Patients with progressive pseudorheumatoid dysplasia: From clinical diagnosis to molecular studies

Abstract

Abstract. Progressive pseudorheumatoid dysplasia (PPD) is a rare inherited autosomal recessive disease for which no prevalent data have been reported in China. We aimed to identify PPD based on clinical manifestations and imaging analysis of the bony skeleton and then to investigate gene mutations of Wnt1-inducible signaling pathway protein 3 (WISP3) in Chinese patients with PPD. Seven patients (aged 9-49 years) from six unrelated Chinese families all presented with a waddling gait, progressive swelling and restricted joint movements, and all were diagnosed as having PPD according to clinical signs and symptoms, as well as radiographic imaging. The radiographic imaging revealed no erosive arthropathy, but showed platyspondyly, irregular or wedged/ovoid anterior end-plates of the vertebral bodies, coxa vara and widened epiphyses or metaphyses including the femoral head and the metacarpophalangeal and interphalangeal joints. Normal laboratory values were found for the erythrocyte sedimentation rate, C-reactive protein and rheumatoid factors in all patients. Molecular studies revealed that five patients carried c.624_625insA/c.729_735delGAGAAAA, c.624_625insA/ c.866_867insA, c.866_867 insA/c.866_867insA, Q46X/ C114W and C223G/C114W mutations, respectively. In conclusion, our findings suggest that in order to avoid misdiagnosis, physicians should carefully examine the entire skeleton, including the spine, in addition to the skeletal extremities. Mutation analysis of the WISP3 gene is useful for confirming the clinical and radiographic diagnosis of PPD.

Delayed-onset of progressive pseudorheumatoid dysplasia in a Chinese adult with a novel compound WISP3 mutation: a case report

“…We found that the proband carried a frameshift mutation (c.670dupA) and a nonsense mutation (c.756C > A, p.Cys252*) in exon 4 of WISP3 (Fig. 2a, b), which have been reported previously [7, 8]. Furthermore, the frameshift mutation (c.670dupA) was found in the paternal allele (Fig.…”

“…Subsequently, a total of 18 WISP3 mutations located in exons 2 to 5 have been described in China (Table 1) [2, 7, 8, 11–15]. They include five different mutations (two frameshift mutations and one nonsense mutation) located in exons 2 and 3 (two missense mutations), respectively, as well as five mutations in exon 5 (three frameshift mutations, one nonsense mutation and one missense mutation).…”

“…They include five different mutations (two frameshift mutations and one nonsense mutation) located in exons 2 and 3 (two missense mutations), respectively, as well as five mutations in exon 5 (three frameshift mutations, one nonsense mutation and one missense mutation). To date, 8 WISP3 gene mutations in exon 4 (c. 624delA, c.624_625insA, c.667 T > G, c.679dupA, c.716_722delAAATGAG, c.721 T > G, c.727_733delGAGAAAA, c.756C > A) have been identified in the Chinese population [7, 8, 13, 14]. …”

“…To date, 8 WISP3 gene mutations in exon 4 (c. 624delA, c.624_625insA, c.667 T > G, c.679dupA, c.716_722delAAATGAG, c.721 T > G, c.727_733delGAGAAAA, c.756C > A) have been identified in the Chinese population [7, 8, 13, 14]. …”

A genotyping assay for missense mutation in WISP3 gene associated with childhood onset pseudorheumatoid arthropathy

“…WISP3 gene spans over 5 exons and encodes several functional domains each corresponding to one of the exons. Exon 1 encodes a peptide sequence that plays role in Wisp secretion (7,(10)(11)(12); exon 2 codes for insulin-like growth factor binding proteins (IGFBPs) that contains twelve cysteine residues (7,10,12-15); exon 3 encodes a cysteine rich, von Willebrand factor type C repeat domain (10,11,13,15); exon 4 contains information for a thrombospondin type 1 domain biosynthesis (with six cysteine residues) that may bind to sulfated glycosaminoglycan's either at cell surfaces or in extracellular matrix (11,12,(15)(16)(17)(18); and exon 5 that encodes a cysteine knot domain comprised of ten cysteine residues possibly involved in dimerization and receptor binding (10)(11)(12)(14)(15)(16)(17)(19)(20)(21)(22)(23)(24). Until now, a number of mutations and polymorphisms were found throughout the WISP3 sequence with geographically localized origin ( Table 2).…”