[Clinical diagnosis and WISP3 gene mutation analysis for progressive pseudorheumatoid dysplasia]

Progressive pseudorheumatoid dysplasia (PPD) (MIM#208230) is a rare autosomal recessive disease of cartilage homeostasis characterized by axial and peripheral skeletal dysplasia. Analysis of WISP3 (Wnt1-inducible signaling pathway protein 3, MIM#603400) gene mutation can confirm the clinical and radiographic diagnosis for PPD. This study aimed to recognize PPD based on clinical manifestations and imaging characteristics of bones, and to investigate the mutations of WISP3 gene in three patients with PPD.

Three male patients (9 - 16 years old) from three unrelated Chinese families, who presented with joint pain, swelling, deformities and motion limitation, were referred to this study. PPD was diagnosed on the basis of the clinical manifestations, imaging characteristics of bones and laboratory evaluation. All five exons and their exon/intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) from the peripheral blood DNA of three PPD family members, and mutation analysis was performed by bidirectional DNA sequencing.

(1) Three patients were diagnosed as PPD by characteristic evidences: all patients presented with non-inflammatory multiple joints swelling and stiffness including joints in hand and feet as they age. Radiographs showed platyspondyly, ovoid or wedged anterior end-plate of vertebral bodies, coxa vara, widened epiphyses or metaphyses including capital femoral, metacarpophalangeal, interphalangeal joints and metatarsals. Normal laboratory values were found for the erythrocyte sedimentation rate and C-reactive protein, rheumatoid factors, antinuclear antibodies etc. (2) The three different mutations of WISP3 gene were identified in three patients with PPD, including two small insert mutations (c.624_625insA, c.866_867insA), one was deletion mutation (c.729_735delGAGAAAA). The types of mutation of two alleles in three patients were c.624_625insA/c.729_735delGAGAAAA, c.624_625insA/c.866_867insA and c.866_867 insA/c.866_867insA, respectively. These mutations were found in exon 4 and exon 5 of WISP3 gene, accounting for 50%(3/6) respectively. All three different mutations were novel variations, and none of 3 novel variations was found in the 50 controls.

The characteristic evidences of PPD were non-inflammatory multiple enlarged joints (including hand and feet), limited movement, normal laboratory values such as rheumatoid factors. It is essential for making diagnosis to carefully examine the entire skeleton including spine. The characteristics of bone imaging are platyspondyly, widened epiphyses or metaphyses including large and small joints and narrow joint spaces. Three different novel variations of WISP3 gene were identified in three PPD patients, they are c.624_625insA, c.866_867insA and c.729_735delGAGAAAA. Each of novel mutations is insert or deletion mutation.