The camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare congenital autosomal recessive disorder caused by mutations in the PRG4 (Proteoglycan 4) gene. Manifestations vary across families as well as between affected individuals from the same family, with camptodactyly and arthropathy of the knees the most ubiquitous, while pericarditis is evident in only one-fifth of all reported cases. CACP syndrome is characterized by early onset camptodactyly, non-inflammatory arthropathy, synovial hyperplasia, and progressive coxa vara deformity. In the case of CACP, the camptodactyly is bilateral, and although in most cases, is congenital, it has also been seen to appear in early childhood. The arthropathy in this condition affects only the large joints, such as wrists, elbows, hips, knees, and ankles. Progressive coxa vara deformity is seen in 60% of the cases, while mild and self limiting non-inflammatory pericarditis is seen in 30% of cases. Patients have a normal facial appearance, and show no signs of respiratory distress.
CACP is diagnosed on the basis of the clinical features. The various different aspects of the condition are treated separately. Camptodactyly can be initially managed by splinting, and if needed, by a surgery to remove tendons from adhesions (tenolysis) and/or resection of the tendon sheath (tenosynovectomy). Arthropathy can be temporarily managed by the use of physiotherapy and medications. Coxa vara deformity may sometimes involve the hip and spine, in which case hip replacement may be required. In cases of severe pericarditis where constrictive heart failure is likely, a pericardiectomy may be necessary.
Hammoudeh and Siam (1993) reported a 14-year old male patient who presented with hand and feet deformities, knee swelling, and joint movement limitation. He had flexion deformities in his fingers since at least the age of 4-years. Upon examination, he was found to have flexion contractures in the elbows and proximal IP joints of the fingers and toes, swelling with synovial thickenings in the wrists, limited hip motion, and swollen knees with effusion and mild flexion contractures. Synovial biopsy revealed hyalinization of the stroma and a few giant cells. There was no sign of inflammation. Soft tissue swellings in the absence of any erosions or osteoporosis was evidenced in the knee and wrist X-rays. Three years later, the patient's neonate brother also presented with finger contractures. An aunt was also reported to have had finger deformities and knee swelling. Three other female siblings of these patients were normal.
Alazami et al. (2006) examined seven newly diagnosed childhood patients with CACP syndrome, hailing from four unrelated families of Saudi origin. Five novel mutations in the PRG4 gene were uncovered, including four frameshift deletions and one nonsense mutation. No genotype/phenotype association was observed.
Bahabri et al. (1998) studied four new patients and four previously reported patients who presented with congenital camptodactyly and developed large joint arthropathy during childhood. They compared the clinical features of these eight patients, aged 2 to 15 years, with those of 21 previously reported patients. Seven of these children developed bilateral coxa vara deformity, while one developed coxa magna with cystic erosions. Clinical pericarditis occurred in two of their eight patients and in 40% of published cases. All their patients, from four unrelated kindreds, had consanguineous parents. Genome wide linkage analysis demonstrated that all patients were homozygous for a contiguous series of markers on 1q, compatible with homozygosity by descent. Affected patients from two of the four kindreds had an identical haplotype within this region, compatible with a shared common ancestor. The regions of homozygosity overlapped at a 1.9-cM interval defined by D1S2701 and D1S222. Using fully informative markers within this interval, a lod score of 3.3 at theta = 0.0 was obtained. Therefore, Bahabri et al. (1998) concluded that a locus for the autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome resides on chromosome 1q25-q31.
Al-Mayouf (2007) undertook a retrospective review of children who presented with arthropathy and a positive family history of a similar condition between 1990 and 2005 in a tertiary hospital in Saudi Arabia. Of the 62 patients thus identified, 16 (11 males, 5 females) were diagnosed with CAC Syndrome. These included patients that were studied by Bahabri et al. (1998) and Alazami et al. (2006). The patients came from eight unrelated families. Parents of all patients were consanguineous. Camptodactyly presented at birth or very soon after. Two patients showed signs of pericarditis.
Albuhairan and Al-Mayouf (2013) reviewed medical records of all the children with CACP syndrome seen between June 1990 and June 2012 at King Faisal Specialist Hospital and Research Center, Riyadh. Twenty-two patients (including 15 boys) with mean age at diagnosis 3.7 (1-14) years, were included in this cohort study. The referral diagnosis was inaccurate in all patients; juvenile idiopathic arthritis (JIA) was the referral diagnosis in majority of the patients. Six families had more than one affected child. Camptodactyly and large joints arthropathy were present in all the cases. Camptodactyly was observed in the neonatal period in all the patients, while other joint involvement was observed through the 1st year of life. All patients had a normal cardiac evaluation, but two children had evidence of pericarditis. All patients had normal inflammatory markers and the result for rheumatoid factor test was negative. Radiological findings included coxa vara with a short femoral neck and flat, irregular femoral heads and intra-osseous cysts, increased joint space, and abnormal modeling of the acetabulum with small iliac wings. Other joints (knees, ankle, elbow and wrist) showed soft-tissue swelling consistent with thick cartilage and abnormal modeling with evidence of intra-articular fluid in majority of the patients. Synovial biopsy from three patients revealed proliferating synovial epithelium with moderate fibro-collagenous densities and multinucleated giant cells, occasional lymphocytes or neutrophils were identified. All patients were referred to while they were on NSAIDs, 10 patients used antirheumatic drugs (prednisone and methotrexate) and two patients were treated with etanercept. In all patients, treatment was ineffective apart from mild pain relief.
A consanguineous family with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) in UAE has been studied by Akawi et al. (2012). The family had many affected individuals with congenital camptodactyly and arthropathy. Additionally, all of these patients lacked pericarditis, and one of them was born with bilateral cataract; this latter symptom has never been reported before in patients with CACP. All coding exons and splice sites of the PRG4 gene were sequenced and a novel mutation was identified by the researchers; an insertion of a cytosine (c.1320dupC) in the highly repetitive stretch of the coding region of the gene. This insertion results in a frameshift and a premature termination codon (p.P440fsX197), which is likely to produce a nonfunctional protein.