Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Abstract

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4 . Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2-23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910_1911del and c.2816_2817del) were identified in homozygous state in PRG4 . We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India.

Fig. 1

Hand radiographs of the patients (arranged chronologically) show camptodactyly in all. Wrist joint spaces are reduced in older individuals (P6, P9, P8 and P12). We observed delayed carpal ossification in P4, P10, P11 and P13. Squaring of metacarpals is more evident in P3, P6, P10 and P13. Flexion deformities at interphalangeal joints were noted in several individuals progressively.

Fig. 2

Pelvic radiographs of the patients at different ages (arranged chronologically) demonstrate short femoral neck and coxa vara in all. Small iliac wings were seen in P1, P2, P8 and P9. Hip joint space is reduced in older patients. Narrow sacrosciatic notch in P13. Intraosseous cysts are evident at acetabular surface in P2, P3, P5, P8, P10, P12 and P13 (white arrows).

Fig. 3. Knee radiographs show the progression of arthritis with age. An exostosis can be observed at the proximal end of left tibia in P3.

Fig. 4

(a) Cartoon illustration of the structure of the gene (PRG4) and (b) domains of PRG4 protein with biallelic disease-causing variants identified in individuals with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome in this study; novel variants are shown in red. HX, hemopexin-like repeats; SO, somatomedin-like domain.