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

Background Progressive 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 presentation A 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. Conclusion Progressive 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.

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

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.

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

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.

AB0779 CAN INFLAMMATION COEXIST IN PATIENTS WITH PROGRESSIVE PSEUDORHEUMATOID DYSPLASIA?

Background:Progressive pseudorheumatoid dysplasia(PPRD) is considered as a degenerative genetic bone disorder. It is caused by loss of function mutation in WNT-1 inducible signaling pathway protein-3(WISP-3)1. WISP-3 gene function is required for the normal function of cartilage and skeletal development. The patients are normal at birth and start developing symptoms around 3-6 years of age2. The disease is characterised by stiffness, pain, deformity due to enlargement of the ends of short and long bones. Often, such patients are misdiagnosed as Juvenile idiopathic arthritis(JIA). In general, PPRD being considered as non-inflammatory disease, immunosuppressants or disease modifying anti rheumatic drugs(DMARDS) like methotrexate treatment are not used for treatment.Objectives:We report a patient with characteristic findings of PPRD but with coexisting clinical and imaging evidence of inflammation.Methods:16 year old male boy born of third degree consanguineous asymptomatic parents presented with progressive swelling, deformity of bilateral small and large joints of upper and lower limbs. He also had pain in both hip and knee for past two years. Pain is associated with difficulty in walking and squatting. On examination he had bony enlargement around bilateral elbow, wrist, proximal and distal interphalangeal joints(Figure 1A). He also had restriction of bilateral hip movements and swelling of bilateral knee with effusion. He had exaggerated lumbar lordosis and flexion deformity of bilateral hip, knee. His blood counts, ESR, CRP were normal. Analysis of Knee joint synovial fluid showed cell count of 200/mm3 with no crystals and sterile culture. USG knee showed evidence of synovial thickening with increased power Doppler signals. Skeletal survey showed typical findings of PPRD with enlargement of epiphysis and osteoarthritis changes(Figure 1B). MRI hip showed minimal effusion, synovial thickening, edema with STIR hyperintensity and enlargement of bilateral femoral epiphysis. MRI knee showed minimal effusion, marrow edema in patella(Figure 1C, arrow head), femoral condyle, diffuse synovial thickening with contrast enhancement(Figure 1D, arrow) and deformed patellar contour. Immunological tests showed negative RF, ACPA and positive ANA(Hep2) speckled 4+. Immunoblot for ENA was negative. His ophthalmological evaluation showed no evidence of uveitis.Figure 1.Clinical picture showing typical hand deformity and swelling at bone ends(A), hand radiograph showing epiphyseal enlargement(B), MRI knee T2 STIR showing bone marrow edema(arrow head) in patella(C) and synovial thickening(arrow) with contrast enhancement in fat saturated T1 MRI with contrast.Results:Patient tested positive for homozygous mutation in WISP-3 gene. He was treated with ibuprofen and supportive measures. Orthopedic consultation obtained and planned for hip, knee replacement during follow up. Follow up imaging and acute phase response was advised after three months.Conclusion:Although PPRD was classically described as a degenerative disease, the findings presented in our case show coexisting inflammation. Bone marrow edema in weight bearing areas, synovial effusion may be explained as part of cartilage degeneration like in osteoarthritis but synovial hypertrophy with contrast enhancement, power Doppler signals in ultrasound, ANA positivity may be signs of coexisting inflammatory or autoimmune phenomenon.References:[1]Hurvitz JR, Suwairi WM et al. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet. 1999 Sep;23(1):94-8. doi: 10.1038/12699. PMID: 10471507.[2]Garcia Segarra N, Mittaz L et al. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):217-29. doi: 10.1002/ajmg.c.31333. Epub 2012 Jul 12. PMID: 22791401.Disclosure of Interests:None declared

A Retrospective Study of Nine Patients with Progressive Pseudorheumatoid Dysplasia: To Explore Early Diagnosis and Further Treatment

Background: Most patients with progressive pseudorheumatoid dysplasia (PPRD) are initially misdiagnosed because of disease rarity and lack of awareness by most clinicians. The purpose of this present study was to provide further early diagnostic options and potential treatment to patients with PPRD. Methods: This was a retrospective study. Clinical manifestations, laboratory test results, radiographic features, Sanger Sequencing to determine CCN6 gene variants, treatment and follow-up records were collected in the patients with PPRD. Time to diagnosis, phenotype and genotype correlation were analyzed. Results: Nine PPRD children were included. There were 3 pairs of siblings and one patient had parental consanguinity. Five patients were misdiagnosed as juvenile idiopathic arthritis (JIA). The onset of disease in 8 patients was between 3 to 6 years of age. The interval from onset of symptoms to obtaining the diagnosis for 8 of the patients varied from 3.6 years to 20 years. The onset of symptoms included enlarged and stiff interphalangeal joints of the fingers, gait disturbance or joint pain. Laboratory tests revealed normal range of inflammatory parameters. Serum levels of 25-hydroxyvitamin D3 in six patients were below the normal range. Radiographic findings included different degree of abnormal vertebral bodies, epiphyseal enlargement of the interphalangeal joints with juxta-articular osteopenia, or cyst-like structures femoral head. All the patients harbored CCN6 variants, and a total of 7 variants were identified. After the treatment of calcitriol in 5 patients with low level of 25-hydroxyvitamin D3 for 1.25 years to 1.75 years, two of them kept stable, while 3 of them improved gradually. Conclusions: Combining the patient’s family history, clinical features presenting with abnormal gait or enlarged and stiff interphalangeal joints of the fingers, normal inflammatory markers, and the characteristic radiographic findings, we can obtain the clinical diagnosis of PPRD for the patients at a very early stage of the disease. Anterior blunt of the vertebral bodies could be an early radiological sign in the patient even without obvious clinical symptoms and characteristics yet. The patients with PPRD having c.624dupA variant in CCN6 may have delayed onset. Underlying vitamin D deficiency should be sought and corrected in patients with PPRD. Keywords: progressive pseudorheumatoid dysplasia; noninflammatory; articular cartilage; CCN6 gene variant; vitamin D deficiency