{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:07:00Z","timestamp":1789182420950,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Progressive pseudorheumatoid arthropathy of childhood (PPAC) is a rare autosomal recessive progressive condition that affects the cartilage of joints and bones. The symptoms of PPAC include stiffness of the joints, bony swelling of the toes and fingers, short stature, kyphosis, and muscle weakness. The radiologic manifestations are often mistaken for juvenile rheumatoid arthritis and include platyspondyly, widened metaphyses, flattened epiphyses, and large femoral heads. The disease is caused by variants in the\n                    <jats:italic>WISP3<\/jats:italic>\n                    (also known as\n                    <jats:italic>CCN6<\/jats:italic>\n                    ) gene, which encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. We describe three affected female siblings in an Indian family with PPAC, all of whom manifest a severe phenotype of the disease. The girls all walked with a crouching gait from severe joint contractures. Radiographic findings included generalized periarticular osteopenia and widened metaphyses. The radiographs of the hands and feet showed similar changes with narrow joint spaces, widened metaphyses, and flattened epiphyses. Elbows and knees revealed gracile bones, and contractures with severe muscle atrophy. Spine films were significant for marked beaking, lumbar vertebrae anterior narrowing, irregular end plates and rotational scoliosis. X\u2010rays of the hips revealed deformed femurs, coxa vara, and large flat epiphyses. All affected individuals were compound heterozygotes for two pathogenic variants in the\n                    <jats:italic>WISP3\/CCN6<\/jats:italic>\n                    gene, a novel nonsense variant (c.172A&gt;T [p.Lys58*]) and a 2\u2010base pair deletion (c.740_741delGT [p.Cys247Leufs*31]). This combination of a nonsense and frameshift variant has not previously been reported and may be the explanation for the severe clinical manifestation of PPAC in this family. Further investigation into the mechanism of the disease may provide promising therapies to modify disease progression.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70233","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:43:17Z","timestamp":1789180997000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Severe Phenotype in an Indian Family With Progressive Pseudorheumatoid Arthropathy of Childhood"],"prefix":"10.1002","author":[{"given":"Narinder","family":"Singh","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics University of California  Irvine California USA"},{"name":"Chino Valley Medical Center  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpita","family":"Neogi","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics University of California  Irvine California USA"},{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Internal Medicine Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliane H.","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Pediatric Radiology, Department of Radiology University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdish","family":"Soni","sequence":"additional","affiliation":[{"name":"Gandhi Lincoln Hospital  Deesa Gujarat India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Chao","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics University of California  Irvine California USA"},{"name":"Ambry Genetics  Aliso Viejo California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-4449","authenticated-orcid":false,"given":"Virginia","family":"Kimonis","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics University of California  Irvine California USA"},{"name":"Department of Neurology University of California  Irvine California USA"},{"name":"Department of Pathology University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"a002139","DOI":"10.1101\/mcs.a002139","article-title":"Late Diagnosis of a Truncating WISP3 Mutation Results in a Severe Phenotype of Progressive Pseudorheumatoid Dysplasia","volume":"4","author":"Alwabathani S.","year":"2017","journal-title":"Molecular Case Studies"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37164"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.664168"},{"issue":"4","key":"e_1_2_9_5_1","first-page":"255","article-title":"Progressive Pseudorheumatoid Dysplasia in North and West Africa: Clinical Description in Ten Patients With Mutations of WISP3","volume":"39","author":"Chouery E.","year":"2017","journal-title":"Egyptian Rheumatologist"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35620"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30906"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-003-0341-0"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2012.09.001"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050784"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31333"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/12699"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.1.414-421.2005"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224304"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2014.10.005"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2015.03.029"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-019-0787-x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep27684"},{"issue":"7","key":"e_1_2_9_19_1","first-page":"1650","article-title":"WISP3\u2010IGF1 Interaction Regulates Chondrocyte Hypertrophy","volume":"126","author":"Repudi S. 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