{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:16:23Z","timestamp":1780398983418,"version":"3.54.1"},"reference-count":22,"publisher":"Walter de Gruyter GmbH","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n The biosynthesis of 3\u2032-phosphoadenosine 5\u2032-phosphosulfate (PAPS), a universal sulfate donor, is catalyzed by two isoenzymes: PAPS synthetase 1 (PAPSS1) and PAPS synthetase 2 (PAPSS2). While PAPSS1 is ubiquitously expressed, PAPSS2 shows tissue-specific expression and plays\u00a0a key role in cartilage development and adrenal steroid\u00a0metabolism. PAPSS2 deficiency impairs dehydroepiandrosterone sulfation (DHEA-S), leading to increased bioactive androgens and hyperandrogenism. Biallelic PAPSS2 variants cause skeletal dysplasias from brachyolmia (BO) to severe spondyloepimetaphyseal dysplasia (SEMD). This study aimed to expand the PAPSS2 mutational spectrum and explore potential genotype\u2013phenotype correlations, including the distribution of variants across functional domains.<\/jats:p>\n <\/jats:sec>\n \n Case presentation<\/jats:title>\n Two siblings with disproportionate short stature underwent clinical, radiological, and biochemical evaluation. Targeted next-generation sequencing of skeletal dysplasia-associated genes was performed. Serum DHEA-S levels were measured to assess steroid sulfation. A literature review of previously reported PAPSS2 variants was conducted to explore genotype\u2013phenotype correlations. A novel homozygous missense variant, c.1466C>G (p.Pro489Arg), in the ATP sulfurylase domain of PAPSS2, was identified in both siblings. The male proband exhibited a severe SEMD phenotype, while his sister presented with milder BO features. Both had markedly reduced DHEA-S levels (4.04\u202f\u03bcg\/dL and 31.8\u202f\u03bcg\/dL), consistent with impaired adrenal androgen sulfation. Review of the literature indicates an enrichment of SEMD-associated variants within the ATP sulfurylase domain, although phenotypic overlap with BO is evident, as also observed in the present family.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n This study expands the known PAPSS2 mutational spectrum by identifying a novel pathogenic variant. The observed intrafamilial variability highlights the complexity of genotype\u2013phenotype relationships, particularly in the context of limited case numbers, while low DHEA-S levels represent a robust biochemical marker of impaired steroid sulfation.<\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/jpem-2025-0640","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:04:14Z","timestamp":1780394654000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel PAPSS2 pathogenic variant: expanding the mutational spectrum and genotype\u2013phenotype landscape in skeletal dysplasia"],"prefix":"10.1515","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2821-3038","authenticated-orcid":false,"given":"Behiye","family":"Sar\u0131kaya \u00d6zdemir","sequence":"first","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7683-371X","authenticated-orcid":false,"given":"Naz","family":"G\u00fcleray Lafc\u0131","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics , University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Department of Medical Genetics , Hacettepe University Faculty of Medicine , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bet\u00fcl Emine","family":"Derinkuyu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Cincinnati Children\u2019s Hospital Medical Center , University of Cincinnati College of Medicine , Cincinnati , OH , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-2872","authenticated-orcid":false,"given":"Semra","family":"\u00c7etinkaya","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"\u015eakar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melik\u015fah","family":"Keskin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8215-0146","authenticated-orcid":false,"given":"Nursel","family":"Murato\u011flu \u015eahin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehra","family":"Aycan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Division of Pediatric Endocrinology, Department of Pediatrics , Ankara University Faculty of Medicine , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eenay","family":"Sava\u015f Erdeve","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology , 146993 University of Health Sciences, Dr. Sami Ulus Obstetrics, Gynecology and Child Health and Diseases Training and Research Hospital , Ankara , T\u00fcrkiye"},{"name":"Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"2026060210412048964_j_jpem-2025-0640_ref_001","doi-asserted-by":"crossref","unstructured":"Perez Garcia, EM, Whalen, P, Gurtunca, N. 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Disease-related protein variants of the highly conserved enzyme PAPSS2 show marginal stability and aggregation in cells. Front Mol Biosci 2022;9:860387. https:\/\/doi.org\/10.3389\/fmolb.2022.860387.","DOI":"10.3389\/fmolb.2022.860387"},{"key":"2026060210412048964_j_jpem-2025-0640_ref_022","doi-asserted-by":"crossref","unstructured":"van den Boom, J, Heider, D, Martin, SR, Pastore, A, Mueller, JW. 3\u2032-Phosphoadenosine 5\u2032-phosphosulfate (PAPS) synthases, naturally fragile enzymes specifically stabilized by nucleotide binding. J Biol Chem 2012;287:17645\u201355. https:\/\/doi.org\/10.1074\/jbc.M111.325498.","DOI":"10.1074\/jbc.M111.325498"},{"key":"2026060210412048964_j_jpem-2025-0640_ref_019","doi-asserted-by":"crossref","unstructured":"Alnouti, Y, Klaassen, CD. Tissue distribution and ontogeny of sulfotransferase enzymes in mice. 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