Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome

A number sign (#) is used with this entry because of evidence that the camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) can be caused by homozygous mutation in the proteoglycan-4 gene (PRG4; 604283) on chromosome 1q31.

Description

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome is an autosomal recessive condition characterized by the association of congenital or early-onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions are found in some patients (summary by Faivre et al., 2000).

Clinical Features

Jacobs and Downey (1974) and Jacobs et al. (1976) described in brief a familial arthropathy associated with congenital flexion contractures of the fingers and characteristic changes on synovial biopsy. They called it 'E family arthritis,' or 'congenital familial hypertrophic synovitis.' They studied 4 cases from 2 families. Jacobs' first family was American black and the second Pakistani (Jacobs, 1981).

Athreya and Schumacher (1978) reported the condition in the first, third, and fifth sibs of a 5-sib family born to parents who were not known to be related, but came from the same small village in Ireland. The first sib, a girl aged 16 at study, was born with flexion deformity of the right middle finger and developed polyarticular large joint arthritis in early infancy. The finger straightened spontaneously as she got older. The second affected sib, a boy aged 14, had flexion deformity of the thumb at birth which was corrected surgically. He also had symmetric swelling of multiple large joints with normal sedimentation rate. He had synovectomy of both hip joints at age 6. The youngest affected sib, a girl aged 4, was born with a flexed right middle finger. At age 2, she developed painless swelling of both knees and 2 years later of both ankles. She complained intermittently of hip pain and had generalized morning stiffness. Histologically, the synovium showed hyperplasia, necrotic villi, deposition of eosinophilic and PAS-positive material, and many multinucleate giant cells.

Ochi et al. (1983) reported 2 sisters in whom several tenosynovectomies of the hands and synovectomy of the knee joints were performed to maintain mobility of affected joints. Abnormalities in tendons were restricted to the tenosynovium, with secondary involvement of tendons which in late stages were replaced by fibrous tissue. They suggested that the disorder is the result of an intrauterine tenosynovitis.

In Newfoundland, Martin et al. (1985) observed an affected brother and sister and 2 other unrelated patients. Flexion contractures of the fingers were present at birth. There was synovial cell hyperplasia and giant cells but no inflammatory process. X-rays showed flattening of the metacarpal and metatarsal heads and the proximal femoral ossification centers. In the oldest patient the process had subsided, leaving slight contractures but severe impairment of hip mobility. It is likely that the familial syndrome of arthropathy, camptodactyly and pericarditis is the same disorder.

Martinez-Lavin et al. (1983) described a family from a small village in southern Mexico in which 5 of 7 sibs had constrictive pericarditis in association with arthritis of large joints and flexion contracture of the fingers. Parental consanguinity was denied, but the parents shared the haplotype A1-Bw21. The proband was well until age 8 years when she developed enlargement of the right knee and exertional dyspnea. At age 9 she was found to have bilateral contracture of the fifth fingers due to fixation of the flexor tendons at the level of the proximal interphalangeal joints and swollen wrists, elbows and knees, as well as signs of pericardial constriction. Echocardiogram showed large pericardial effusion. After failure of response to empiric antituberculous therapy and prednisone, pericardiectomy was performed. The pericardium was markedly thickened, and fibrosis was demonstrated histologically. The circulatory problem was corrected, but the arthritis and camptodactyly were unchanged. A second sib had onset of flexion contractures of the fingers at age 12 years. Synovial biopsy of the right knee showed prominent fibrosis with mild inflammatory cell infiltration. He did not have pericardial involvement. A third sib had onset of joint and pericardial manifestations at age 4 years. Pericardiectomy was performed at age 6 with relief of symptoms. A fourth sib had onset of wrist and knee swelling at age 4 years. Although asymptomatic, examination showed signs of constrictive pericarditis for which pericardiectomy was performed with relief. A fifth sib, aged 4 years, had swollen knees and ankles without tenderness and flexion contractures of both thumbs but no signs of pericardial involvement. Histoplasmin skin tests were negative in the proband and fourth sib but positive in the second and third sibs mentioned above. Mulibrey nanism (253250), a clinically quite different disorder, has constrictive pericarditis as a consistent feature.

From Istanbul, Turkey, Bulutlar et al. (1986) reported this disorder in 4 sisters. In addition to pericarditis and contractures of the elbows and wrists, all 4 had coxa vara. Three were teenagers; the fourth was aged 7 years. Camptodactyly and trigger finger were described. The oldest required pericardiectomy at age 13; histologic studies showed chronic nonspecific pericarditis. In 2, livedo reticularis of the legs was described.

Laxer et al. (1986) reported a single case in a 5-year-old French-Canadian boy who was born with camptodactyly and developed painful swelling of the knees and ankles at age 18 months. Pericarditis developed at age 5. The parents were distant cousins.

Verma et al. (1995) used the designation 'familial fibrosing serositis' for the disorder they described in 2 sisters with fibrosing pleuritis, pericarditis, and synovitis with infantile contractures of fingers and toes. The family came from northern India. The illness began at age 6 months in the younger sister, and by 2 years of age all her fingers and toes were deformed. Starting at age 9, she had recurrent left pleuritic chest pain and abdominal distention. At the age of 10 years, pericardiectomy was performed for pericardial constriction. The older sister had a strikingly similar disorder. At the age of 14 years, she had pleural pericardial effusion, which did not respond to antituberculous therapy given empirically. She showed severe contractures of the toes with a round foot deformity, flexion contractures of all fingers and both elbows, and bilateral swelling and tenderness of the wrist, knee, and ankle joints. Pericardiectomy was also necessary in the older sister. Verma et al. (1995) noted that it may be significant that the younger sister had mitral valve prolapse with mitral regurgitation. Verma et al. (1995) differentiated 4 types of familial arthropathies: (1) noninflammatory arthropathy, congenital flexion contractures of the fingers, and synovial hyperplasia with a large number of multinucleated giant cells, as reported by Jacobs et al. (1976), Athreya and Schumacher (1978), and Ochi et al. (1983); (2) familial arthritis and camptodactyly with inflammatory changes in synovial biopsy specimens, later onset of camptodactyly, iridocyclitis, elevated ESR, and erosive changes, as described by Malleson et al. (1981) and Gigante et al. (1990); see 108050; (3) Blau syndrome (186580), a syndrome of familial granulomatous arthritis, uveitis, rash and camptodactyly; and (4) the camptodactyly arthropathy pericarditis (CAP) syndrome, described by Martinez-Lavin et al. (1983) and Bulutlar et al. (1986), as well as by Laxer et al. (1986). Verma et al. (1995) concluded that the sisters they studied were in the fourth category.

Suwairi et al. (1997) and Bahabri et al. (1998) evaluated 4 new patients and 4 previously reported patients who presented with congenital camptodactyly and developed large joint arthropathy during childhood. They compared the clinical features of these 8 patients, aged 2 to 15 years, with those of 21 previously reported patients. Coxa vara deformity occurred in all 8 of their patients and in 60% of published cases. Clinical pericarditis occurred in 2 of their 8 patients and in 40% of published cases. All 8 of their patients, from 4 different kindreds, were products of consanguineous marriages.

Studying 12 CACP syndrome patients from 8 unrelated families, Faivre et al. (2000) emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies supported genetic homogeneity of the disorder.

Yilmaz et al. (2018) described the clinical findings of CACP syndrome in 35 patients from 11 unrelated families, 10 of which were from the southeast region of Turkey. Consanguinity was noted in 9 of the 11 families. Median age was 16 years and mean follow-up duration was 7.8 years. Age at diagnosis ranged from 1 to 52 years. Seven families had more than 1 affected subject. Camptodactyly of the hands was the first sign seen in most patients (68%). Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Increased levels of pain were noted after the age of 10 years, with severe hip involvement after age 20. All patients had developmental coxa vara, and 7 (22%) had pleural effusion, ascites, and/or pericarditis. Mitral regurgitation or mitral valve prolapse was seen on echocardiography in 4 patients. There was a significant correlation between age of the patient and the number of clinical features, consistent with features being related to cumulative mechanical stress over time.

Mapping

By linkage studies in 4 kindreds with autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Suwairi et al. (1997) and Bahabri et al. (1998) demonstrated that all patients were homozygous for a contiguous series of markers on 1q, compatible with homozygosity by descent. Affected patients from 2 of the 4 kindreds (both from Saudi Arabia) 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, Suwairi et al. (1997) and Bahabri et al. (1998) concluded that a locus for the disorder resides on chromosome 1q25-q31.

Molecular Genetics

In 6 unrelated patients with CACP, Marcelino et al. (1999) identified homozygous mutations in the PRG4 gene, including 4 frameshifts, 1 insertion, and 1 nonsense mutation (604283.0001-604283.0006).

Yilmaz et al. (2018) performed whole-exome sequencing in 28 patients with CACP syndrome and identified 11 mutations in the PRG4 gene, including 9 novel mutations, which were confirmed by Sanger sequencing. The mutations were homozygous in 9 and compound heterozygous in 2 families. In this cohort, 6 frameshift mutations, 2 nonsense mutations, and the first case of a homozygous deletion of a complete exon (604283.0007) were identified. All of the mutations were predicted to abolish the functions of both copies of the PRG4 protein. Yilmaz et al. (2018) noted that of the 38 known CACP disease-causing mutations in PRG4, 70% are in exon 6, with the rest being distributed in other exons.