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Progressive pseudorheumatoid dysplasia: a case series report.

ABSTRACT: rogressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, noninflammatory arthropathy. Several cases have been reported worldwide; however, diagnosis remains challenging. Three unrelated children with PPRD were retrospectively studied. All three patients in this study were initially misdiagnosed. The misdiagnoses included juvenile rheumatoid arthritis, myodystrophy and idiopathic short stature. The time from the onset of symptoms to a definitive diagnosis was 3 to 8 years. Clinical signs and radiological phenotypes were analyzed carefully, and they were all consistent with the characteristics of PPRD and noninflammatory polyarticular enlargement. The small joints of both the hands and lower limbs are the most affected. The imaging findings of the patients were flat vertebrae with beak- or bullet-like changes in front of the cone and peripheral metaphysis widening. DNA samples obtained from the family were sequenced to identify the causal gene using whole-exome sequencing (WES). Four Wnt1-inducible signaling pathway protein 3 (WISP3) mutations were verified. c.271delC was not reported previously. The other three mutations, namely, c.136C>T (p. Gln46*), c.667T>G (p. Cys223Gly) and c.589+2T>C, were previously identified. All three patients had a long journey to diagnosis. Early genetic diagnosis can help prevent unnecessary treatments and procedures in patients. Growth hormone is not a good choice for treatment.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8349966 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Progressive pseudorheumatoid dysplasia misdiagnosed as juvenile idiopathic arthritis: a case report.

Project description:BackgroundProgressive pseudorheumatoid dysplasia is a rare, autosomal recessively inherited, noninflammatory musculoskeletal disorder caused by mutations occurring in the WNT1-inducible signaling pathway protein 3 gene. Joint cartilage is the primary site of involvement, leading to arthralgia, joint stiffness, contractures, enlargement of the epiphyses and metaphysis of the hand joints, spinal abnormalities, short stature, early osteoarthritis, and osteoporosis. Juvenile idiopathic arthritis is the most common chronic rheumatic disease in childhood and has unknown etiology. Clinical features of progressive pseudorheumatoid dysplasia resemble those of juvenile idiopathic arthritis. Patients with progressive pseudorheumatoid dysplasia are usually misdiagnosed as having juvenile idiopathic arthritis.Case presentationA 13-year-old Yemeni female presented to the rheumatology clinic with a history of joint pains, bone pains, and bone deformity for 7 years. Weight and height were below the third percentiles. There was no tender swelling of metacarpophalangeal and interphalangeal joints, and she presented with scoliosis. Radiographs of the hands revealed the widening of the epiphyses. Progressive pseudorheumatoid dysplasia was suspected, and genetic testing for WNT1-inducible signaling pathway protein 1, 2, and 3 was requested with these findings. A homozygous, likely pathogenic variant was identified in the WNT1-inducible signaling pathway protein 3 gene, which confirmed our diagnosis.ConclusionProgressive pseudorheumatoid dysplasia is a rare form of spondyloepimetaphyseal dysplasia and is clinically misdiagnosed as juvenile idiopathic arthritis. It is crucial to consider progressive pseudorheumatoid dysplasia, especially in patients with standard inflammatory markers who are being followed up for juvenile idiopathic arthritis and not improving with antirheumatic intervention.

| S-EPMC8576979 | biostudies-literature

Progressive Pseudorheumatoid Dysplasia of Childhood (PPRD)-A Case Series with Recurrent c.740_741del Variant.

Project description:Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive arthropathy, affecting school-aged children. It is characterized by progressive degeneration of the articular cartilage. The majority of the pathogenic variations are found in exon 2, exon 4, and exon 5 of the putative gene, CCN6 (WISP3). Three unrelated individuals with clinical diagnosis of PPD were included in this study. Detailed clinicoradiological evaluation was attempted with brief literature review. Exome sequencing was performed in all three cases. All the pathogenic variations detected in our cohort were located in exons 2 and 4 of WISP3 gene. Though the clinicoradiological features are already well described, this study in north India highlights the occurrence of a recurring pathogenic variant. The c.740_741del variant was a recurrent pathogenic variant seen in all three patients in this cohort. This may be a common pathogenic variant in the North Indian population; however, a larger cohort needs to be studied before drawing final conclusions. A proper molecular diagnosis is a must to end the diagnostic odyssey, safeguarding patients with PPRD from unnecessary use of drugs like corticosteroids.

| S-EPMC10984709 | biostudies-literature

Ilizarov technique in an adolescent patient with progressive pseudorheumatoid dysplasia: A case report.

Project description:Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive inherited disease that causes severe systemic joint deformity and articular dysfunction in young patients.Ilizarov technique treatment in PPD patients has never been reported before.A 17-year-old male patient presented with a 10-year history of polyarthritis and 4-year history of progressive hip and knee pain and stiffness. Genetic testing for the WISP3 gene was done and showed compound heterozygous mutations: NM_198239.1 (WISP3):c.1064_1065dupGT (p.Gln356ValfsTer33) and NM_198239.1 (WISP3):c.643+2T?>?C.Taking his young age into consideration, the Ilizarov external fixation technique was adopted for the treatment of the deformity in knees.One year after the operation, the improvement of joint deformity was satisfactory.The Ilizarov technique is economical and less invasive, and most importantly, it can delay the possible arthroplasty. It gives young PPD patients with arthropathy an alternative treatment.

| S-EPMC6081158 | biostudies-literature

Case Report: Recurrent Variant c.298 TA in CCN6 Gene Found in Progressive Pseudorheumatoid Dysplasia Patients From Patni Community of Gujarat: A Report of Three Cases

Project description:Biallelic mutations in the CCN6 gene are known to cause a rare genetic disorder—progressive pseudorheumatoid dysplasia (PPD). PPD is characterized by distinct joint deformities of interphalangeal joints, stiffness, gait disturbance, abnormal posture, and absence of inflammation, resulting in significant morbidity. The largest case series of PPD from India suggests c.233G>A and c.1010G>A to be the most common mutations in the CCN6 gene, although the distribution of these variants among endogamous communities in India has not been carried out. We here report three cases of PPD from three independent families belonging to the Patni community of Gujarat, a community known to practice endogamy. All three cases had short stature, gait disturbance, scoliosis, and interphalangeal joint deformities. Analysis by whole-exome sequencing in the first case showed the presence of a previously known, homozygous, missense variant c.298T>A (p.Cys100Ser) in exon 3 of the CCN6 gene in all cases. Due to all three families belonging to the same community, analysis by Sanger sequencing in the remaining two cases for the variant mentioned earlier showed both cases to be of homozygous mutant genotype. Unaffected family members, i.e., parents and siblings, were either heterozygous carriers or wildtype for the said variant. The present case series is the first report of a recurrent variant occurring across multiple PPD-affected individuals from unrelated families belonging to the same community from India.

| S-EPMC8505801 | biostudies-literature

Fine mapping of progressive pseudorheumatoid dysplasia: a tool for heterozygote identification.

Project description:Progressive pseudorheumatoid dysplasia is a skeletal genetic disorder affecting primarily the articular cartilage, causing joint stiffness and leading to a crippling status. More than two-thirds of the reported patients belong to Arab and Mediterranean populations. The disease locus has been mapped to chromosome 6q22 in a region of 12.9 cM using a Jordanian family. We examined two additional families, one Jordanian and one Palestinian, to test for homogeneity of the disorder and the presence of a common haplotype, to fine map the disorder, and to use all the information to derive a tool for heterozygote identification. The two families showed linkage to the same previously reported locus, thus suggesting homogeneity, but they did not share a common haplotype. They also provided information that refined the genetic region for the disease locus to 2.1 cM with three microsatellite markers. The absence of a common haplotype indicates that no common ancestor mutations were inherited by our patients. Genotyping for the three-marker haplotype showed that it can be used as a heterozygote identification tool.

| S-EPMC6141022 | biostudies-literature

WISP3 mutational analysis in Indian patients diagnosed with progressive pseudorheumatoid dysplasia and report of a novel mutation at p.Y198.

Project description:ObjectivesTo determine the pattern of mutations of the WISP3 gene in clinically identified progressive pseudorheumatoid dysplasia (PPD) in an Indian population.Patients and methodsA total of 15 patients with clinical features of PPD were enrolled in this study. Genomic DNA was isolated and polymerase chain reaction performed to amplify the WISP3 gene. Screening for mutations was done by conformation-sensitive gel electrophoresis, beginning with the fifth exon and subsequently proceeding to the remaining exons. Sanger sequencing was performed for both forward and reverse strands to confirm the mutations.ResultsIn all, two of the 15 patients had compound heterozygous mutations: one a nonsense mutation c.156C>A (p.C52*) in exon 2, and the other a missense mutation c.677G>T (p.G226V) in exon 4. All others were homozygous, with three bearing a nonsense mutation c.156C>A (p.C52*) in exon 2, three a missense mutation c.233G>A (p.C78Y) in exon 2, five a missense mutation c.1010G>A (p.C337Y) in exon 5, one a nonsense mutation c.348C>A (p.Y116*) in exon 3, and one with a novel deletion mutation c.593_597delATAGA (p.Y198*) in exon 4.ConclusionWe identified a novel mutation c.593_597delATAGA (p.Y198*) in the fourth exon of the WISP3 gene. We also confirmed c.1010G>A as one of the common mutations in an Indian population with progressive pseudorheumatoid dysplasia.Cite this article: V. Madhuri, M. Santhanam, K. Rajagopal, L. K. Sugumar, V. Balaji. WISP3 mutational analysis in Indian patients diagnosed with progressive pseudorheumatoid dysplasia and report of a novel mutation at p.Y198* Bone Joint Res 2016;5:301-306. DOI: 10.1302/2046-3758.57.2000520.

| S-EPMC4957178 | biostudies-literature

Novel <i>WISP3</i> mutations causing progressive pseudorheumatoid dysplasia in two Chinese families.

Project description:Progressive pseudorheumatoid dysplasia (PPD) is a rare disease caused by mutations in the gene for Wnt1-inducible signaling pathway protein 3 (WISP3). Here, we report the clinical and radiographic manifestations of two Chinese PPD patients. We performed whole-exome sequencing for one patient and sequenced the WISP3 for the other. Three WISP3 mutations (c.396T>G, c.721T>G and c.679dup) were identified; the two missense mutations were novel. Our study expanded the WISP3 mutation spectrum.

| S-EPMC5143363 | biostudies-literature

Novel and recurrent mutations of WISP3 in two Chinese families with progressive pseudorheumatoid dysplasia.

Project description:BackgroundThe WNT1-inducible signaling pathway protein 3 (WISP3), which belongs to the CCN (cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed) family, is a secreted cysteine-rich matricellular protein that is involved in chondrogenesis, osteogenesis and tumorigenesis. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230), an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism.Methodology/principal findingsFour PPD patients from two unrelated Chinese families were recruited for this study. The clinical diagnosis was confirmed by medical history, physical examinations, laboratory results and radiological abnormalities. WISP3 mutations were detected by direct DNA sequence analysis. In total, four different mutations were identified, which consisted of two missense mutations, one deletion and one insertion that spanned exons 3, 5 and 6 of the WISP3 gene. One of the missense mutations (c.342T>G/p.C114W) and a seven-base pair frameshift deletion (c.716_722del/p.E239fs*16) were novel. The other missense mutation (c.1000T>C/p. S334P) and the insertion mutation (c.866_867insA/p.Q289fs*31) had previously been identified in Chinese patients. All four cases had a compound heterozygous status, and their parents were heterozygous carriers of these mutations.Conclusions/significanceThe results of our study expand the spectrum of WISP3 mutations that are associated with PPD and further elucidate the function of WISP3.

| S-EPMC3369844 | biostudies-literature

Novel homozygous variant in <i>WISP3</i> in a family with unrecognized progressive pseudorheumatoid dysplasia.

Project description:We present the use of whole-genome sequencing to correctly diagnose progressive pseudorheumatoid dysplasia in patients with atypical clinical and radiologic findings and prior diagnosis of juvenile idiopathic arthritis.

| S-EPMC7455413 | biostudies-literature

The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling.

Project description:In humans, loss-of-function mutations in the gene encoding Wnt1 inducible signaling pathway protein 3 (WISP3) cause the autosomal-recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD). However, in mice there is no apparent phenotype caused by Wisp3 deficiency or overexpression. Consequently, the in vivo activities of Wisp3 have remained elusive. We cloned the zebrafish ortholog of Wisp3 and investigated its biologic activity in vivo using gain-of-function and loss-of-function approaches. Overexpression of zebrafish Wisp3 protein inhibited bone morphogenetic protein (BMP) and Wnt signaling in developing zebrafish. Conditioned medium-containing zebrafish and human Wisp3 also inhibited BMP and Wnt signaling in mammalian cells by binding to BMP ligand and to the Wnt coreceptors low-density lipoprotein receptor-related protein 6 (LRP6) and Frizzled, respectively. Wisp3 proteins containing disease-causing amino acid substitutions found in patients with PPD had reduced activity in these assays. Morpholino-mediated inhibition of zebrafish Wisp3 protein expression in developing zebrafish affected pharyngeal cartilage size and shape. These data provide a biologic assay for Wisp3, reveal a role for Wisp3 during zebrafish cartilage development, and suggest that dysregulation of BMP and/or Wnt signaling contributes to cartilage failure in humans with PPD.

| S-EPMC1964511 | biostudies-literature

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