CACP Syndrome: A Rare Non-inflammatory Arthropathy Often Misdiagnosed as Juvenile Idiopathic Arthritis – Clinical Insights and Diagnostic Approach

CACP Syndrome: A Rare Non-inflammatory Arthropathy Often Misdiagnosed as Juvenile Idiopathic Arthritis – Clinical Insights and Diagnostic Approach | 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 CACP Syndrome: A Rare Non-inflammatory Arthropathy Often Misdiagnosed as Juvenile Idiopathic Arthritis – Clinical Insights and Diagnostic Approach Renu Kumawat, Sundeep K. Upadhyaya, Divya Agarwal, Meera Shah, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7137225/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 CACP (Camptodactyly-arthropathy-coxa-vera- pericarditis) is rare autosomal recessive genetic condition characterized by progressive joint involvement at an early age. The prevalence of this condition remains unknown. It occurs due to defect in the gene PRG-4 (Proteoglycan-4) on chromosome 1q encoding for protein lubricin. Camptodactyly is non-traumatic flexion deformity of proximal interphalangeal joints (PIPs). It is commonly seen involving little finger as a sporadic condition. In CACP, it is usually congenital or early childhood onset and involves both the hands. Arthropathy is non-inflammatory and tend to involve large joint with mirror image symmetry. It is unresponsive to DMARDs. (disease modifying anti-rheumatic drugs) Children with CACP present to rheumatology clinics with joint swellings and frequently misdiagnosed with JIA (Juvenile idiopathic arthritis) as it is the most prevalent cause of joint swellings in children. However, diagnosis of JIA is clinical and there is lack of clear diagnostic markers, which causes further confusion. Absence of other inflammatory signs, mirror image symmetry of joint involvement and partial response to treatment for JIA may be the clues to reinvestigate for genetic causes in such cases. X-rays findings may be helpful in differentiating the two as well. Camptodactyly CACP JIA Non-inflammatory Figures Figure 1 Figure 2 Key message Non-inflammatory joint involvement with mirror image symmetry along with early onset and family history should raise suspicion of genetic causes X-rays are helpful in distinguishing the two. Awareness among clinicians for this entity will play a crucial role in early diagnosis and might help in preventing the disease transmission in family through means of genetic counselling and testing of parents. Introduction Camptodactyly-arthropathy-coxa-vera-pericarditis (CACP) syndrome is a rare genetic condition with autosomal recessive mode of inheritance. [OMIM 208250] It has constellation of 4 features characterized by camptodactyly, non-inflammatory joint involvement, progressive coxa vera, and pericarditis. Prevalence of this disease is not yet reported. However, it is thought to be more prevalent in areas of consanguinity. [ 1 , 2 ] Jacobs and Didier were among the first ones to recognize this familial condition. [ 3 ] This syndrome was first described in literature in 1980s. Bulutlar et al, described this constellation in 1986. [ 4 ] Genotypic studies were conducted on 4 related family members detected a common region on chromosome 1q25-31 in 1997. [ 5 ] In 1998, Marcelino et al, studied the same family and identified the gene as PRG-4 (Proteoglycan-4). [ 6 ] It encodes for a mucinous glycoprotein known as Lubricin. The term ‘Lubricin’ was coined by David Swann in 1975. [ 7 ] Lubricin plays an important role in the lubrication of articular cartilage and protects from wear and tear. [ 8 ] Also, after its discovery in CACP, lubricin has been studied in animal models to see its potential therapeutic role in lubrication of cartilage and the initial results are encouraging. [ 9 ] In CACP, PRG-4 deletion leads to deficiency of lubricin, thereby causing impaired joint mechanics and arthropathy.[ 10 ] Since then, there has been a growing interest in genotypic studies of this disease. Several pathogenic mutations have been reported with ever expanding list. A key concern among clinicians is that CACP can mimic JIA. As both the conditions affect children and young adults, resulting into the joint swellings and hip involvement. JIA is the commonest cause of joint swelling in children. The diagnosis of JIA is still clinical in the absence of clear diagnostic markers. This causes much confusion, subjecting the CACP patient to DMARDs treatment. Joint involvement in CACP is non-inflammatory and do not respond to DMARDs. In this review, we will discuss the current understanding of the clinical features, differences between JIA and CACP, role of radiographs in distinguishing the two. Case Discussion A 14-year-old male presented with a long-standing history of progressive joint pain and swelling, which began in early childhood and had gradually worsened over time. His symptoms included swelling and pain in the wrist, ankles, knees, elbows, and hands, along with noticeable gait disturbances. The joint swelling had been present intermittently since early childhood, but it had become more severe and persistent in the last few years. His condition was initially diagnosed as Juvenile Idiopathic Arthritis (JIA), and he was started on Disease-Modifying Anti-Rheumatic Drugs (DMARDs), including methotrexate, as part of the treatment regimen. Despite these interventions, his symptoms persisted and even progressed, prompting a referral to our center for further evaluation. On physical examination, the patient exhibited visible swelling in the wrist, knees, elbows, and few PIPs, flexion deformities of PIPs and both elbow and his gait was also abnormal, with a limp and difficulty in weight-bearing. There was no history of skin rashes, systemic involvement, or organomegaly, and the patient denied any recent infections or trauma. Laboratory tests revealed normal blood counts and normal ESR and CRP. Rheumatoid factor (RF) and anti-CCP antibodies were negative. X-rays of the affected joints showed characteristic signs of coxa vera [ Fig. 1 ] in the hips and mild joint deformities of PIPs, epiphyseal splaying and irregularities of margin in both wrist but no erosions or joint space narrowing typical of inflammatory arthritis. The patient’s younger brother, a 10-year-old boy, had similar complaints of progressive joint pain and swelling in the knees, hands along with gait abnormalities since infancy. Both brothers presented with a very similar clinical course, further supporting the diagnosis of some genetic affection. These findings, combined with the unusual presentation, led us to reconsider the initial diagnosis of JIA. Further evaluation with whole exome sequencing identified a homozygous likely pathogenic variant in exon 7 of the PRG4 gene: c.1910_1911delCT (p.Pro637Argfs*9). This variant is associated with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis (CACP) syndrome. The c.1910_1911delCT variant has been previously reported and is predicted to result in a truncated protein due to a frameshift, leading to loss-of-function through nonsense-mediated decay. [ 11 ] It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset, with an allele frequency of 0.000025, indicating its rarity in the general population. This variant has been documented in a family comprising six affected individuals- three siblings and three cousins, and two other patients from unrelated families diagnosed with CACP syndrome. The importance of distinguishing CACP syndrome from JIA was highlighted in this case, as the initial treatment with DMARDs, while appropriate for JIA, did not lead to significant improvement in this patient’s condition. Clinical Features Of CACP The clinical hallmark of CACP syndrome is presence of camptodactyly. It is a non-traumatic, progressive flexion deformity of PIP joints. It can be either congenital or acquired. It can be sporadic or associated with congenital anomalies. It is more often seen as an isolated entity, affecting little finger. [ 12 ] In CACP it is part of spectrum of other manifestations. It is usually the first symptom to present and often present at birth or appears in early childhood.[ 5 ] It is usually seen in both the hands with mirror image symmetry. However, the degree of flexion may vary. It is important to differentiate camptodactyly from inflammatory small joint involvement in JIA as both the conditions causes swellings and deformity of joints. However, in CACP, these swellings have peculiar bony feel and not associated with much of pain, tenderness. Inflammatory markers are also negative. This is non-inflammatory joint involvement. It is universal in CACP but may not be evident on radiographs, complicating further its differentiation from JIA. Arthropathy is the main presenting complaints of these patients. It usually starts from the wrist joint and can involve other joints including hip, knee, ankle and elbows. [ 1 , 5 ] There is symmetrical involvement with similar mirror image symmetry like camptodactyly but degree of involvement may somewhat vary at any given point of time. This mirror-image symmetry is a distinguishing feature that sets CACP apart from other arthropathies like JIA. Other signs of inflammation are usually absent. Joint involvement is progressive, causing contractures, deformities and functional limitation. This symmetry of involvement, coupled with the absence of classic inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), is one of the key diagnostic clues in distinguishing CACP from other inflammatory diseases. There is progressive bilateral hip joint involvement. It causes flattening of head of femur and shortening of femoral neck. Thereby resulting in coxa-vara deformity. This is a major concern for functional limitation and mobility restriction in day today life with total hip arthroplasty as only possible hope for these patients [ 13 ]. It has been reported in 50–100 percent of cases. [ 1 , 5 , 14 ] These patients are frequently misdiagnosed as JIA, and started on DMARDs. Slow progressive joint involvement can sometimes give rise to incomplete disease picture and thereby adds to the confusion. However, there is progressive joint involvement, despite therapy, further consolidating its non-inflammatory origin. Pericarditis is seen in one-third of cases. It is usually mild and self-limiting, and in rare cases, it may cause severe constrictive pericarditis and right sided heart failure. [ 5 , 15 , 16 ] A few cases of mitral valve pathologies have also been reported to be associated. [ 17 , 18 ] Family history of similar disease course in siblings and history of consanguinity is often present and may provide additional clue towards etiology when a genetic condition is suspected. Differentiating CACP From JIA – There is a clinical overlap between CACP, and JIA, regarding age of presentation, joint swellings and deformities. JIA is a heterogenous group of disease that cause joint inflammation without known cause, starting before age 16. [ 19 ] It is the most prevalent form of chronic inflammatory arthritis in children. The classification and terminology for JIA are guided by the criteria set forth by the International League of Associations for Rheumatology. [ 20 ] However, in clinical practice, JIA refers to any arthritis that lasts longer than six weeks. The disease course is rapidly progressive or may show a remitting and relapsing pattern. Also, it is associated with raised inflammatory markers and positive autoantibodies such as Rheumatoid factor (RF), Anti-cyclic citrullinated peptide (CCP) antibodies. X-rays of involved joints have signs of inflammation like joint space reduction, erosions and destruction of articular surfaces along with non-specific osteopenia and osteoporosis. To diagnose JIA, recognizing certain patterns of symptoms to tell apart arthritis caused by rheumatic conditions from those caused by non-inflammatory diseases is crucial, as there is no single diagnostic investigation for JIA. On the other hand, CACP is characterized by non-inflammatory progressive joint involvement with swellings, eventually leading to deformities without much of pain and tenderness. It causes progressive functional limitation in joint movement and associated with difficulty in day today life. Particularly, bilateral Coxa vera deformities impose functional burden causing difficulty in walking and squatting, with resulting absence from school and leave the child dependent on the parents at an early age. Unfortunately, there are no medical therapy available for modifying the disease course unlike JIA, where we have a full list of conventional and biologicals therapy available. Tables 1 and 2 summarise differentiating features of CACP and JIA. Table 1 Clues to CACP in a child with joint involvement 1.History Often child and parents would complaints of deformities, restriction of range of movement, restriction and bending of joints more than joint pains, with resulting functional limitation of joints 2. Examination On examination, joint swellings have peculiar bony feeling with no or minimal pain and tenderness with limitation in range of movement because of mechanical effects of swelling and not because of pain, tenderness and inflammation. 3.Investigations Repeated inflammatory markers and serologies are negative. 4.Family history Detailed history can reveal other features suggestive of similar affection and progression of disease in siblings or family members Table 2 Differentiating CACP from JIA JIA CACP Joint Pains +++ -/+ Joint swellings ++ + Joint tenderness +++ -/+ Joint deformities ++ ++ Hip involvement ++ +++ Inflammatory markers (ESR/CRP) +++ -/+ Role Of X-Rays In Differentiating CACP From JIA X-rays can help us distinguish inflammatory etiologies from non-inflammatory etiologies, till the time we have better diagnostic markers and tools available to differentiate the two. [Table 3 ] Most important feature is presence of erosions of articular margins seen in inflammatory causes. Presence of erosions make it obvious of inflammatory cause, eroding the cartilage. Other features like osteopenia, joint space narrowing and soft tissue swelling will further support the inflammation, if present. However, these findings are not as specific as erosions. However, there is one very important limitation of X-rays, which should not be overlooked, X-rays will be grossly normal in the early stages of inflammatory arthritis without erosions. X-rays can help us distinguish inflammatory etiologies from non-inflammatory etiologies, till the time we have better diagnostic markers and tools available to differentiate the two. [Table 3] Most important feature is presence of erosions of articular margins seen in inflammatory causes. Presence of erosions make it obvious of inflammatory cause, eroding the cartilage. Other features like osteopenia, joint space narrowing and soft tissue swelling will further support the inflammation, if present. However, these findings are not as specific as erosions. However, there is one very important limitation of X-rays, which should not be overlooked, X-rays will be grossly normal in the early stages of inflammatory arthritis without erosions. Flow Chart -X-Ray Diagnostic Algorithm Table 3 Differentiating X-rays features of inflammatory arthritis vs non-inflammatory arthropathy in CACP Inflammatory Arthritis Non-Inflammatory Arthropathy Of CACP Osteopenia ++ ++ Soft Tissue Swellings +++ - Joint space Reduction Apparent increased space, and flattening of articular surfaces Erosions Most important +++ -- Intra-Osseous Cysts - ++ Conclusion CACP syndrome is a rare, autosomal recessive disorder with significant musculoskeletal and systemic manifestations, including camptodactyly, non-inflammatory arthropathy, coxa vera, and pericarditis. Distinguishing CACP from other arthritic conditions, particularly JIA, is crucial for appropriate management and genetic counselling. Although the syndrome is unresponsive to conventional treatments for inflammatory arthritis, early recognition of the condition, along with genetic testing, can help prevent unnecessary treatments and guide management. Despite limited understanding of this condition in modern medicine, the identification of PRG4 mutations offers a pathway for definitive diagnosis, while advances in genetic testing and counselling can assist families in understanding the inheritance and management of this rare disorder. Abbreviations CACP – Camptodactyly-arthropathy-coxa-vera-pericarditis OMIM- Online mendelian inheritance in man PRG-4- Proteoglycan-4 PIP-Proximal interphalangeal JIA- Juvenile idiopathic arthritis DMARDs – Disease modifying anti-rheumatic drugs ESR- Erythrocyte sedimentation rate CRP – C- reactive protein RF- Rheumatoid Factor Anti-CCP- Anti-cyclic citrullinated peptide NSAIDs- Non steroidal anti-inflammatory drugs Declarations Author contributions RK: conceptualization, writing–original draft, writing–review and editing, patient management, and literature review, SK: patient management, and literature review, supervision, editing of manuscript, critical appraisal, and final approval of manuscript SM: review of literature, and preparation of first draft, MS: patient management, literature review, AA: patient management, literature review, DA: patient management, genetic testing, literature review, and editing of manuscript, KM: patient management, genetic testing, genetic counselling Funding - No funding involved in the study or preparation of the manuscript. Compliance with ethical standards Conflict of interest - All authors declare that he/she has no potential conflict of interest. Ethics approval and consent to participate - This case report did not involve any experimental studies on human participants or animals. Written consent was obtained from the parents of patient for participation in this case report and for the publication of their clinical details. Consent for publication - Written informed consent for the publication of this case report, including any accompanying images or relevant clinical information, was obtained from the patient. Acknowledgements – We genuinely thank all our patients and their family for their co-operation. References Yilmaz S, Uludağ Alkaya D, Kasapçopur Ö, et al. Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. Mol Genet Genomic Med. 2018 Mar;6(2):230-248. Offiah AC, Woo P, Prieur A-M, et al. Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome versus juvenile idiopathic arthritis. Am J Roentgenol. 2005;185(2):522–529. El-Garf A, Mahmoud G, Gheith R, et al. Camptodactyly, arthropathy, coxa vara, and pericarditis syndrome among Egyptians. J Rheumatol. 2003;30(5):1081–1086. Bulutlar G, Yazici H, Ozdogan H, Schreuder I. A familial syndrome of pericarditis, arthritis, camptodactyly and coxa vara. Arthritis Rheum 1986; 29:436 –438. Bahabri, S. A., Suwairi, W. M., Laxer, R. M., et al. The camptodactylyarthropathy-coxa vara-pericarditis syndrome: Clinical features and genetic mapping to human chromosome 1. Arthritis and Rheumatism, 1998 41(4), 730–735. Marcelino, J., Carpten, J. D., Suwairi, W. M., et al. CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathycoxa vara-pericarditis syndrome. Nature Genetics. 1999;23(3), 319–322. D.A. Swann, et al. The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem. J. 1985; 225. Jay GD, Waller KA. The biology of lubricin: Near frictionless joint motion. Matrix Biol 2014;39: 17-24. Watkins AR, Reesink HL. Lubricin in experimental and naturally occurring osteoarthritis: a systematic review. Osteoarthritis Cartilage. 2020 Oct;28(10):1303-1315. Drewniak EI, Jay GD, Fleming BC, Zhang L, Warman ML, Crisco JJ. Cyclic loading increases friction and changes cartilage surface integrity in lubricin-mutant mouse knees. Arthritis Rheum 2012;64: 465-73. Hatice Ağır, İsmihan Sunar, Mehmet Burak Mutlu. Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Caused by Truncating Mutations in the Prg4 Gene: Case Series and Literature Review. Mol Syndromol. 2025;16(3):223–234. Hamilton KL, Netscher DT. Evaluation of a stepwise surgical approach to camptodactyly. Plast Reconstr Surg. 2015 Mar;135(3):568e-576e. Murphy JM, Vanderhave KL, Urquhart AG. Total hip arthroplasty in adolescents with severe hip arthropathy and dysplasia associated with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome. J Arthroplast. 2012;27(8): 1581.e5–1581.e8. Verma UN, Misra R, Radhakrisnan S, Maitra SC, Agarwal SS, Singh RR. A syndrome of fibrosing pleuritis, pericarditis, and synovitis with infantile contractures of fingers and toes in 2 sisters. “familial fihrosing serositis.“ J Rheumatol 1905;22:2349-55. Ciullini Mannurita S, Vignoli M, Bianchi L, Kondi A, Gerloni V, Breda L, Ten Cate R, Alessio M, Ravelli A, Falcini F, Gambineri E. CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort. Eur J Hum Genet. 2014 Feb;22(2):197-201. Patil DV, Phadke MS, Pahwa JS, Dalal AB (2016) Brothers with constrictive pericarditis - A novel mutation in a rare disease. Indian Heart J 68(2): S284–S287. Johnson N, Chaudhary H, Kumrah R, et al. Syndrome of progressive deforming non-inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Rheumatol Int. 2021;41(10):1875–1882. Şimşekli D, Ayabakan C, Oktay A, et al. Camptodactyly-arthropathy-coxa vara-pericarditis syndrome and an unusual association with mitral stenosis. Turk J Pediatr. 2024;66(1):134–138. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138–49. Rose E, Petty TRS, Manners P, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol . 2004; 2 : 390-392. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-7137225","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":493376403,"identity":"b14aaada-99a1-41e2-b7c8-4c19c2fa9608","order_by":0,"name":"Renu Kumawat","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYJACxgYo4+AHHhsQv/EAkVqYGQ9LyKSB+URrYT7AY3MYzMSrxby995jkzLZt8gbHzx84IJFz3m5t+2GgLTU20bi0yJw5lya5se224YYzyQwHCs7cTt52JhGo5VhabgMOLRISOWaSD9tuM247ANQi2XM72ewAUAtjw2HcWuTfgLXYbzv/mOEA779zyWbnHxLQIsFjBnJY4rYbQFt4eA7Ymd0gZAtPjrHljHO3k/ffeGxwWIInOcHsBtCWBHx+YT9jeLOn7LbtzP7Exx8/8NjZm51Pf/jgQ40NTi0YIBGsMoFY5SBgT4riUTAKRsEoGBkAAN0BaoaduMyBAAAAAElFTkSuQmCC","orcid":"","institution":"Indraprastha Apollo Hospitals","correspondingAuthor":true,"prefix":"","firstName":"Renu","middleName":"","lastName":"Kumawat","suffix":""},{"id":493376406,"identity":"3b996057-0659-41a5-8c76-20478a8813aa","order_by":1,"name":"Sundeep K. Upadhyaya","email":"","orcid":"","institution":"Indraprastha Apollo Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Sundeep","middleName":"K.","lastName":"Upadhyaya","suffix":""},{"id":493376409,"identity":"2c8a036c-d5c9-46e2-866b-5919e87c78d6","order_by":2,"name":"Divya Agarwal","email":"","orcid":"","institution":"Apollo Genomics Institute, Indraprastha Apollo Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Divya","middleName":"","lastName":"Agarwal","suffix":""},{"id":493376412,"identity":"25a96046-261b-4530-8e21-7b7ca2b1ce40","order_by":3,"name":"Meera Shah","email":"","orcid":"","institution":"Indraprastha Apollo Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Meera","middleName":"","lastName":"Shah","suffix":""},{"id":493376416,"identity":"2584238a-cfe5-4daf-a55e-c83e14b8482d","order_by":4,"name":"Anushka Aggarwal","email":"","orcid":"","institution":"Indraprastha Apollo Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Anushka","middleName":"","lastName":"Aggarwal","suffix":""},{"id":493376419,"identity":"a15d2d48-3ac1-4521-95aa-71d01bf1d8d7","order_by":5,"name":"S M Swamy","email":"","orcid":"","institution":"All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"S","middleName":"M","lastName":"Swamy","suffix":""},{"id":493376421,"identity":"c8428aa8-1b6c-4281-9931-0652b411766a","order_by":6,"name":"Kriti Menon","email":"","orcid":"","institution":"Apollo Genomics Institute, Indraprastha Apollo Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Kriti","middleName":"","lastName":"Menon","suffix":""}],"badges":[],"createdAt":"2025-07-16 07:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7137225/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7137225/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88229664,"identity":"bbf7b6c8-6341-4566-825b-1c4f5d5d74fc","added_by":"auto","created_at":"2025-08-04 09:17:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":547851,"visible":true,"origin":"","legend":"\u003cp\u003eclinical and radiological features in CACP. X-ray pelvis with both hips anteroposterior view of index case [1A] and his sibling [1B] with bilateral coxa-vera deformity. Camptodactyly and swelling of wrist joint denoting epiphyseal enlargement. [1C]\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7137225/v1/b9b5af2e2b1c44c0164ebba2.png"},{"id":88229665,"identity":"0527e02e-a7be-4e73-8feb-1bd2061fe009","added_by":"auto","created_at":"2025-08-04 09:17:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64077,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image of \u003cu\u003e\u003cstrong\u003eFlow Chart -X-Ray Diagnostic Algorithm\u003c/strong\u003e\u003c/u\u003e.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7137225/v1/65b9dddcdbadfdced49cace9.png"},{"id":108006551,"identity":"f7b6503e-2504-4a92-b3ad-3c09eba25c33","added_by":"auto","created_at":"2026-04-28 12:56:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1077935,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7137225/v1/20e5ea6a-6919-4132-9243-8d31204c2a28.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"CACP Syndrome: A Rare Non-inflammatory Arthropathy Often Misdiagnosed as Juvenile Idiopathic Arthritis – Clinical Insights and Diagnostic Approach","fulltext":[{"header":"Key message ","content":"\u003col\u003e\n \u003cli\u003eNon-inflammatory joint involvement with mirror image symmetry along with early onset and family history should raise suspicion of genetic causes\u003c/li\u003e\n \u003cli\u003eX-rays are helpful in distinguishing the two.\u003c/li\u003e\n \u003cli\u003eAwareness among clinicians for this entity will play a crucial role in early diagnosis and might help in preventing the disease transmission in family through means of genetic counselling and testing of parents.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Introduction","content":"\u003cp\u003eCamptodactyly-arthropathy-coxa-vera-pericarditis (CACP) syndrome is a rare genetic condition with autosomal recessive mode of inheritance. [OMIM 208250]\u003c/p\u003e\u003cp\u003eIt has constellation of 4 features characterized by camptodactyly, non-inflammatory joint involvement, progressive coxa vera, and pericarditis. Prevalence of this disease is not yet reported. However, it is thought to be more prevalent in areas of consanguinity. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eJacobs and Didier were among the first ones to recognize this familial condition. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] This syndrome was first described in literature in 1980s. Bulutlar et al, described this constellation in 1986. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Genotypic studies were conducted on 4 related family members detected a common region on chromosome 1q25-31 in 1997. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In 1998, Marcelino et al, studied the same family and identified the gene as PRG-4 (Proteoglycan-4). [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] It encodes for a mucinous glycoprotein known as Lubricin.\u003c/p\u003e\u003cp\u003eThe term ‘Lubricin’ was coined by David Swann in 1975. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Lubricin plays an important role in the lubrication of articular cartilage and protects from wear and tear. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Also, after its discovery in CACP, lubricin has been studied in animal models to see its potential therapeutic role in lubrication of cartilage and the initial results are encouraging. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIn CACP, PRG-4 deletion leads to deficiency of lubricin, thereby causing impaired joint mechanics and arthropathy.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Since then, there has been a growing interest in genotypic studies of this disease. Several pathogenic mutations have been reported with ever expanding list.\u003c/p\u003e\u003cp\u003eA key concern among clinicians is that CACP can mimic JIA. As both the conditions affect children and young adults, resulting into the joint swellings and hip involvement. JIA is the commonest cause of joint swelling in children. The diagnosis of JIA is still clinical in the absence of clear diagnostic markers. This causes much confusion, subjecting the CACP patient to DMARDs treatment. Joint involvement in CACP is non-inflammatory and do not respond to DMARDs. In this review, we will discuss the current understanding of the clinical features, differences between JIA and CACP, role of radiographs in distinguishing the two.\u003c/p\u003e"},{"header":"Case Discussion","content":"\u003cp\u003eA 14-year-old male presented with a long-standing history of progressive joint pain and swelling, which began in early childhood and had gradually worsened over time. His symptoms included swelling and pain in the wrist, ankles, knees, elbows, and hands, along with noticeable gait disturbances. The joint swelling had been present intermittently since early childhood, but it had become more severe and persistent in the last few years. His condition was initially diagnosed as Juvenile Idiopathic Arthritis (JIA), and he was started on Disease-Modifying Anti-Rheumatic Drugs (DMARDs), including methotrexate, as part of the treatment regimen. Despite these interventions, his symptoms persisted and even progressed, prompting a referral to our center for further evaluation.\u003c/p\u003e\u003cp\u003eOn physical examination, the patient exhibited visible swelling in the wrist, knees, elbows, and few PIPs, flexion deformities of PIPs and both elbow and his gait was also abnormal, with a limp and difficulty in weight-bearing. There was no history of skin rashes, systemic involvement, or organomegaly, and the patient denied any recent infections or trauma. Laboratory tests revealed normal blood counts and normal ESR and CRP. Rheumatoid factor (RF) and anti-CCP antibodies were negative. X-rays of the affected joints showed characteristic signs of coxa vera [ Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e] in the hips and mild joint deformities of PIPs, epiphyseal splaying and irregularities of margin in both wrist but no erosions or joint space narrowing typical of inflammatory arthritis. The patient’s younger brother, a 10-year-old boy, had similar complaints of progressive joint pain and swelling in the knees, hands along with gait abnormalities since infancy. Both brothers presented with a very similar clinical course, further supporting the diagnosis of some genetic affection.\u003c/p\u003e\u003cp\u003eThese findings, combined with the unusual presentation, led us to reconsider the initial diagnosis of JIA.\u003c/p\u003e\u003cp\u003eFurther evaluation with whole exome sequencing identified a homozygous likely pathogenic variant in exon 7 of the PRG4 gene: c.1910_1911delCT (p.Pro637Argfs*9). This variant is associated with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis (CACP) syndrome. The c.1910_1911delCT variant has been previously reported and is predicted to result in a truncated protein due to a frameshift, leading to loss-of-function through nonsense-mediated decay. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset, with an allele frequency of 0.000025, indicating its rarity in the general population. This variant has been documented in a family comprising six affected individuals- three siblings and three cousins, and two other patients from unrelated families diagnosed with CACP syndrome.\u003c/p\u003e\u003cp\u003eThe importance of distinguishing CACP syndrome from JIA was highlighted in this case, as the initial treatment with DMARDs, while appropriate for JIA, did not lead to significant improvement in this patient’s condition.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Features Of CACP\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe clinical hallmark of CACP syndrome is presence of camptodactyly. It is a non-traumatic, progressive flexion deformity of PIP joints.\u003c/p\u003e\u003cp\u003eIt can be either congenital or acquired. It can be sporadic or associated with congenital anomalies. It is more often seen as an isolated entity, affecting little finger. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIn CACP it is part of spectrum of other manifestations. It is usually the first symptom to present and often present at birth or appears in early childhood.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] It is usually seen in both the hands with mirror image symmetry. However, the degree of flexion may vary.\u003c/p\u003e\u003cp\u003eIt is important to differentiate camptodactyly from inflammatory small joint involvement in JIA as both the conditions causes swellings and deformity of joints. However, in CACP, these swellings have peculiar bony feel and not associated with much of pain, tenderness. Inflammatory markers are also negative. This is non-inflammatory joint involvement. It is universal in CACP but may not be evident on radiographs, complicating further its differentiation from JIA.\u003c/p\u003e\u003cp\u003eArthropathy is the main presenting complaints of these patients. It usually starts from the wrist joint and can involve other joints including hip, knee, ankle and elbows. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] There is symmetrical involvement with similar mirror image symmetry like camptodactyly but degree of involvement may somewhat vary at any given point of time. This mirror-image symmetry is a distinguishing feature that sets CACP apart from other arthropathies like JIA. Other signs of inflammation are usually absent. Joint involvement is progressive, causing contractures, deformities and functional limitation. This symmetry of involvement, coupled with the absence of classic inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), is one of the key diagnostic clues in distinguishing CACP from other inflammatory diseases.\u003c/p\u003e\u003cp\u003eThere is progressive bilateral hip joint involvement. It causes flattening of head of femur and shortening of femoral neck. Thereby resulting in coxa-vara deformity. This is a major concern for functional limitation and mobility restriction in day today life with total hip arthroplasty as only possible hope for these patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It has been reported in 50–100 percent of cases. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThese patients are frequently misdiagnosed as JIA, and started on DMARDs. Slow progressive joint involvement can sometimes give rise to incomplete disease picture and thereby adds to the confusion. However, there is progressive joint involvement, despite therapy, further consolidating its non-inflammatory origin.\u003c/p\u003e\u003cp\u003ePericarditis is seen in one-third of cases. It is usually mild and self-limiting, and in rare cases, it may cause severe constrictive pericarditis and right sided heart failure. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] A few cases of mitral valve pathologies have also been reported to be associated. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eFamily history of similar disease course in siblings and history of consanguinity is often present and may provide additional clue towards etiology when a genetic condition is suspected.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDifferentiating CACP From JIA\u003c/span\u003e –\u003c/p\u003e\u003cp\u003eThere is a clinical overlap between CACP, and JIA, regarding age of presentation, joint swellings and deformities.\u003c/p\u003e\u003cp\u003eJIA is a heterogenous group of disease that cause joint inflammation without known cause, starting before age 16. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] It is the most prevalent form of chronic inflammatory arthritis in children. The classification and terminology for JIA are guided by the criteria set forth by the International League of Associations for Rheumatology. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] However, in clinical practice, JIA refers to any arthritis that lasts longer than six weeks. The disease course is rapidly progressive or may show a remitting and relapsing pattern. Also, it is associated with raised inflammatory markers and positive autoantibodies such as Rheumatoid factor (RF), Anti-cyclic citrullinated peptide (CCP) antibodies. X-rays of involved joints have signs of inflammation like joint space reduction, erosions and destruction of articular surfaces along with non-specific osteopenia and osteoporosis.\u003c/p\u003e\u003cp\u003eTo diagnose JIA, recognizing certain patterns of symptoms to tell apart arthritis caused by rheumatic conditions from those caused by non-inflammatory diseases is crucial, as there is no single diagnostic investigation for JIA.\u003c/p\u003e\u003cp\u003eOn the other hand, CACP is characterized by non-inflammatory progressive joint involvement with swellings, eventually leading to deformities without much of pain and tenderness. It causes progressive functional limitation in joint movement and associated with difficulty in day today life. Particularly, bilateral Coxa vera deformities impose functional burden causing difficulty in walking and squatting, with resulting absence from school and leave the child dependent on the parents at an early age. Unfortunately, there are no medical therapy available for modifying the disease course unlike JIA, where we have a full list of conventional and biologicals therapy available. Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarise differentiating features of CACP and JIA.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClues to CACP in a child with joint involvement\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.History\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOften child and parents would complaints of deformities, restriction of range of movement, restriction and bending of joints more than joint pains, with resulting functional limitation of joints\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. Examination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOn examination, joint swellings have peculiar bony feeling with no or minimal pain and tenderness with limitation in range of movement because of mechanical effects of swelling and not because of pain, tenderness and inflammation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3.Investigations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRepeated inflammatory markers and serologies are negative.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4.Family history\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDetailed history can reveal other features suggestive of similar affection and progression of disease in siblings or family members\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDifferentiating CACP from JIA\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eJIA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCACP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint Pains\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-/+\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint swellings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint tenderness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-/+\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint deformities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHip involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInflammatory markers (ESR/CRP)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-/+\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eRole Of X-Rays In Differentiating CACP From JIA\u003c/span\u003e\u003c/p\u003e\u003cp\u003eX-rays can help us distinguish inflammatory etiologies from non-inflammatory etiologies, till the time we have better diagnostic markers and tools available to differentiate the two. [Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eMost important feature is presence of erosions of articular margins seen in inflammatory causes. Presence of erosions make it obvious of inflammatory cause, eroding the cartilage. Other features like osteopenia, joint space narrowing and soft tissue swelling will further support the inflammation, if present. However, these findings are not as specific as erosions.\u003c/p\u003e\u003cp\u003eHowever, there is one very important limitation of X-rays, which should not be overlooked, X-rays will be grossly normal in the early stages of inflammatory arthritis without erosions.\u003c/p\u003e\u003cp\u003eX-rays can help us distinguish inflammatory etiologies from non-inflammatory etiologies, till the time we have better diagnostic markers and tools available to differentiate the two. [Table 3]\u003c/p\u003e\u003cp\u003eMost important feature is presence of erosions of articular margins seen in inflammatory causes. Presence of erosions make it obvious of inflammatory cause, eroding the cartilage. \u0026nbsp;Other features like osteopenia, joint space narrowing and soft tissue swelling will further support the inflammation, if present. However, these findings are not as specific as erosions.\u003c/p\u003e\u003cp\u003eHowever, there is one very important limitation of X-rays, which should not be overlooked, X-rays will be grossly normal in the early stages of inflammatory arthritis without erosions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFlow Chart -X-Ray Diagnostic Algorithm\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDifferentiating X-rays features of inflammatory arthritis vs non-inflammatory arthropathy in CACP\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInflammatory Arthritis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon-Inflammatory Arthropathy Of CACP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSoft Tissue Swellings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint space\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eApparent increased space, and flattening of articular surfaces\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eErosions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMost important\u003c/p\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntra-Osseous Cysts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e++\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCACP syndrome is a rare, autosomal recessive disorder with significant musculoskeletal and systemic manifestations, including camptodactyly, non-inflammatory arthropathy, coxa vera, and pericarditis. Distinguishing CACP from other arthritic conditions, particularly JIA, is crucial for appropriate management and genetic counselling. Although the syndrome is unresponsive to conventional treatments for inflammatory arthritis, early recognition of the condition, along with genetic testing, can help prevent unnecessary treatments and guide management. Despite limited understanding of this condition in modern medicine, the identification of PRG4 mutations offers a pathway for definitive diagnosis, while advances in genetic testing and counselling can assist families in understanding the inheritance and management of this rare disorder.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCACP \u0026ndash; Camptodactyly-arthropathy-coxa-vera-pericarditis\u003c/p\u003e\n\u003cp\u003eOMIM- Online mendelian inheritance in man\u003c/p\u003e\n\u003cp\u003ePRG-4- Proteoglycan-4\u003c/p\u003e\n\u003cp\u003ePIP-Proximal interphalangeal\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJIA- Juvenile idiopathic arthritis\u003c/p\u003e\n\u003cp\u003eDMARDs \u0026ndash; Disease modifying anti-rheumatic drugs\u003c/p\u003e\n\u003cp\u003eESR- Erythrocyte sedimentation rate\u003c/p\u003e\n\u003cp\u003eCRP \u0026ndash; C- reactive protein\u003c/p\u003e\n\u003cp\u003eRF- Rheumatoid Factor\u003c/p\u003e\n\u003cp\u003eAnti-CCP- Anti-cyclic citrullinated peptide\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSAIDs- Non steroidal anti-inflammatory drugs\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRK: conceptualization, writing–original draft, writing–review and editing, patient management, and literature review, SK: patient management, and literature review, supervision, editing of manuscript, critical appraisal, and final approval of manuscript SM: review of literature, and preparation of first draft, MS: patient management, literature review, AA: patient management, literature review, DA: patient management, genetic testing, literature review, and editing of manuscript, KM: patient management, genetic testing, genetic counselling\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding - No funding involved in the study or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003eCompliance with ethical standards\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConflict of interest - All authors declare that he/she has no potential conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate - This case report did not involve any experimental studies on human participants or animals. Written consent was obtained from the parents of patient for participation in this case report and for the publication of their clinical details.\u003c/p\u003e\n\u003cp\u003eConsent for publication - Written informed consent for the publication of this case report, including any accompanying images or relevant clinical information, was obtained from the patient.\u003c/p\u003e\n\u003cp\u003eAcknowledgements – We genuinely thank all our patients and their family for their co-operation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYilmaz S, Uludağ Alkaya D, Kasap\u0026ccedil;opur \u0026Ouml;, et al. Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. Mol Genet Genomic Med. 2018 Mar;6(2):230-248.\u003c/li\u003e\n \u003cli\u003eOffiah AC, Woo P, Prieur A-M, et al. Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome versus juvenile idiopathic arthritis. Am J Roentgenol. 2005;185(2):522\u0026ndash;529.\u003c/li\u003e\n \u003cli\u003eEl-Garf A, Mahmoud G, Gheith R, et al. Camptodactyly, arthropathy, coxa vara, and pericarditis syndrome among Egyptians. J Rheumatol. 2003;30(5):1081\u0026ndash;1086.\u003c/li\u003e\n \u003cli\u003eBulutlar G, Yazici H, Ozdogan H, Schreuder I. A familial syndrome of pericarditis, arthritis, camptodactyly and coxa vara. \u003cem\u003eArthritis Rheum\u003c/em\u003e 1986; 29:436 \u0026ndash;438.\u003c/li\u003e\n \u003cli\u003eBahabri, S. A., Suwairi, W. M., Laxer, R. M., et al. The camptodactylyarthropathy-coxa vara-pericarditis syndrome: Clinical features and genetic mapping to human chromosome 1. Arthritis and Rheumatism, 1998 41(4), 730\u0026ndash;735.\u003c/li\u003e\n \u003cli\u003eMarcelino, J., Carpten, J. D., Suwairi, W. M., et al. CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathycoxa vara-pericarditis syndrome. Nature Genetics. 1999;23(3), 319\u0026ndash;322.\u003c/li\u003e\n \u003cli\u003eD.A.\u0026nbsp;Swann,\u0026nbsp;et al. The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem. J. 1985;\u0026nbsp;225.\u003c/li\u003e\n \u003cli\u003eJay GD, Waller KA. The biology of lubricin: Near frictionless joint motion. Matrix Biol 2014;39: 17-24.\u003c/li\u003e\n \u003cli\u003eWatkins AR, Reesink HL. Lubricin in experimental and naturally occurring osteoarthritis: a systematic review. Osteoarthritis Cartilage. 2020 Oct;28(10):1303-1315.\u003c/li\u003e\n \u003cli\u003eDrewniak EI, Jay GD, Fleming BC, Zhang L, Warman ML, Crisco JJ. Cyclic loading increases friction and changes cartilage surface integrity in lubricin-mutant mouse knees. Arthritis Rheum 2012;64: 465-73.\u003c/li\u003e\n \u003cli\u003eHatice Ağır, İsmihan Sunar, Mehmet Burak Mutlu. Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Caused by Truncating Mutations in the \u003cem\u003ePrg4\u003c/em\u003e Gene: Case Series and Literature Review. \u003cem\u003eMol Syndromol.\u003c/em\u003e 2025;16(3):223\u0026ndash;234.\u003c/li\u003e\n \u003cli\u003eHamilton KL, Netscher DT. Evaluation of a stepwise surgical approach to camptodactyly. Plast Reconstr Surg. 2015 Mar;135(3):568e-576e.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMurphy JM, Vanderhave KL, Urquhart AG. Total hip arthroplasty in adolescents with severe hip arthropathy and dysplasia associated with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome. J Arthroplast. 2012;27(8): 1581.e5\u0026ndash;1581.e8.\u003c/li\u003e\n \u003cli\u003eVerma UN, Misra R, Radhakrisnan S, Maitra SC, Agarwal SS, Singh RR. A syndrome of fibrosing pleuritis, pericarditis, and synovitis with infantile contractures of fingers and toes in 2 sisters. \u0026ldquo;familial fihrosing serositis.\u0026ldquo; J Rheumatol 1905;22:2349-55.\u003c/li\u003e\n \u003cli\u003eCiullini Mannurita S, Vignoli M, Bianchi L, Kondi A, Gerloni V, Breda L, Ten Cate R, Alessio M, Ravelli A, Falcini F, Gambineri E. CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort. Eur J Hum Genet. 2014 Feb;22(2):197-201.\u003c/li\u003e\n \u003cli\u003ePatil DV, Phadke MS, Pahwa JS, Dalal AB (2016) Brothers with constrictive pericarditis - A novel mutation in a rare disease. Indian Heart J 68(2): S284\u0026ndash;S287.\u003c/li\u003e\n \u003cli\u003eJohnson N, Chaudhary H, Kumrah R, et al. Syndrome of progressive deforming non-inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Rheumatol Int. 2021;41(10):1875\u0026ndash;1882.\u003c/li\u003e\n \u003cli\u003eŞimşekli D, Ayabakan C, Oktay A, et al. Camptodactyly-arthropathy-coxa vara-pericarditis syndrome and an unusual association with mitral stenosis. Turk J Pediatr. 2024;66(1):134\u0026ndash;138.\u003c/li\u003e\n \u003cli\u003ePrakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138\u0026ndash;49.\u003c/li\u003e\n \u003cli\u003eRose E, Petty TRS, Manners P, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. \u003cem\u003eJ Rheumatol\u003c/em\u003e. 2004; \u003cstrong\u003e2\u003c/strong\u003e: 390-392.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Camptodactyly, CACP, JIA, Non-inflammatory","lastPublishedDoi":"10.21203/rs.3.rs-7137225/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7137225/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCACP (Camptodactyly-arthropathy-coxa-vera- pericarditis) is rare autosomal recessive genetic condition characterized by progressive joint involvement at an early age. The prevalence of this condition remains unknown. It occurs due to defect in the gene PRG-4 (Proteoglycan-4) on chromosome 1q encoding for protein lubricin. Camptodactyly is non-traumatic flexion deformity of proximal interphalangeal joints (PIPs). It is commonly seen involving little finger as a sporadic condition. In CACP, it is usually congenital or early childhood onset and involves both the hands.\u003c/p\u003e\u003cp\u003eArthropathy is non-inflammatory and tend to involve large joint with mirror image symmetry. It is unresponsive to DMARDs. (disease modifying anti-rheumatic drugs) Children with CACP present to rheumatology clinics with joint swellings and frequently misdiagnosed with JIA (Juvenile idiopathic arthritis) as it is the most prevalent cause of joint swellings in children. However, diagnosis of JIA is clinical and there is lack of clear diagnostic markers, which causes further confusion.\u003c/p\u003e\u003cp\u003eAbsence of other inflammatory signs, mirror image symmetry of joint involvement and partial response to treatment for JIA may be the clues to reinvestigate for genetic causes in such cases. X-rays findings may be helpful in differentiating the two as well.\u003c/p\u003e","manuscriptTitle":"CACP Syndrome: A Rare Non-inflammatory Arthropathy Often Misdiagnosed as Juvenile Idiopathic Arthritis – Clinical Insights and Diagnostic Approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-04 09:17:25","doi":"10.21203/rs.3.rs-7137225/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":"519e9e02-7688-488b-9f92-272485ce520e","owner":[],"postedDate":"August 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T07:43:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-04 09:17:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7137225","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7137225","identity":"rs-7137225","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}