient management [ 1 , 7 ]. In this context, multidisciplinary consultations are increasingly crucial in contemporary clinical practice, facilitating timely diagnosis, coordinated care, and optimal decision-making for patients with rare and complex disorders such as CACP syndrome. Declarations Conflict of Interest The authors declare no conflicts of interest. Funding Nataliya Tkachenko is supported by a PhD grant from the Fundação Ciência e Tecnologia (FCT), Portugal (Ref. 2025.06234.BDANA). Author Contribution NT: Conceptualization, clinical evaluation, data interpretation, manuscript drafting and revision. CCB: Conceptualization, critical revision of the manuscript. All authors read and approved the final manuscript. Acknowledgement The authors would like to thank our patient, the kindest child in the world, and her parents, for their trust, collaboration, and consent to share this case for educational and scientific purposes. Ethical Considerations Written informed consent for publication was obtained from the patient’s parents. All clinical data were anonymized. The study was conducted in accordance with institutional ethical standards. References Madhusudan S, Gupta A, Prakash M, Matta D, Suri D, Singh S (2016) Camptodactyly-arthropathy-coxa vara-pericarditis syndrome: a mimicker of juvenile idiopathic arthritis. Scand J Rheumatol 45(1):77–78. https://doi.org/10.3109/03009742.2015.1085085 Offiah AC, Woo P, Prieur AM, Hasson N, Hall CM (2005) Camptodactyly-arthropathy-coxa vara-pericarditis syndrome versus juvenile idiopathic arthropathy. AJR Am J Roentgenol 185(2):522–529. https://doi.org/10.2214/ajr.185.2.01850522 Ombrello MJ, Remmers EF, Tachmazidou I, Grom A, Foell D, Haas JP, International Childhood Arthritis Genetics (INCHARGE) Consortium et al (2015) HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 112(52):15970–15975. https://doi.org/10.1073/pnas.1520779112 Trochain J, Moscovici C, Le Nezet M, Legendre P (2025) CACP syndrome and PRG4 mutation. BMJ Case Rep 18(9):e266148. https://doi.org/10.1136/bcr-2025-266148 Ciullini Mannurita S, Vignoli M, Bianchi L, Kondi A, Gerloni V, Breda L et al (2014) CACP syndrome: identification of five novel mutations and of the first case of uniparental disomy in the largest European cohort. Eur J Hum Genet 22(2):197–201. https://doi.org/10.1038/ejhg.2013.123 Yilmaz S, Uludağ Alkaya D, Kasapçopur Ö, Barut K, Akdemir ES, Celen C et al (2018) Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Mol Genet Genomic Med 6(2):230–248. https://doi.org/10.1002/mgg3.364 Sathiyaseelan SL, Krishna K, Agarwal D, Oswal JS (2024) Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. BMJ Case Rep 17(7):e260146. https://doi.org/10.1136/bcr-2024-260146 Sparchez M, Fodor D (2025) Ultrasound’s role in differentiating camptodactyly-arthropathy-coxa vara-pericarditis syndrome from inflammatory arthritis in children: a narrative review. Med Ultrason 27(4):459–465. https://doi.org/10.11152/mu-4452 Shayan K, Ho M, Edwards V, Laxer R, Thorner PS (2005) Synovial pathology in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Pediatr Dev Pathol 8(1):26–33. https://doi.org/10.1007/s10024-004-3035-z Singh S, Badiger VA, Balan S, Nampoothiri S, Rao AP, Shah H et al (2024) Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Clin Dysmorphol 33(4):152–159. https://doi.org/10.1097/MCD.0000000000000500 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8788802","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":588512761,"identity":"70f85816-caa0-4891-ad17-d6216d564720","order_by":0,"name":"Nataliya Tkachenko¹˒²","email":"data:image/png;base64,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","orcid":"","institution":"Hospital do Divino Espírito Santo","correspondingAuthor":true,"prefix":"","firstName":"Nataliya","middleName":"","lastName":"Tkachenko¹˒²","suffix":""},{"id":588512762,"identity":"630e2bdd-9b4d-4aeb-a6b4-3fc79364003c","order_by":1,"name":"Cláudia Castelo Branco¹","email":"","orcid":"","institution":"Hospital do Divino Espírito Santo","correspondingAuthor":false,"prefix":"","firstName":"Cláudia","middleName":"Castelo","lastName":"Branco¹","suffix":""}],"badges":[],"createdAt":"2026-02-04 16:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8788802/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8788802/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102316266,"identity":"c11d3a41-1894-4c86-b255-b4f8942cb9c4","added_by":"auto","created_at":"2026-02-10 12:43:20","extension":"tif","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3235265,"visible":true,"origin":"","legend":"\u003cp\u003eClinical and radiological features of the patient with camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome.\u003c/p\u003e\n\u003cp\u003e(A) Radiograph of the right hand showing residual camptodactyly of the index finger, with persistent flexion at the proximal interphalangeal joint and preserved bone structure, without erosions. (B) Clinical photograph of the hands demonstrating mild camptodactyly, more evident in the third finger of the right hand, associated with slender, tapered fingers, with no signs of local inflammation. (C) Lateral radiographs of both knees showing periarticular soft tissue enlargement consistent with joint effusion, without erosive changes. (D) Anteroposterior radiographs of both knees demonstrating metaphyseal widening of the distal femora and proximal tibiae, producing a characteristic Erlenmeyer flask–like deformity. (E) Posterior view of the lower limbs showing involvement of the knees, ankles, and feet, with flat feet and symmetrical hindfoot alignment. (F) Anterior view of the lower limbs demonstrating symmetrical, painless swelling of the knees and ankles, without external inflammatory signs.\u003c/p\u003e","description":"","filename":"Figure1300dbiNT04022026.tif","url":"https://assets-eu.researchsquare.com/files/rs-8788802/v1/a74ec50809d3cc32acb7b27c.tif"},{"id":102316289,"identity":"9514ba4e-1a2d-4ea1-9fa6-e625054f5b6f","added_by":"auto","created_at":"2026-02-10 12:43:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6265569,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8788802/v1/6d5e91db-3ce7-4316-ab51-700f14a9a63c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"When juvenile idiopathic arthritis is not inflammatory: a case-based review of camptodactyly–arthropathy–coxa vara–pericarditis syndrome in early childhood","fulltext":[{"header":"What is know – What is new","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eNot all chronic arthropathies presenting in early childhood are inflammatory in origin.\u003c/li\u003e\n \u003cli\u003ePersistently normal inflammatory markers and a poor or absent response to immunosuppressive therapy represent important diagnostic red flags.\u003c/li\u003e\n \u003cli\u003eImaging findings, particularly metaphyseal flaring and absence of erosive changes, are critical in differentiating non-inflammatory conditions from juvenile idiopathic arthritis.\u003c/li\u003e\n \u003cli\u003eMolecular confirmation of \u003cem\u003ePRG4\u003c/em\u003e variants establishes the diagnosis, prevents unnecessary exposure to immunosuppressive therapies, and guides appropriate long-term management and genetic counselling.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eJuvenile idiopathic arthritis (JIA) represents the most frequent cause of chronic arthritis in children and is primarily defined by clinical and laboratory features of inflammation. In routine pediatric practice, persistent joint swelling in early childhood is often presumed to be inflammatory in origin, leading to early initiation of immunosuppressive therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although genetic susceptibility plays a role in certain JIA subtypes, most notably systemic JIA, in which associations with \u003cem\u003eHLA-DRB1*\u003c/em\u003e11 and other MHC class II variants have been described [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], the presence of arthritis alone does not equate to immune-mediated disease.\u003c/p\u003e \u003cp\u003eHowever, a subset of pediatric arthropathies is non-inflammatory and genetically determined. Among these, camptodactyly\u0026ndash;arthropathy\u0026ndash;coxa vara\u0026ndash;pericarditis (CACP) syndrome is a rare autosomal recessive condition caused by pathogenic variants in the \u003cem\u003ePRG4\u003c/em\u003e gene, encoding lubricin, a critical glycoprotein for joint lubrication and cartilage protection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The clinical presentation of CACP syndrome often overlaps with JIA, particularly in early childhood, resulting in frequent misdiagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we present a case-based review illustrating how CACP syndrome can mimic juvenile idiopathic arthritis and highlight key clinical and radiological features that should prompt diagnostic reconsideration in pediatric practice [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In addition, this work underscores the growing importance of a multidisciplinary clinical approach in the evaluation and management of children with atypical or treatment-refractory arthropathies.\u003c/p\u003e"},{"header":"Case Description","content":"\u003cp\u003eA 4-year-old girl, the second child of young, healthy, non-consanguineous parents, was referred to the genetics consultation for further evaluation of chronic joint swelling. Pregnancy and perinatal history were unremarkable. Growth, head circumference, and global psychomotor development were appropriate for age.\u003c/p\u003e \u003cp\u003eHer medical history was notable for plagiocephaly treated with physiotherapy, recurrent episodes of painful radial head subluxation since the first year of life, and trigger fingers, surgically corrected at 2 years of age, with residual flexion contracture of the third finger of the right hand.\u003c/p\u003e \u003cp\u003eFrom approximately 2\u0026ndash;3 years of age, she developed progressive bilateral knee swelling, later involving the ankles. Importantly, this occurred without pain, morning stiffness, functional limitation, fever, or systemic symptoms. There was no history of trauma.\u003c/p\u003e \u003cp\u003eShe was initially followed in Pediatric Rheumatology and diagnosed with oligoarticular JIA. Antinuclear antibodies were negative, and uveitis was excluded. Treatment with methotrexate (10 mg/week; 15 mg/m\u0026sup2;) was initiated, followed by adalimumab (20 mg every two weeks) due to poor response. Despite therapy, there was no meaningful clinical improvement, and she developed recurrent respiratory infections and hepatic steatosis as treatment-related adverse effects.\u003c/p\u003e \u003cp\u003eSerial laboratory investigations consistently demonstrated normal or minimally elevated inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), negative autoimmunity (ANA, rheumatoid factor, anti-CCP antibodies, HLA-B*27 and -DRB1*11), and negative infectious workup. Synovial fluid analysis revealed low cellularity (330 cells/mm\u0026sup3;) with mononuclear predominance, normal glucose and protein levels, and no evidence of a frankly inflammatory process.\u003c/p\u003e \u003cp\u003eImaging studies showed bilateral joint effusion and synovial hypertrophy. Plain radiographs of the knees demonstrated metaphyseal widening with an Erlenmeyer flask\u0026ndash;like deformity of the distal femora and proximal tibiae, with preserved joint alignment and absence of erosions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Gaucher disease and mucopolysaccharidosis type I were excluded.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the absence of systemic inflammation, lack of response to immunosuppression, history of trigger fingers and flat feet, and characteristic radiographic findings, a non-inflammatory genetic arthropathy was suspected. Clinical exome sequencing identified compound heterozygosity for a pathogenic variant (c.2806_2810del; p.(Lys936AspfsTer40)) and a likely pathogenic variant (c.3787_3788del; p.(Lys1263GlufsTer11)) in the \u003cem\u003ePRG4\u003c/em\u003e gene, confirming the diagnosis of CACP syndrome.\u003c/p\u003e \u003cp\u003eFollowing diagnosis, the initial diagnosis of JIA was revised and immunosuppressive therapy was discontinued. The patient was referred for multidisciplinary follow-up focused on orthopedic and rehabilitative management.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCACP syndrome as a mimicker of juvenile idiopathic arthritis\u003c/h2\u003e \u003cp\u003eCACP syndrome is a well-documented mimicker of juvenile idiopathic arthritis (JIA), particularly the oligoarticular form, as both conditions may present with joint swelling in early childhood accompanied by preserved joint function and minimal pain [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This clinical overlap frequently leads to initial misclassification as JIA. However, in contrast to inflammatory arthritis, patients with CACP syndrome typically exhibit normal inflammatory markers and lack systemic features, key elements that should raise suspicion of an alternative, non-inflammatory diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic pitfalls in pediatric practice\u003c/h3\u003e\n\u003cp\u003eThe clinical resemblance between CACP syndrome and JIA contributes to a major diagnostic pitfall in pediatric rheumatology: the assumption that persistent joint effusion necessarily reflects inflammatory arthritis. This assumption may delay accurate diagnosis and expose patients to unnecessary immunosuppressive therapies. In particular, persistence of joint swelling despite normal inflammatory parameters and absence of clinical response to methotrexate or biologic agents should prompt careful diagnostic reassessment and consideration of CACP syndrome [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eRole of imaging\u003c/h3\u003e\n\u003cp\u003eIn this context, imaging becomes a critical tool for refining the differential diagnosis. Radiological findings play a central role in distinguishing CACP syndrome from inflammatory arthropathies. The absence of erosive changes, together with metaphyseal widening and the characteristic Erlenmeyer flask\u0026ndash;like deformity, strongly supports a non-inflammatory etiology [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Complementary imaging with ultrasound typically reveals joint effusion without Doppler signal or other features of active synovitis, further helping to differentiate CACP syndrome from JIA [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSynovial fluid and pathology\u003c/h3\u003e\n\u003cp\u003eWhen diagnostic uncertainty persists, synovial fluid analysis and histopathological evaluation provide additional supportive evidence. Synovial fluid in CACP syndrome usually demonstrates low cellularity with mononuclear predominance, in contrast to the inflammatory profiles seen in JIA [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Histopathological studies further corroborate this distinction, revealing synovial hyperplasia in the absence of inflammatory infiltrates, findings that are consistent with lubricin deficiency rather than immune-mediated synovitis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGenotype\u0026ndash;phenotype considerations\u003c/h2\u003e \u003cp\u003eFinally, integration of clinical, imaging, and pathological findings underscores the importance of genetic confirmation. Genetic studies have demonstrated marked phenotypic variability among patients with CACP syndrome, even within the same family, highlighting the limitations of clinical criteria alone [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Identification of pathogenic variants in \u003cem\u003ePRG4\u003c/em\u003e establishes a definitive diagnosis and provides essential information for prognosis, family screening, and genetic counseling.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eEarly recognition of CACP syndrome is critical to avoid misdiagnosis as juvenile idiopathic arthritis and to prevent unnecessary and potentially harmful exposure to immunosuppressive therapies. A comprehensive, integrated assessment incorporating clinical presentation, laboratory results, imaging findings, and genetic analysis enables accurate diagnosis and supports appropriate, individualized patient management [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In this context, multidisciplinary consultations are increasingly crucial in contemporary clinical practice, facilitating timely diagnosis, coordinated care, and optimal decision-making for patients with rare and complex disorders such as CACP syndrome.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNataliya Tkachenko is supported by a PhD grant from the Funda\u0026ccedil;\u0026atilde;o Ci\u0026ecirc;ncia e Tecnologia (FCT), Portugal (Ref. 2025.06234.BDANA).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eNT: Conceptualization, clinical evaluation, data interpretation, manuscript drafting and revision. CCB: Conceptualization, critical revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank our patient, the kindest child in the world, and her parents, for their trust, collaboration, and consent to share this case for educational and scientific purposes.\u003c/p\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from the patient\u0026rsquo;s parents. All clinical data were anonymized. The study was conducted in accordance with institutional ethical standards.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMadhusudan S, Gupta A, Prakash M, Matta D, Suri D, Singh S (2016) Camptodactyly-arthropathy-coxa vara-pericarditis syndrome: a mimicker of juvenile idiopathic arthritis. 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Proc Natl Acad Sci U S A 112(52):15970\u0026ndash;15975. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1073/pnas.1520779112\u003c/span\u003e\u003cspan address=\"10.1073/pnas.1520779112\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrochain J, Moscovici C, Le Nezet M, Legendre P (2025) CACP syndrome and PRG4 mutation. BMJ Case Rep 18(9):e266148. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bcr-2025-266148\u003c/span\u003e\u003cspan address=\"10.1136/bcr-2025-266148\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCiullini Mannurita S, Vignoli M, Bianchi L, Kondi A, Gerloni V, Breda L et al (2014) CACP syndrome: identification of five novel mutations and of the first case of uniparental disomy in the largest European cohort. 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Med Ultrason 27(4):459\u0026ndash;465. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.11152/mu-4452\u003c/span\u003e\u003cspan address=\"10.11152/mu-4452\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShayan K, Ho M, Edwards V, Laxer R, Thorner PS (2005) Synovial pathology in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Pediatr Dev Pathol 8(1):26\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10024-004-3035-z\u003c/span\u003e\u003cspan address=\"10.1007/s10024-004-3035-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh S, Badiger VA, Balan S, Nampoothiri S, Rao AP, Shah H et al (2024) Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Clin Dysmorphol 33(4):152\u0026ndash;159. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/MCD.0000000000000500\u003c/span\u003e\u003cspan address=\"10.1097/MCD.0000000000000500\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"juvenile idiopathic arthritis, CACP syndrome, PRG4, pediatric arthropathy, misdiagnosis","lastPublishedDoi":"10.21203/rs.3.rs-8788802/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8788802/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eJuvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood; however, not all early-onset arthropathies are inflammatory. We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate and subsequently with a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers. Clinical reassessment raised suspicion of a non-inflammatory arthropathy, supported by characteristic radiographic findings, including metaphyseal flaring of the distal femora and proximal tibiae. Genetic evaluation identified compound heterozygous pathogenic and likely pathogenic variants in the \u003cem\u003ePRG4\u003c/em\u003e gene, confirming the diagnosis of camptodactyly\u0026ndash;arthropathy\u0026ndash;coxa vara\u0026ndash;pericarditis (CACP) syndrome (OMIM #208250). This case highlights common diagnostic pitfalls in pediatric practice and emphasizes the importance of considering genetic, non-inflammatory causes of chronic arthropathy when clinical, laboratory, and therapeutic features are atypical for JIA. Early recognition of CACP syndrome prevents unnecessary immunosuppression and allows appropriate multidisciplinary management.\u003c/p\u003e","manuscriptTitle":"When juvenile idiopathic arthritis is not inflammatory: a case-based review of camptodactyly–arthropathy–coxa vara–pericarditis syndrome in early childhood","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 12:41:12","doi":"10.21203/rs.3.rs-8788802/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b91e878f-ae61-422c-80ff-5c8da0c40702","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T12:42:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 12:41:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8788802","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8788802","identity":"rs-8788802","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}