CACP: Study on Camptodactyly - Arthropathy - Coxa Vara - Pericarditis (CACP) Syndrome

Official title

Profiling Camptodactyly - Arthropathy - Coxa Vara - Pericarditis (CACP) Syndrome: A Multicenter European Study

Overview

CACP syndrome is a rare autosomal recessive disorder characterized by the triad of camptodactyly, non-inflammatory arthropathy with synovial hyperplasia, and coxa vara. Occasionally, non-inflammatory pericarditis and pleural effusion may also occur. This syndrome is likely underdiagnosed due to its rarity. Epidemiological information is limited to isolated case reports or small patient series, with the largest reported cohort including 35 patients. The genetic cause of CACP syndrome is associated with mutations in the PRG4 gene, located on chromosome 1q31.1. While clinical signs (camptodactyly, non-inflammatory arthropathy, and coxa vara) and radiological findings suggest the diagnosis, genetic testing confirms it by identifying pathogenic biallelic mutations in PRG4. To date, twenty-two mutations have been identified, all leading to premature stop codons and the absence of functional lubricin. However, the exact pathophysiology of CACP syndrome remains incompletely understood. Clinical manifestations of CACP syndrome can vary, even within the same family. The progressive and slow onset can initially present as an incomplete clinical picture. However, camptodactyly (85- 100%) and arthropathy (100%) are constant features. Although genetically homogeneous, CACP exhibits significant intra- and interfamilial phenotypic variability due to secondary genetic factors, environmental modifiers, and complex molecular mechanisms. Camptodactyly is symmetrical, with variable distribution. It may affect fingers or toes and can be congenital or develop during childhood. Arthropathy is symmetrical, primarily involving large joints (wrists, knees, ankles, elbows, and hips). Coxa vara is present in 50-90% of cases, is progressive, and tends to worsen with age. Spinal abnormalities such as lordosis, scoliosis, and kyphosis are possible, though the cervical spine is generally spared. The articular manifestations of CACP syndrome may mimic juvenile idiopathic arthritis (JIA), and patients are often initially misdiagnosed and treated inappropriately. Joints appear swollen due to non-inflammatory synovial effusion and synovial thickening. They develop contractures, functional limitations, and sometimes musculoskeletal pain. Non-inflammatory pericarditis is reported in 30% of published cases, with variable clinical courses that may require surgical intervention in cases of constrictive pericarditis. The routine pathway of assessments and follow-up for patients with CACP syndrome includes an initial detailed evaluation and regular monitoring. Following the diagnosis, which is based on clinical history, imaging studies, and genetic confirmation of PRG4 mutations, patients undergo periodic clinical visits, generally scheduled every six months. During these visits, the progression of the disease, articular symptoms (e.g., camptodactyly, mobility limitations), and possible extraarticular complications, such as pericarditis, are assessed. Radiological (e.g., X-rays, MRI) and laboratory assessments, however, can be spaced out over longer intervals compared to the schedule of clinical visits, typically every 1-2 years, unless specific indications arise. Nonetheless, these examinations may be requested based on contingent clinical needs, such as a sudden worsening of symptoms or suspicion of complications. This flexible approach helps to balance thorough disease monitoring with minimizing the burden on patients, while ensuring personalized and timely management of the condition. At present, there is no specific pharmacological treatment for CACP. Management is primarily symptomatic and aimed at preventing joint deformities and extra-articular complications. Currently, no experimental therapies are available for CACP syndrome, but future research could explore gene therapy, regenerative medicine, and biologics. This study, involving pediatric and pediatric rheumatology centers across Italy and Europe, aims to collect epidemiological, clinical, and therapeutic data from a large cohort of patients. Its goals include better defining the disease's characteristics, understanding its natural history, and evaluating different therapeutic approaches and their efficacy. The study will also analyze potential genotypephenotype correlations.

Primary outcome measures

• Incidence of CACP Syndrome [Time frame: From enrollment to the next 10 years]
• Geographic and Ethnic Distribution of CACP Cases [Time frame: From the enrollment to the next 10 years]
• Clinical Characteristics [Time frame: From enrollment to the next 10 years]
• Disease progression [Time frame: From enrollment to the next 10 years]
• Disease Complications [Time frame: From enrollment to the next 10 years]
• Distribution of PRG4 Gene Variants [Time frame: from the enrollment to the next 10 years]
• Genotype-Phenotype Association [Time frame: From enrollment to the next 10 years]
• Geographic and Ethic Distribution of PRG4 Variants [Time frame: From enrollment to the next 10 years]
• Post-Diagnosis Treatments [Time frame: from the enrollment to the next 10 years]

Secondary outcome measures (7)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Time frame: from the enrollment to the next 10 years]
• Change from baseline in functional disability assessed by Childhood Health Assessment Questionnaire (CHAQ) score [Time frame: from the enrollment to the next 10 years]
• Change from baseline in musculoskeletal pain intensity assessed by Visual Analogue Scale (VAS) [Time frame: from enrollement to the next 10 years]
• Change from baseline in patient global well-being assessed by Patient Global Assessment (PGA) scale [Time frame: from enrollement to the next 10 years]
• Time from symptom onset to confirmed diagnosis of CACP syndrome [Time frame: from the enrollment to the next 10 years]
• Number of participants with prior misdiagnosis before confirmed diagnosis of CACP syndrome [Time frame: from the enrollement to the next 10 years]
• Types of alternative diagnoses prior to confirmed CACP diagnosis [Time frame: from the enrollement to the next 10 years]

Eligibility criteria

Inclusion criteria

• Patients with clinical diagnosis and genetic confirmation of CACP syndrome.
• Patients diagnosed during pediatric age (<18 years).
• Time frame: Patients diagnosed with CACP between January 2005 and January 1, 2026.
• Informed consent obtained from parents or legal guardians.

Exclusion criteria

• Patients without genetic confirmation of the diagnosis.
• Lack of informed consent from parents or legal guardians.
• Patients diagnosed before January 1, 2005, or after January 1, 2026.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 8 centers

• Ospedale Pediatrico Giovanni XXIII — Bari
• Rheumatology Unit, Meyer Children's Hospital — Florence
• IRCCS Istituto Giannina Gaslini, — Genova
• ASST Fatebenefratelli — Milan
• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan
• Azienda Ospedaliera di Padova — Padova
• Santa Maria Goretti Hospital — Roma
• Centro di Reumatologia Pediatrica — Udine

Spain · 1 center

• Hiospedal Sant Joan de Déu — Barcelona

Turkey (Türkiye) · 1 center

• Ankara Pediatrik Romatoloji Bilim Dalý Hacettepe Üniversitesi — Ankara

Publications

• Al-Mayouf SM, Almutairi N, Alismail K. The Efficacy of Yttrium-90 Radiosynovectomy in Patients with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome. Mol Imaging Radionucl Ther. 2017 Feb 5;26(1):33-37. doi: 10.4274/mirt.29484. PMID 28291008
• Albuhairan I, Al-Mayouf SM. Camptodactyly-arthropathy-coxavara-pericarditis syndrome in Saudi Arabia: clinical and molecular genetic findings in 22 patients. Semin Arthritis Rheum. 2013 Oct;43(2):292-6. doi: 10.1016/j.semarthrit.2012.11.004. Epub 2013 Jan 2. PMID 23290693
• Singh S, Badiger VA, Balan S, Nampoothiri S, Rao AP, Shah H, Bhavani GS, Narayanan DL, Girisha KM. Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Clin Dysmorphol. 2024 Oct 1;33(4):152-159. doi: 10.1097/MCD.0000000000000500. Epub 2024 Mar 22. PMID 38856641
• 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. doi: 10.1038/ejhg.2013.123. Epub 2013 Jun 12. PMID 23756439
• Sathiyaseelan SL, Krishna K, Agarwal D, Oswal JS. Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. BMJ Case Rep. 2024 Jul 1;17(7):e260146. doi: 10.1136/bcr-2024-260146. PMID 38955384
• Yilmaz S, Uludag Alkaya D, Kasapcopur O, Barut K, Akdemir ES, Celen C, Youngblood MW, Yasuno K, Bilguvar K, Gunel M, Tuysuz B. 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. doi: 10.1002/mgg3.364. Epub 2018 Feb 4. PMID 29397575

Identifiers

NCT: NCT07468461 · CACP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗