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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Arthropathy; Pericarditis; Coxa Vara; Camptodactyly

• Study Type: Observational
• Enrollment (Estimated): 15

Contacts and Locations

• Study Contact: Name: Teresa Giani, MD, PhD; Phone Number: +39 0555662924; Email: teresa.giani@gmail.com

Study Locations

• Italy
  • Bari, Italy
    • Not yet recruiting
    • Ospedale Pediatrico Giovanni XXIII
    • Contact: Francesco Latorre
  • Florence, Italy
    • Recruiting
    • Rheumatology Unit, Meyer Children's Hospital
    • Contact: Teresa Giani, MD, PhD; Phone Number: +39 0555662924; Email: teresa.giani@gmail.com
  • Genova, Italy
    • Recruiting
    • IRCCS Istituto Giannina Gaslini,
    • Contact: Riccardo Papa
  • Milan, Italy
    • Recruiting
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
    • Contact: Giovanni Filocamo
  • Milan, Italy
    • Not yet recruiting
    • ASST Fatebenefratelli
    • Contact: Angela Mauro
  • Padua, Italy
    • Not yet recruiting
    • Azienda Ospedaliera di Padova
    • Contact: Alessandra Meneghel
  • Roma, Italy
    • Not yet recruiting
    • Santa Maria Goretti Hospital
    • Contact: Emanuela Delgiudice
  • Udine, Italy
    • Not yet recruiting
    • Centro di Reumatologia Pediatrica
    • Contact: Giorgia Martini
• Spain
  • Barcelona, Spain, 208950
    • Not yet recruiting
    • Hiospedal Sant Joan de Déu
    • Contact: Jordi Anton Lopez
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06105
    • Not yet recruiting
    • Ankara Pediatrik Romatoloji Bilim Dalý Hacettepe Üniversitesi
    • Contact: Ezgi Deniz Batu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Study population will be selected at the participating centers according to inclusion criteria.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of CACP Syndrome	Number of newly diagnosed cases of CACP syndrome identified during the study period, reported per population at risk.	From enrollment to the next 10 years
Geographic and Ethnic Distribution of CACP Cases	Number and proportion of confirmed CACP cases per participating country and center and stratified by self-reported ethnicity.	From the enrollment to the next 10 years
Clinical Characteristics	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.	From enrollment to the next 10 years
Disease progression	Assessment of the clinical and radiological course of CACP syndrome, including measurement of disease severity and progression rate.	From enrollment to the next 10 years
Disease Complications	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.	From enrollment to the next 10 years
Distribution of PRG4 Gene Variants	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.	from the enrollment to the next 10 years
Genotype-Phenotype Association	Statistical association between specific PRG4 variants and predefined clinical manifestations or severity disease.	From enrollment to the next 10 years
Geographic and Ethic Distribution of PRG4 Variants	Number and proportion of specific PRG4 variants stratified by country and center and ethnicity.	From enrollment to the next 10 years
Post-Diagnosis Treatments	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	from the enrollment to the next 10 years

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Publications and helpful links

General 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2038

Study Registration Dates

• First Submitted: February 17, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Camptodactyly - Arthropathy - Coxa Vara - Pericarditis (CACP) Syndrome
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Anatomical; Heart Diseases; Disease; Torsion Abnormality; Pathological Conditions, Signs and Symptoms; Bone Anteversion; Bone Malalignment; Joint Diseases; Syndrome; Pericarditis; Coxa Vara
• Other Study ID Numbers: CACP