Skeletal phenotype/genotype in progressive pseudorheumatoid chondrodysplasia

Kaissi, Ali Al; Kenis, Vladimir; Jemaa, Lamia Ben; Sassi, Hela; Shboul, Mohammad; Grill, Franz; Rudolf, G.; Kircher, Susanne Gerit

doi:10.1007/s10067-019-04783-z

Cited by 11 publications

(20 citation statements)

References 40 publications

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“…Case5 had the homozygous missense mutation c.667T>G, p.C223G in the WISP3 gene. Three of our patients had WISP3 mutations involving c.589+2T>C, showing a homozygous mutation or compound heterozygous mutation with c.667T>G. The c.667T>G mutation, located in exon 4 of the WISP3 gene has beenreported before in Chinese and other ethnic origins' children affected with PPRD8,22 .…”

mentioning

confidence: 48%

“…The clinical and radiological phenotype of patients with PPRD is rather homogeneous with progressive worsening of symptoms and radiological changes during childhood and adolescence 2 . The unspecific symptoms often cause a significant delay in diagnosis 2 , or even lead to misdiagnosis resulting in incorrect treatment 22 . In our nine patients with PPRD presented here, five were misdiagnosed with juvenile idiopathic arthritis (JIA) before they came to our center, and one patient (case9) even had received treatment with immunosuppressants despite their autoimmunity markers and inflammatory parameters all within normal range.…”

Section: Discussionmentioning

confidence: 99%

“…PPRD ACs are characterized by increased proliferation activity and decreased apoptosis and may account for the metaphyseal enlargement seen in PPRD radiographs 23 . They are highly mineralized and significantly stiffer than those from normal articular cartilage which may slow down cartilage growth and repair 14 Exon4 encodes a thrombospondin type 1 domain (TSP-1) with six cysteine residues, which plays a vital role in Notch signaling that regulates chondrocyte differentiation and is also implicated in ossification and osteoarthritis, suggesting its importance in the functionality of WISP3 22 .The c.589+2T>C mutation has been reported only in Chinese children with PPRD and is located in intron 4 of the WISP3 gene 16 . The mutation c.624dupA has been reported in patients from China, India and countries of North and West Africa 15,19,24 .…”

Section: Discussionmentioning

confidence: 99%

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Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

Li¹,

Mao²,

Zhou³

et al. 2020

Preprint

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Background: Progressive pseudorheumatoid dysplasia (PPRD) (MIM 208230) is a rare genetic disease characterized by progressive noninflammatory arthropathy affecting primarily the articular cartilage. Most patients are initially misdiagnosed because of the rarity of the disease and lack of awareness by most clinicians. Therefore, the purpose of the present study was to provide further diagnostic options to help clinicians make early precise diagnosis, and to investigate a new potential treatment for patients with PPRD. Methods: Clinical manifestations, radiographic features, Sanger Sequencing to determine WISP3 gene mutation and follow-up records were collected in 9 Chinese patients with PPRD. The time until diagnosis, relationship between clinical phenotypes and genotypes, and treatment effects were analyzed. Results: The clinical history and characteristics, mutations in the WISP3 gene, radiological data, treatment and outcome of 9 PPRD children were collected and reviewed. There were 3 pairs of siblings in this group and one patient had parental consanguinity. Five patients were misdiagnosed with juvenile idiopathic arthritis (JIA). The onset of disease in most patients (8/9) was between 3 and 6 years of age. The interval between onset of symptoms and obtaining the diagnosis for 8 of the patients varied between 3.6 years to 20 years. The onset of symptoms included enlarged and stiff interphalangeal joints of the fingers, gait disturbance or joint pain. Blood analysis revealed normal range of inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). Serum levels of 25-hydroxyvitamin D3 were analyzed in six patients and ranged from 6.16 to 22.1ng/ml, all lower than the normal range. Radiographic findings included different degree of abnormal vertebral bodies, epiphyseal enlargement of the interphalangeal joints with juxta-articular osteopenia, or reduction in hip articular space and cyst-like structures femoral head. A total of 7 variants in the WISP3 gene were identified in the 9 cases, presenting with three homozygous variants (c.397_404delCAAGTGTT, c.667T>G, and c.589+2T>C) and three compound heterozygous variants (c.589+2T>C/c.667T>G, c.624dupA/c.756C>A, and c.646T>C/c.1000T>C). After the treatment of calcitriol in the 6 patients with low level of 25-hydroxyvitamin D3 for 1.25 years to 1.75 years, two cases showed stable clinical disease activity and the other four patients joints’ pain and abnormal gait had improved. 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. The patients with PPRD having c.624dupA mutation in WISP3 may have delayed onset. Calcitriol showed treatment benefit by improving symptoms and decelerating progression of PPRD disease.

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confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

Li¹,

Mao²,

Zhou³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Our case 5 had parental consanguinity and had the homozygous missense variant c.667T>G, p.C223Gly in the CCN6 gene. The c.667T>G variant, located in exon 4 of the CCN6 gene has been reported before in Chinese and other ethnic origins' children affected with PPRD9,23 .The variant c.624dupA has been reported in patients from China, India and countries of North and West Africa15,19,26 . The onset ages of patients with PPRD having homozygous variant (c.624dupA) or heterozygous (c.624dupA, c.756C>A) in CCN6 were much older (from 7-year old to 18-year old) than the common onset age of PPRD26 .…”

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confidence: 78%

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

Yin

Mao

Zhou

et al. 2021

Preprint

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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

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“…And conforms to history of present illness described repeatedly in the literature on the above-named genetic skeletal syndromes respecting initial misdiagnosis as juvenile idiopathic arthritis ( Zankl et al, 2007 ; Al Aqeel et al, 2000 ; Al Kaissi et al, 2011 ; Castberg et al, 2013 ; Gok et al, 2010 ; Li et al, 2020 ; Park et al, 2018 ; Upadia et al, 2018 ; Gökay et al, 2018 ; Zhuang et al, 2017 ; Sun et al, 2016 ). This applies also to a wider array of genetic skeletal dysplasias which can mimic juvenile idiopathic arthritis clinically as progressive pseudorheumatoid dysplasia ( EL-Sobky et al, 2017a ; Gamal et al, 2017 ; Gaboon et al, 2019 ; Torreggiani et al, 2019 ; Madhusudan et al, 2016 ; Taspinar et al, 2016 ; Kaya Akca et al, 2021 ; Al Kaissi et al, 2020 ). This has two considerable implications.…”

Section: Discussionmentioning

confidence: 99%

Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations

et al. 2021

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Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome is a rare genetic skeletal dysplasia. Its diagnosis can be deceptively similar to childhood-onset genetic skeletal dysplasias and juvenile idiopathic arthritis. We aimed to report the syndrome’s clinical and radiologic features with emphasis on skeletal manifestations. And establish relevant phenotype-genotype correlations. We evaluated two boys, 4-and-7-years-old with MONA syndrome. Both patients had consanguineous parents. We verified the diagnosis by correlating the outcomes of clinical, radiologic and molecular analysis. We specifically evaluated the craniofacial morphology and clinical and radiographic skeletal abnormalities. We contextualized the resultant phenotype-genotype correlations to publications on MONA and its differential diagnosis. Skeletal manifestations were the presenting symptoms and mostly restricted to hands and feet in terms of fixed extension deformity of the metacarpophalangeal and flexion deformity of the interphalangeal joints with extension deformity of big toes. There were arthritic symptoms in the older patient especially of the wrists and minute pathologic fractures. The skeletal radiographs showed osteopenia/dysplastic changes of hands and feet. Both patients had variants in the matrix metalloproteinase2 gene which conformed to phenotype of previously reported literature in one patient while the other had a novel variant which conformed to MONA phenotype. Craniofacial abnormalities were present. However, minimal extra-skeletal manifestations. Overall, there is an emerging distinctive skeletal pattern of involvement in terms of both clinical and radiographic features. This includes age of onset and location of presenting skeletal manifestations, chronological order of joint affection, longitudinal disease progression, specifics of skeletal radiographic pathology and craniofacial features. Nevertheless, physicians are cautioned against differential diagnosis of similar genetic skeletal dysplasias and juvenile idiopathic arthritis.

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Skeletal phenotype/genotype in progressive pseudorheumatoid chondrodysplasia

Cited by 11 publications

References 40 publications

Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

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

Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations

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