Arthropathy, Camptodactyly, Coxa Vara, Pericarditis
Conditions
Keywords
Camptodactyly - Arthropathy - Coxa Vara - Pericarditis (CACP) Syndrome
Brief summary
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.
Interventions
None listed
Sponsors
Meyer Children's Hospital IRCCS
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geographic and Ethic Distribution of PRG4 Variants | From enrollment to the next 10 years | Number and proportion of specific PRG4 variants stratified by country and center and ethnicity. |
| Post-Diagnosis Treatments | from the enrollment to the next 10 years | After a definitive diagnosis, treatments focus on symptom management and improving patients' quality of life. Commonly used medications include: * Non-steroidal anti-inflammatory drugs (NSAIDs) * Corticosteroids * Intra-articular hyaluronic acid (HA) injections |
| Incidence of CACP Syndrome | From enrollment to the next 10 years | Number of newly diagnosed cases of CACP syndrome identified during the study period, reported per population at risk. |
| Geographic and Ethnic Distribution of CACP Cases | From the enrollment to the next 10 years | Number and proportion of confirmed CACP cases per participating country and center and stratified by self-reported ethnicity. |
| Clinical Characteristics | From enrollment to the next 10 years | * Frequency of Individual Clinical Manifestations: Proportion of patients presenting with each predefined clinical feature (camptodactyly, non-inflammatory arthropathy, coxa vara, non-inflammatory pericarditis), reported individually as present/absent. * Interindividual Clinical Variability: Exploration of variations in symptom presentation and disease progression among individuals. |
| Disease progression | From enrollment to the next 10 years | Assessment of the clinical and radiological course of CACP syndrome, including measurement of disease severity and progression rate. |
| Disease Complications | From enrollment to the next 10 years | * Incidence of Complications: Proportion of patients developing predefined complications (e.g., constrictive pericarditis, pleural effusion), each reported separately. * Management of Complications: Type and frequency of therapeutic interventions used for the management of CACP-related complications. |
| Distribution of PRG4 Gene Variants | from the enrollment to the next 10 years | * Number and proportion of participants carrying each identified pathogenic or likely pathogenic variant in the PRG4 gene. * Classification of participants into subgroups based on specific PRG4 variants, with descriptive comparison of associated clinical characteristics. |
| Genotype-Phenotype Association | From enrollment to the next 10 years | Statistical association between specific PRG4 variants and predefined clinical manifestations or severity disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Types of alternative diagnoses prior to confirmed CACP diagnosis | from the enrollement to the next 10 years | The different clinical diagnoses assigned before the final diagnosis of CACP syndrome will be collected and categorized to identify the most common diagnostic errors leading to delayed recognition of CACP syndrome. |
| Time from symptom onset to confirmed diagnosis of CACP syndrome | from the enrollment to the next 10 years | The time between the first reported clinical symptoms and the confirmed diagnosis of CACP syndrome will be recorded for each participant. The average diagnostic delay will be calculated and reported in months. |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | from the enrollment to the next 10 years | Treatment safety will be evaluated by recording the number and type of treatment-related adverse events as assessed by CTCAE v4.0 during the study period. |
| Change from baseline in functional disability assessed by Childhood Health Assessment Questionnaire (CHAQ) score | from the enrollment to the next 10 years | Functional disability and quality of life will be assessed using the Childhood Health Assessment Questionnaire (CHAQ). The CHAQ evaluates motor function, ability to perform daily activities, and level of autonomy. Scores range from 0 to 3, with higher scores indicating greater disability. The change in CHAQ score from baseline to follow-up visits will be analyzed. |
| Change from baseline in musculoskeletal pain intensity assessed by Visual Analogue Scale (VAS) | from enrollement to the next 10 years | Pain intensity will be evaluated using the Visual Analogue Scale (VAS), a continuous scale ranging from 0 (no pain) to 10 (worst imaginable pain). The change in VAS score from baseline during follow-up will be analyzed to assess the relationship between pain, disease progression, and treatment response. |
| Number of participants with prior misdiagnosis before confirmed diagnosis of CACP syndrome | from the enrollement to the next 10 years | The number and proportion of participants who received an alternative diagnosis prior to the confirmed diagnosis of CACP syndrome will be recorded. Misdiagnoses may include conditions such as juvenile idiopathic arthritis or other rheumatologic or orthopedic disorders. |
| Change from baseline in patient global well-being assessed by Patient Global Assessment (PGA) scale | from enrollement to the next 10 years | Psychological and overall well-being will be assessed using the Patient Global Assessment (PGA), a patient-reported outcome measured on a visual analogue scale from 0 to 10, where higher scores indicate worse perceived health status. Changes from baseline will be analyzed during follow-up. |
Countries
Italy, Spain, Turkey (Türkiye)
Contacts
CONTACTTeresa Giani, MD, PhD
Outcome results
None listed