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Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis., (© 2024 Wiley Periodicals LLC.)

Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive hereditary disease of very low prevalence. It is characterized by the affection of multiple joints, generating arthrosis and progressive deformities from a very young age, which significantly affect the quality of life of patients. Its diagnosis is only confirmed by genetic testing, and no specific pharmacological treatment is still available. In the case of hip involvement, one treatment option is arthroplasty. In this case report, we present a 15-year-old boy with bilateral coxarthrosis secondary to PPD who underwent bilateral total hip arthroplasty in two stages. We highlight the characteristics of this rare entity, the intraoperative findings, the functional outcomes, and the impact on quality of life.

Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients., Methods: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis., Results: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R 2  = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027)., Conclusions: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities., (© 2023. The Author(s).)

Objectives: Progressive pseudorheumatoid dysplasia (PPRD) is a spondyloepiphyseal dysplasia caused by biallelic variants in CCN6. This study aimed to describe the early signs and follow-up findings in 44 Turkish PPRD patients., Methods: The patients with progressive stiffness of multiple joints, characteristic wide metaphysis of interphalangeal (IP) joints and platyspondyly were clinically diagnosed with PPRD. Fifteen patients who had first symptoms under 3 years of age were grouped as early-onset, while others were grouped as classical. CCN6 sequencing was performed in 43 patients., Results: Thirteen pathogenic/likely pathogenic variants were identified, five were novel. c.156C>A(p.Cys52*) variant was found in 53.3% of the families. The initial symptom in the early-onset group was genu varum deformity, while it was widening of IP joints in the classical group. The median age of onset of symptoms and of diagnosis was 4 and 9.7 years, respectively. The mean follow-up duration was 5.6 years. The median age of onset of IP, elbow, knee and hip stiffness, which became progressive with growth was 5, 9, 9 and 12.2 years, respectively. Waddling gait occurred in 97.7% of the patients. A total of 47.7% lost independent walking ability at the median age of 12 years. In the early-onset group, waddling gait occurred earlier than in classical group (P < 0.001). Two patients had atypical presentation with late-onset and mild or lack of IP involvement., Conclusion: We observed that genu varum deformity before the age of 3 years was an early sign for PPRD and almost half of the patients lost walking ability at the median age of 12 years., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal recessive non-inflammatory skeletal disease with childhood onset and is characterized by a progressive chondropathy in multiple joints, and skeletal abnormalities. To date, the etiopathological relationship between biological modification occurring in PPRD and genetic mutation remains an open issue, partially due to the limited availability of biological samples obtained from PPRD patients for experimental studies., Case Presentation: We describe the clinical features of a PPRD patient and experimental results obtained from the biological characterization of PPRD mesenchymal stromal cells (MSCs) and osteoblasts (OBs) compared to normal cell populations. Phenotypic profile modifications were found in PPRD compared to normal subjects, essentially ascribed to decreased expression of CD146, osteocalcin (OC) and bone sialoprotein in PPRD MSCs and enhanced CD146, OC and collagen type I expression in PPRD OBs. Gene expression of Dickkopf-1, a master inhibitor of WNT signaling, was remarkably increased in PPRD MSCs compared to normal expression range, whereas PPRD OBs essentially exhibited higher OC gene expression levels. PPRD MSCs failed to efficiently differentiate into mature OBs, so showing a greatly impaired osteogenic potential., Conclusions: Since all regenerative processes require stem cell reservoirs, compromised functionality of MSCs may lead to an imbalance in bone homeostasis, suggesting a potential role of MSCs in the pathological mechanisms of PPRD caused by WNT1-inducible signaling pathway protein-3 (WISP3) mutations. In consideration of the lack of compounds with proven efficacy in such a rare disease, these data might contribute to better identify new specific and effective therapeutic approaches., (© 2022. The Author(s).)

Objectives: 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 study was to provide further early diagnostic options and potential treatment to patients with PPRD., Methods: A retrospective study was performed by collecting and organizing clinical manifestations, radiographic features, laboratory test results, genetic test outcome, treatment, and follow-up records of the patients with PPRD. Age of diagnosis and genotype-phenotype correlation were further analyzed., Results: Nine PPRD children with causative CCN6 mutation were included. There were 3 pairs of siblings and 1 patient from inbred family. Five patients were primarily misdiagnosed as juvenile idiopathic arthritis (JIA). The interval between onset of symptoms and definite diagnosis of 8 patients varied from 3.6 to 20 years. Symptoms at the onset included enlarged and stiff interphalangeal joints of the fingers, gait disturbance, or joint pain. Laboratory tests revealed normal range of inflammatory parameters. Radiographic findings disclosed different degrees of abnormal vertebral bodies and epiphyseal enlargement of the interphalangeal joints. After the treatment of calcitriol in 5 patients with low level 25-hydroxyvitamin D3 for around 1.25 years to 1.75 years, 2 patients kept stable, while 3 of them improved gradually., Conclusions: Combining the patient's family history, clinical features, normal inflammatory markers, and the characteristic radiographic findings, the clinical diagnosis of PPRD for the patients could be obtained at very early stage of the disease. The patients with PPRD carrying c.624dupA variant in CCN6 may have delayed onset. Underlying vitamin D deficiency should be sought and corrected in patients with PPRD., (© 2021. International League of Associations for Rheumatology (ILAR).)

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., (© 2021. The Author(s).)

We report a 6-year-old girl with progressive bilateral conductive hearing loss for 2 years. She passed the newborn hearing screening conducted with otoacoustic emissions testing and had a normal development of speech and language, which indicated that her deafness was delayed-onset. She also had congenital proximal interphalangeal joints. Proximal symphalangism was confirmed by genetic testing ( NOG gene: c.406C > T, p.R136C). Bilateral stapes ankyloses were proved by surgery and her hearing was improved after stapedotomy by over 30 dB. Besides, this case should remind clinicians to carefully distinguish NOG gene-related deafness from congenital ossicular malformation and pediatric otosclerosis.

Background: Progressive pseudorheumatoid dysplasia (PPD) is a rare disease that causes musculoskeletal deformities. There has been no detailed report on the outcome of PPD patients who undergo total hip arthroplasty (THA). The aim of this study was to investigate the clinical and radiological outcome of PPD patients undergoing THA after middle-term follow-up., Methods: This was a medical records review study. Patients with the diagnosis of PPD who underwent THA were enrolled. The PPD diagnosis was confirmed by genetic sequencing. Baseline clinical data were retrieved. The patients were followed for the Harris Hip Score, visual analogue score, range of hip motion, and postoperative complication. Life quality was evaluated with the Short Form 36. Plain x-ray films were used for radiographic evaluation., Results: Four cases were identified from the patient database in our institute. All the patients presented arthropathy of both hips and underwent 1-stage bilateral THA. All the patients had WISP3 mutation after genetic sequencing. The cases were followed at average 47.9 months (range, 18-93 months). Harris Hip Score increased from 39.67 ± 9.73 points preoperatively to 91.67 ± 4.32 points postoperatively (p < 0.05); Short Form 36 increased from 19.67 ± 1.53 points preoperatively to 71.33 ± 3.06 postoperatively (p < 0.05). The hip range of hip motion was significantly improved after operation. X-ray films showed no obvious radiolucent lines or aseptic loosening at the latest follow-up., Conclusions: This study indicated that THA was effective to treat the PPD patients complicated with hip arthropathy with satisfactory clinical and radiological outcome after mid-term follow-up., Competing Interests: Bin Feng is currently receiving a grant from the National Natural Science Foundation in China (grant number 81871740). The authors declare that they have no other conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Historically, total meniscectomy was recommended as the treatment for a symptomatic discoid meniscus. Improved meniscal repair techniques and inferior long-term outcomes associated with meniscectomy have resulted in a trend toward meniscal preservation, with saucerization and repair of meniscocapsular tears. Reoperation rates after treatment of torn discoid menisci vary, with some series reporting high rates of reinjury and reoperation. The purpose of this study is to describe the intermediate-term outcomes of pediatric patients treated with saucerization and meniscocapsular repair of discoid lateral menisci with peripheral rim instability., Methods: A single-institution retrospective review was performed of consecutive patients less than 18 years of age treated with saucerization and repair for a meniscocapsular tear of a discoid lateral meniscus from 2013 to 2017. All patients had a minimum 24-month follow-up. A chart review was performed to describe tear location and repair type. The primary outcomes were revision meniscus surgery and Pedi-International Knee Documentation Committee and Tegner activity scores obtained at the final follow-up., Results: In total, 32 knees in 30 patients, including 15 males and 15 females with a mean age of 12 years (range, 5 to 17 y), were included. Tear patterns included anterior meniscocapsular (14 knees), posterior meniscocapsular (16 knees), and both anterior and posterior meniscocapsular (2 knees). Arthroscopic saucerization and meniscocapsular repair were performed in all knees. Repair types were outside-in (10 knees), inside-out (8 knees), all-inside (8 knees), and hybrid (6 knees). The mean follow-up was 54 months (range, 30 to 86 mo). Three knees (9%) underwent revision meniscus surgery, including 2 all-inside repairs and 1 partial meniscectomy. At the final follow-up, mean International Knee Documentation Committee score was 96 (range, 82 to 100). A total of 89% of patients reported returning to the same or higher level of activity following surgery., Conclusions: Saucerization of discoid lateral menisci with repair of meniscocapsular tears is associated with low rates of revision surgery and good intermediate-term outcomes., Level of Evidence: Level IV.

Background: Progressive pseudorheumatoid dysplasia is a rare skeletal dysplasia mainly caused by abnormal autosomal recessive inheritance. Although the main function of cartilage is mechanical support and the characteristics of this disease is the degradation of AC, previous studies on it had been mainly focused on clinical and genetic aspects and the mechanical behavior of the cartilage affected by PPRD is still ambiguous. In this study, we investigate the mechanics and structure of the cartilage suffered disease at multi-scale, from individual chondrocytes to the bulk-scale tissue., Methods: Depth-sensing indenter were employed to investigate the mechanics of cartilage; we performed atomic force microscope nanoindentation to investigate the cell mechanics and scanning electron microscopy were used to explore the structure feature and chemical composition., Findings: The elastic modulus of chondrocytes harvested from cartilage suffered from progressive pseudorheumatoid dysplasia is significantly higher than from normal cartilage, same trend were also found in tissue level. Moreover, denser collagen meshwork and matrix calcification were also observed., Interpretation: The elastic modulus of cartilage should closely related to its denser structure and the calcification, and may potentially be an indicator for clinical diagnosis. The stiffening of chondrocytes during PPRD progression should play a rather important role in its pathogenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Background: A spectrum of rare noninflammatory disorders may present with arthropathy that arises from bony dysplasia, a thickened synovium, and noninflammatory effusion, leading to a constellation of clinical features that mimics chronic polyarticular juvenile idiopathic arthritis (JIA). We report a unique Arabic family harboring a novel pathogenic variant in the WISP3 gene and presenting with progressive pseudorheumatoid dysplasia (PPRD), a rare noninflammatory arthropathy mimicking polyarticular JIA., Case Presentation: An Arabic family with PPRD was diagnosed using whole-exome sequencing (WES), revealing a novel c.707delG pathogenic variant in the WISP3 gene. The proband was referred at 10 years old for possible diagnosis of polyarticular JIA based on progressive arthropathy for three years. He was already on naproxen and methotrexate. We suspected familial noninflammatory arthropathy based on clinical manifestations, imaging findings, and family history. WES confirmed the molecular diagnosis of PPRD in the proband and one sister with a similar phenotype. An unexpected p.A744S MEFV pathogenic variant was detected in the proband, parents, and affected sister., Conclusions: Early identification and diagnosis of familial noninflammatory arthropathies such as PPRD can prevent unnecessary use of immunosuppressive medications. Diagnosis requires high suspicion in children with early onset arthritic changes, absence of elevated inflammatory markers, specific imaging findings, and positive family history suggestive of an autosomal recessive disorder. We highlight the advantages of WES over single-gene analysis in such cases.

Background: No formal diagnostic criteria for progressive pseudo-rheumatoid dysplasia (PPD) are available because of insufficient clinical data, which results in that PPD is often misdiagnosed with other diseases. Whole exome sequencing (WES) and Sanger sequencing were employed to reveal the novel mutations on CCN6 of five patients with PPD from China in order to increase the clinical data of PPD., Methods: Four suspected PPD pedigrees containing five patients in total were collected from 1998 to 2018 in our medical center. The phenotypes of each suspected PPD case were recorded in detail, and peripheral blood samples were collected for subsequent sequencing. Genomic DNA was extracted from peripheral blood samples, and Agilent liquid phase chip capture system was utilized for efficient enrichment of whole exome region DNA. After acquiring raw sequenced reads of whole exome region, bioinformatics analysis was completed in conjunction with reference or genome sequence (GRCh37/hg19). Sanger sequencing was performed to identify the results of WES., Results: In total, four novel PPD-related mutation sites in CCN6 gene were identified including (CCN6):c.643 + 2T>C, (CCN6):c.1064&#95;1065dupGT(p.Gln356ValfsTer33), (CCN6):c.1064G > A), and exon4:c.670dupA:p.W223fs., Conclusion: Our findings increase the clinical data of PPD including the CCN6 mutation spectrum, the clinical symptoms and signs. Moreover, the study highlights the utility of WES in reaching definitive diagnoses for PPD., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2-5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635&#95;636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1., (© 2020 The Author(s).)

A 25-year-old man presented to us with progressive multiple joint pain, enlargement, and restricted movements. X-rays showed platyspondyly, multiple epiphyseal widening, synovial chondromatosis, and decreased bone stock and cortical thickness. Genetic testing showed biallelic pathogenic variants in CCN6 which confirmed the diagnosis of progressive pseudorheumatoid dysplasia. Supportive care, physical therapy, genetic and psychological counselling were provided to the patient., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Axial and extra-axial deceleration in function and progressive joint pain with subsequent development of antalgic gait associated with swellings, and stiffness of the joints with loss of the physiological spine biomechanics were the natural history in this group of patients. Clinical and radiological phenotypes have been analysed carefully to further understand the aetiology behind., Methods: Seven patients (three children around the age of 9-11 and one child of 17 years old). Three adults aging 25, 30, 33 and 40 years old were seen and examined. The paediatric group of patients were initially diagnosed with myopathy followed later by juvenile rheumatoid arthritis in other institutions. Clinical and imaging documentation were collected in our departments, followed by mutation screening, was carried out by bidirectional sequencing of the WISP3 gene., Results: Clinical and radiological phenotypic studies confirmed the diagnosis of progressive pseudorheumatoid chondrodysplasia. A constellation of abnormalities such as early senile hyperostosis of the spine (Forestier disease), osteoarthritis of the hips showed progressive diminution and irregularities of the hip joint spaces associated with progressive capital femoral epiphyseal dysplasia and coxa vara have been encountered. Loss-of-function homozygous mutations (c.667T>G, p.Cys223Gly) and (c.170C>A, p.Ser57*) in the WISP3 gene were identified in our patients., Conclusion: The definite diagnosis was not defined via vigorous myopathic and rheumatologic investigations. Detailed clinical examination and skeletal survey, followed by genotypic confirmation, were our fundamental pointers to rule out the false diagnosis of juvenile rheumatoid arthritis and rheumatoid polyarthritis in the adult group of patients. We wish to stress that the clinical/radiological phenotype is the baseline tool to establish a definite diagnosis and to guide the geneticist toward proper genotype.Key Points•Joint pain and difficulties in walking/climbing the stairs are characteristic features encountered in early childhood. False diagnosis of juvenile rheumatoid arthritis can be made at this point.•False positive-like muscular wasting resembling myopathy results in ensuing vigorous troublesome investigations.•Flattened vertebral bodies associated with defective ossification of the anterior end plates are characteristic features of progressive pseudorheumatoid chondrodysplasia.•Joint expansions, which are usually accompanied by narrowing of the articular ends of the appendicular skeletal system, show a clear radiological phenotype of pseudorheumatoid chondrodysplasia.

Purpose of Review: We present the reader with insight on the most common disorders of the knee in newborns and infants. Knee issues in this population may confuse the first contact physicians due to certain peculiarities of the immature immune system, small size and underdevelopment of joint anatomy. Data presented here are recent and significant, and something to bear in mind when caring for children of this age., Recent Findings: With the advent of new diagnostic methods, a shift in the causative agent of pediatric knee infections has been noted. Minimally invasive methods such as arthrocentesis and arthroscopy are successfully employed in treatment of knee problems in newborns and infants. A trial of conservative therapy in congenital patellar instability can give good results, and obviate the need for surgery in some cases. Various syndromes that affect the knee have specific characteristics that need to be recognized early to avoid problems in the future., Summary: Although rare, knee problems in infants can and do occur. Their cause varies significantly and good outcomes require a multidisciplinary approach. Early diagnosis, referral and initiation of treatment protocols can significantly influence the fate of the joint and with it the patients' functional status for life.

Background: Proximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations., Case Presentation: Here, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing., Conclusion: In this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.

Progressive pseudorheumatoid dysplasia (PPD) is a rare disorder of postnatal skeletal and cartilage development that often presents with similar clinical findings to juvenile idiopathic arthritis. Patients with PPD display findings of progressive cartilage loss and secondary osteoarthritis over serial imaging studies and have an absence of elevation of inflammatory markers. Awareness of the imaging features of PPD on radiographs and magnetic resonance imaging (MRI) may be important for early diagnosis and surveillance of the disease.

Background: Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet., Methods: We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics., Results: Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM&#95;005450) c.124C > T, p.(Pro42Ser) in all patients. This c.124C > T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic., Conclusion: Our results suggest that heterozygous c.124C > T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.

Rationale: Valgus knees are relatively rare in the clinic. Treatments for valgus deviations >90° represent a surgical challenge to achieve a balance between the soft tissue and bone and prevent nerve damage., Patient Concerns: A 63-year-old woman with valgus deviations >90° in both knees complained that she had been unable to walk for 50 years., Diagnoses: Congenital malformation valgus deformity., Interventions: Bilateral total knee arthroplasty (TKA) was performed using a rotating hinge knee instrument from Endo-Model for axial correction and stabilization of the joint., Outcomes: The patient fully recovered 3 months after surgery. At the follow-up 6 years after the operation, the function of the knee joint clearly improved. The knee society score (KSS) increased from 35 to 90., Lessons: Constrained implants are commonly used to stabilize the joint and correct the bone axis in patients with severe ligamental instability, gross deformity, bone loss, and extreme deviation of the straight leg axis. Intraoperative exploration of the common peroneal nerve and the postoperative flexed position of the knee joints could help prevent nerve injuries.

Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Although several hundred cases were reported worldwide, the diagnosis remains challenging. Subsequently, the syndrome is often unrecognized and misdiagnosed (for instance, as Juvenile Idiopathic Arthritis), leading to unnecessary procedures and treatments. The objective of the current study was to identify the molecular basis in a family with PPRD and describe their phenotype and course of illness., Patients and Methods: We present here a multiply affected consanguineous family of Iraqi-Jewish descent with PPRD. The proband, a 6.5 years old girl, presented with bilateral symmetric bony enlargements of the 1st interphalangeal joints of the hands, without signs of synovitis. Molecular analysis of the family was pursued using Whole Exome Sequencing (WES) and homozygosity mapping., Results: WES analysis brought to the identification of a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene. Following this diagnosis, an additional 53 years old affected family member was found to harbor the mutation. Two other individuals in the family were reported to have had similar involvement however both had died of unrelated causes., Conclusion: The reported family underscores the importance of recognition of this unique skeletal dysplasia by clinicians, and especially by pediatric rheumatologists and orthopedic surgeons.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic bone disorder characterised by the progressive degeneration of articular cartilage that leads to pain, stiffness and joint enlargement. As PPRD is a rare disease, available literature is mainly represented by single case reports and only a few larger case series. Our aim is to review the literature concerning clinical, laboratory and radiological features of PPRD. PPRD is due to a mutation in Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis. The disease onset in childhood and skeletal changes progresses over time leading to significant disability. PPRD is a rare condition that should be suspected if a child develops symmetrical polyarticular involvement without systemic inflammation, knobbly interphalangeal joints of the hands, and gait abnormalities. A full skeletal survey, or at least a lateral radiograph of the spine, can direct towards a correct diagnosis that can be confirmed molecularly. More than 70 WISP3 mutations have so far been reported. Genetic testing should start with the study of genomic DNA extracted from blood leucocytes, but intronic mutations in WISP3 causing splicing aberrations can only be detected by analysing WISP3 mRNA, which can be extracted from cultured skin fibroblasts. A skin biopsy is, therefore, indicated in patients with typical PPRD findings and negative mutation screening of genomic DNA.

Background: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive skeletal dysplasia caused by mutations in the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. Available literatures in PPD emphasized treatment strategy for polyarthritis, while few mentioned spinal deformity and related surgical intervention., Methods: Here, we present a Chinese man with PPD who underwent spinal surgery twice because of canal stenosis and related symptoms caused by the disease. Whole-exon sequencing (WES) was performed to confirm diagnosis before the second surgery., Results: A homozygous missense mutation (c.395G>A/p.C132Y) in WISP3 was identified that co-segregated with affected family members., Conclusions: Our study illustrated a surgical outcome of PPD and highlighted the significance of early diagnosis and individualized surgical strategy, and also verified the value of WES in the diagnosis of PPD.

DDH is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the hip, suboptimal joint function and accelerated wear of the articular cartilage resulting in early onset crippling arthritis of the hip in 20-40 year olds. Current diagnostic tests in newborns using physical manipulation of the femur or ultrasound either under or over-diagnose this condition. Developing an accurate, cost effective diagnostic test is a goal of this study. To better understand the biologic pathways involved in acetabular development, DNA from severely affected individuals in a four generation family that showed inter-generational transmission of the disorder was isolated and whole exome sequenced. A novel A to C transversion at position 183721398 on human chromosome four was found to co-segregate with the affected phenotype in this family. This mutation encodes a glutamine to proline change at position 2665 in the Teneurin 3 (TENM3) gene and was judged damaging by four prediction programs. Eight week old knock-in mutant mice show delayed development of the left acetabulum and the left glenoid fossa as shown by the presence of more Alcian blue staining on the socket rims of both the hip and the shoulder. We hypothesize that mutated TENM3 will slow chondrogenesis. MMP13 has been shown to impair extracellular matrix remodeling and suppress differentiation. Bone marrow cells from the knock-in mouse were found to overexpress MMP13 with or without BMP2 stimulation. This variant may elucidate pathways responsible for normal hip development and become part of an accurate test for DDH. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

In this study, we reported a case of progressive pseudorheumatoid dysplasia in Peking University Third Hospital. A 56-year-old male patient presented with hip joint pain for more than 40 years and multiple joints pain with limitation of movements of these joints for 28 years. This patient suffered from joint pain and impaired range of motion of the hip, knee, elbow and shoulder gradually, associated with difficulty in walking and inability to take care of himself. He was diagnosed with "femoral head necrosis" or "ankylosing spondylitis" in local hospitals, but the treatment of nonsteroidal antiinflammatory drugs (NSAIDs) and sulfasalazine was not effective. Up to the age of 14, the patient displayed normal physical development, with the highest height was about 158 cm, according to the patient recall. However, his height was 153 cm at present. There was no history of similar illness in any family member. Physical examinations descried limitation of movement of almost all joints. Enlargement and flexion deformity of the proximal interphalangeal (PIP) joints of the hands resulted in the claw hand appearance. Limited abduction and internal and external rotation of the shoulder and hip could be find. He had normal laboratory findings for blood routine test, biochemical indexes and acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Furthermore, HLA-B27 and autoimmune antibodies such as rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody and antinuclear antibody (ANA) were all negative. X-ray of the hip showed loss of the joint space and irregularities of the femoral head, both femoral head were flattened, it could be see hyperplasia, osteophytes, bilateral femoral neck thicken, neck dry angle turned smaller. The radiological findings of the spinal vertebra indicated kyphosis deformity, narrowing of the intervertebral discs, vertebral syndesmophytes and flattening of the vertebra. However, there was no clues of bone marrow edema in the lumbar MRI. At last, genetic testing for the Wnt1-inducible signaling pathway protein 3 (WISP3) gene was done and indicated compound heterozygous mutations: 756C>G and c.866dupA. These two mutations were derived from the patient's mother and father (the patient's parents each had a heterozygous mutation). Two exons of the WISP3 gene had nucleotide changes leading to amino acid mutations. According to the patient's history, symptoms, physical examinations, radiological findings and genetic testing, the final definitive diagnosis was progressive pseudorheumatic dysplasia.

Introduction: Total hip arthroplasty in patients with altered anatomy of the hip and femur, such as in congenital dysplasia of the hip, is challenging and often requires specially designed stems. Müller straight stems have shown excellent long-term results; however, long-term data on the analogous cemented Müller CDH stem are still missing. The aim of this study was to analyze long-term survival, identify potential risk factors for aseptic loosening, and analyze radiological outcome of the cemented Müller CDH stems., Materials and Methods: Between 01/1985 and 06/2005, 95 Müller CDH stems (Zimmer, Winterthur, Switzerland) made up of 3 different materials were cemented using 2 different bone cements: 38 of stainless steel/high-viscosity cement, 31 of a cobalt-chrome-based alloy (CoCr)/low-viscosity cement, and 26 of a titanium-based alloy (Ti)/low-viscosity cement. All patients had a prospective clinical and radiological follow-up according to the standards of our institution. The cumulative incidence for revision of the stem was calculated using a competing risk model. To identify demographic and implant-related risk factors for aseptic loosening of the stem, a multivariate regression model for competing risks was performed., Results: The cumulative risk of revision at 15 years was 12.5% (95% CI 6.6-20.5%) for aseptic loosening of the stem as endpoint, with marked differences for the various stem materials used: stainless steel 2.7% (0.2-12.3%), CoCr 12.9% (4.0-27.3%), and Ti 24.5% (9.6-43.1%). Regression modeling revealed that Ti stems in combination with low-viscosity cement (HR 10.2) and implantation with an axis deviation greater than 3° (HR 3.8) are risk factors for aseptic loosening., Conclusions: Long-term survival of the cemented Müller CDH stem is comparable to other Müller-type straight stems and uncemented implants. Similar to the original Ti Müller straight stem, the Ti Müller CDH stem also showed an increased risk for aseptic loosening and should, therefore, no longer be used.

Background: As one kind of osteochondrodysplasia, progressive pseudorheumatoid dysplasia (PPD) is also known as spondyloepiphyseal dysplasia tarda with progressive arthropathy or arthropathy progressive pseudorheumatoid of childhood. PPD is a very rare disease, especially in China, and has an estimated prevalence of 1/1000000 due to lacking definite prevalence survey. It is an autosomal recessive disorder caused by gene mutation of Wntl inducible signaling pathway protein 3 (WISP3). Its basic pathological change is persistent degeneration and loss of articular cartilage in multiple joints. Its clinical appearances include bone enlargement, platyspondyly, irregular endplate, secondary osteoarthritis, extensive osteoporosis, joint rigidity and function loss. Clinical diagnosis of PPD is made based on clinical appearance and imaging examinations, whereas its definite diagnosis depends on gene sequencing. PPD has no severe effect on life span, but causes high disability rate and very poor prognosis. There are only case reports with limited information in China., Case Presentation: One female patient was diagnosed as PPD and secondary osteoarthritis. She had typical clinical appearance and imaging examinations, and received individualized therapeutic regimens. She had a gene mutation (c.72delT, p.T24TfsX4) of WISP3. This gene mutation has not been reported by previous literatures and included in Single Nucleotide Polymorphism Database., Conclusions: As the first time, this paper reported a patient with PPD caused by new-found gene mutation (c.72delT, p.T24TfsX4) of WISP3.

Rationale: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive inherited disease that causes severe systemic joint deformity and articular dysfunction in young patients., Patient Concerns: Ilizarov technique treatment in PPD patients has never been reported before., Diagnoses: 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&#95;198239.1 (WISP3):c.1064&#95;1065dupGT (p.Gln356ValfsTer33) and NM&#95;198239.1 (WISP3):c.643+2T > C., Interventions: Taking his young age into consideration, the Ilizarov external fixation technique was adopted for the treatment of the deformity in knees., Outcomes: One year after the operation, the improvement of joint deformity was satisfactory., Lessons: 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.

Developmental dysplasia of the hip (DDH) is a common skeletal disorder whereby genetic factors play a role in etiology. Multiple genes have been reported to be associated with the occurrence of DDH. WISP3 gene was found to be a causative gene for progressive pseudorheumatoid dysplasia (PPD). Reports of WISP3 gene in association with DDH are lacking. We conducted a case-control candidate gene association study enrolling three hundred and eighty-six patients with radiology confirmed DDH and 558 healthy controls. Additional haplotype-analysis was conducted to find the significant haplotype for DDH. Five SNPs rs69306665 (upstream of WISP3), rs1022313 (WISP3), rs1230345 (WISP3), rs17073268 (WISP3) and rs10456877 (downstream of WISP3) were identified for association with DDH, showing significant difference of allele frequencies with similar odds ratio ranging from 0.71 to 0.77 (p < 0.01) between cases and controls. Two haplotypes were identified between cases and controls through haplotype analysis: AAAAA with an odds ratio of 0.76 (95% CI: 0.60-0.98, p = 0.032299) and GGCGG with an odds ratio of 1.67 (95% CI: 1.37-2.04, p = 3.67 ∗ 10 -7 ). The results suggested WISP3 gene was associated with DDH in Chinese Han population. GGCGG haplotype might be a biomarker for DDH., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disease that is characterized by pain, stiffness and enlargement of multiple joints with an age of onset between 3 and 8 years old. Mutations in the WISP3 (Wnt1-inducible signal pathway) gene are known to be the cause of PPD., Case Presentation: We present a case of delayed-onset PPD in a Chinese man. The 35-year-old proband presented with an almost 20-year history of pain and limitations in mobility in multiple joints. Based on the clinical manifestations, the patient was diagnosed with PPD; however, there was no specific evidence to confirm this diagnosis. Through mutational analyses, two WIPS3 mutations in exon 4, including a novel frameshift mutation (c.670dupA) in the paternal allele and an already described nonsense mutation (c.756C > A, p.Cys252*) in the maternal allele, were identified in the proband. Thus, the patient was diagnosed with PPD. Furthermore, we found that the proband's son only carried one of the mutations (c.670dupA) and therefore determined that he would not be affected by PPD in the future., Conclusions: In this case, we successfully diagnosed the disease that the proband was affected precisely after the reunion of clinical diagnosis and genetic analysis. These findings demonstrate the clinical utility of genetic analysis to diagnose skeletal dysplasia and guide genetic counseling.

Discoid meniscus is a congenital variant of the knee joint that typically involves abnormal morphology and potential instability of the lateral meniscus. Some discoid menisci have abnormal peripheral attachments and are unstable. Discoid menisci are prone to tearing secondary to increased thickness, poor tissue quality, and instability. Patients may or may not be symptomatic. Torn or unstable discoid menisci cause mechanical symptoms, pain, and swelling. Symptomatic patients in whom nonsurgical management fails most frequently are treated with arthroscopic surgery. Historically, complete meniscectomy has successfully alleviated symptoms but has resulted in poor midterm results, with degenerative changes to the knee joint. Current treatment emphasizes the saucerization of the meniscus, with removal of the central disk and retention of the peripheral crescent. Peripheral meniscal repair is performed when instability is present. Short-term results are good; however, degenerative changes have been reported at intermediate follow-up.

Background: The anterior part of the distal femur in trochlear dysplasia has been well investigated; however, to date, posterior morphological characteristics have not been well studied. This study aimed to evaluate whether the posterior femoral condyle in patients with trochlear dysplasia differs from those without trochlear dysplasia., Methods: Computed tomography scans of 75 knees with trochlear dysplasia and 55 knees with normal anatomy of the patellofemoral joint were analyzed retrospectively. Three observers assessed the width, length, and height of the posterior condyle between the two groups. The intra-class correlation coefficient was used to evaluate inter-observer reliability. The independent Student's t-test was used to assess the statistical significance of the qualitative variables., Results: There was excellent inter-observer reliability (intra-class correlation coefficient 0.91-0.99) for all of the quantitative measurements. There were significant differences between trochlear dysplastic and normal knees. The trochlear dysplasia group had a larger medial posterior condyle and smaller lateral posterior condyle than the control group. Furthermore, proportion of the posterior condyle in the distal femur markedly differed between the two groups: in the trochlear dysplasia group, the medial posterior condyle accounted for a bigger proportion, while the lateral posterior condyle accounted for a smaller proportion., Conclusion: Patients with trochlear dysplasia have different posterior femoral condyles compared with those without trochlear dysplasia. Patients with this condition have bigger medial posterior condyles and smaller lateral posterior condyles. A greater amount of attention needs to be paid to this abnormality., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Progressive pseudorheumatoid dysplasia (PPD) is a rare spondylo-epi-metaphyseal dysplasia (SEMD). It can be confused with juvenile idiopathic arthritis (JIA), both clinically and radiologically. Early detection and diagnosis of PPD are important in helping to relieve the pain and disability associated with this disease and in avoiding unnecessary investigations and anti-rheumatic interventions., Case Details: We report the case of a 15-year-old girl with PPD who was misdiagnosed with JIA., Conclusion: In conclusion, PPD is a rare SEMD and can be confused with JIA, both clinically and radiologically. Early detection and diagnosis of PPD are important in helping to relieve the pain and disability associated with this disease and in avoiding unnecessary investigations and anti-rheumatic interventions.

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP&#95;003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia associated with pain and stiffness of multiple joints, enlargement of the interphalangeal joints, normal inflammatory parameters, and absence of extra-skeletal manifestations. Homozygous or compound heterozygous WISP3 mutations cause PPD. We report two siblings from a non-consanguineous Ecuadorian family with a late-onset spondyloepiphyseal dysplasia. Mutation screening was undertaken in the two affected siblings using a customized skeletal dysplasia next generation sequencing (NGS) panel and confirmed by Sanger sequencing. Two compound heterozygous mutations were identified in WISP3 exon 2, c.[190G>A];[197G>A] (p.[(Gly64Arg)];[(Ser66Asn)]) in the two siblings, both of which had been inherited. The p. (Gly64Arg) mutation has not been previously described whilst the p. (Ser66Asn) mutation has been reported in two PPD families. The two siblings presented with atypical PPD, as they presented during late childhood, yet the severity was different between them. The progression was particularly aggressive in the male sibling who suffered severe scoliosis by the age of 13 years. This case reaffirms the clinical heterogeneity of this disorder and the clinical utility of NGS to genetically diagnose skeletal dysplasias, enabling adequate management, monitorization, and genetic counseling. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Progressive pseudorheumatoid arthropathy of childhood is a rare disease with an estimated prevalence of approximately 1/1,000,000. The disease manifests around the age of three to eight years and progresses with symptoms of early fatigue, muscle weakness, joint swelling and stiffness. The resulting functional limitations are often described as having a waddling gait. Walking is difficult and can be managed with multilevel compensation movements only. Aims of this study were to determine typical malpositions that arise during walking and to identify preventive strategies to reduce excessive joint damage., Methods: This study presents data of three-dimensional gait analysis of nine patients with progressive pseudorheumatoid arthropathy of childhood (♀=2; ♂=7; 13.3y; 47.0kg; 1.39m; BMI: 24.2kg/m(2)) performed with eight infrared cameras and the Plug-in-Gait Model. For comparison of spatiotemporal and kinematic parameters with age-matched healthy controls (♀=6; ♂=3; 13.4y; 49.0kg; 1.61m; BMI: 18.9kg/m(2)), the Mann-Whitney U-test was applied with a significance level of P<0.05., Findings: The patients had a significantly lower height, but higher BMI. Walking speed was reduced with wide, but short steps and significant motion anomalies in the pelvis, hips, knees and ankles. Small ranges of motion in propulsion-supporting movements were typical, especially in the sagittal plane. The gait analysis revealed dominant compensatory movements in pelvic obliquity and rotation., Interpretation: The deficits can be attributed to pronounced muscle weakness plus functional joint impairment and pain. Therapeutic preventive strategies therefore should consider continuous muscle power exercises, stretching programmes and restrictive weight control., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type., (© 2015 WILEY PERIODICALS, INC.)