{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:43:42Z","timestamp":1791035022154,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,3,24]],"date-time":"2018-03-24T00:00:00Z","timestamp":1521849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["SAF2012\u201030871"],"award-info":[{"award-number":["SAF2012\u201030871"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["SAF2015\u201066831\u2010R"],"award-info":[{"award-number":["SAF2015\u201066831\u2010R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>Mutations in the aggrecan gene (ACAN<\/jats:styled-content><\/jats:italic>) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK<\/jats:styled-content>), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next\u2010generation sequencing (NGS<\/jats:styled-content>) has aided the identification of heterozygous ACAN<\/jats:styled-content><\/jats:italic> mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA<\/jats:styled-content>), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis.<\/jats:p><\/jats:sec>Design and methods<\/jats:title>This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN<\/jats:styled-content><\/jats:italic> variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK<\/jats:styled-content> (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN<\/jats:styled-content><\/jats:italic>\u2010positive individuals.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 16 ACAN<\/jats:styled-content><\/jats:italic> variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS<\/jats:styled-content>). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA<\/jats:styled-content> compared to 0% in those with a VUS<\/jats:styled-content>. A higher incidence of coxa valga was observed in individuals with a VUS<\/jats:styled-content> (37% vs 0%). Nevertheless, other features were present at similar frequencies.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>ACAN<\/jats:styled-content><\/jats:italic> should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA<\/jats:styled-content> and osteoarticular complications are not obligatory conditions for aggrecanopathies\/aggrecan\u2010associated dysplasias.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.13581","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T20:21:51Z","timestamp":1519244511000},"page":"820-829","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-3352","authenticated-orcid":false,"given":"Luc\u00eda","family":"Sentchordi\u2010Montan\u00e9","sequence":"first","affiliation":[{"name":"Department of Pediatrics Hospital Universitario Infanta Leonor Madrid Spain"},{"name":"Institute of Medical and Molecular Genetics (INGEMM) Hospital Universitario La Paz Universidad Auton\u00f3ma de Madrid IdiPAZ Madrid Spain"},{"name":"Skeletal dysplasia Multidisciplinary Unit (UMDE) Hospital Universitario La Paz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Aza\u2010Carmona","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM) Hospital Universitario La Paz Universidad Auton\u00f3ma de Madrid IdiPAZ Madrid Spain"},{"name":"Skeletal dysplasia Multidisciplinary Unit (UMDE) Hospital Universitario La Paz Madrid Spain"},{"name":"CIBERER ISCIII Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Benito\u2010Sanz","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM) Hospital Universitario La Paz Universidad Auton\u00f3ma de Madrid IdiPAZ Madrid Spain"},{"name":"CIBERER ISCIII Madrid 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