{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T23:34:22Z","timestamp":1788046462487,"version":"build-2784847793"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Arthrogryposis\u2013renal dysfunction\u2013cholestasis (ARC) syndrome, a rare autosomal recessive disorder, exhibits genetic heterogeneity with the <jats:italic>VIPAS39<\/jats:italic> gene pathological variants being a distinct contributor.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We present two related patients from Kosovo, describing the clinical, genetic, and therapeutic aspects of the syndrome. The identified novel <jats:italic>VIPAS39<\/jats:italic> pathological variants (c.762G\u2009&gt;\u2009A; c.1064_1082delinsAGTG) emphasize the complex phenotypic expression of ARC syndrome. A systematic literature review identified 8 <jats:italic>VIPAS39<\/jats:italic>-related ARC cases with notable variability in clinical features. Prognostically, patients fell into severe and milder groups, with some reaching adolescence. Our report aligns with others noting milder ARC courses and emphasizes the value of genetic testing, especially in atypical presentations. Challenges included incomplete literature data, early mortality affecting diagnostic workup, and limited <jats:italic>VIPAS39<\/jats:italic>-related ARC cases. Comparisons with the more prevalent <jats:italic>VPS33B<\/jats:italic> pathological variants revealed no distinct clinical differences.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our study expands understanding of ARC syndrome, highlighting its genetic diversity and clinical variability. Milder presentations underscore diagnostic challenges and the potential prevalence of undiagnosed cases. Increased awareness and comprehensive genetic testing are crucial for early and accurate diagnosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03486-2","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T11:45:35Z","timestamp":1735559135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome\u2014case report and systematic review"],"prefix":"10.1186","volume":"19","author":[{"given":"Jan","family":"Kafol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gnidovec Strazisar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Drole Torkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matjaz","family":"Homan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bertok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"Mlinaric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaka","family":"Sikonja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jernej","family":"Kova\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana","family":"Perkovic Benedik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Kersnik Levart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojca","family":"Zerjav Tansek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Praprotnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadej","family":"Battelino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maru\u0161a","family":"Debeljak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5246-9869","authenticated-orcid":false,"given":"Urh","family":"Groselj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"issue":"5","key":"3486_CR1","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1136\/adc.85.5.415","volume":"85","author":"KM Eastham","year":"2001","unstructured":"Eastham KM, McKiernan PJ, Milford DV, Ramani P, Wyllie J, van\u2019t Hoff W, et al. ARC syndrome: an expanding range of phenotypes. Arch Dis Child. 2001;85(5):415\u201320.","journal-title":"Arch Dis Child"},{"issue":"Database","key":"3486_CR2","doi-asserted-by":"publisher","first-page":"D793","DOI":"10.1093\/nar\/gkn665","volume":"37","author":"J Amberger","year":"2009","unstructured":"Amberger J, Bocchini CA, Scott AF, Hamosh A. McKusick\u2019s Online mendelian inheritance in man (OMIM(R)). Nucleic Acids Res. 2009;37(Database):D793\u20136. https:\/\/doi.org\/10.1093\/nar\/gkn665.","journal-title":"Nucleic Acids Res"},{"issue":"1\u20132","key":"3486_CR3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1159\/000015571","volume":"89","author":"L Carim","year":"2000","unstructured":"Carim L, Sumoy L, Andreu N, Estivill X, Escarceller M. Cloning, mapping and expression analysis of VPS33B, the human orthologue of rat Vps33b. Cytogenet Cell Genet. 2000;89(1\u20132):92\u20135.","journal-title":"Cytogenet Cell Genet"},{"issue":"2","key":"3486_CR4","doi-asserted-by":"publisher","first-page":"E330","DOI":"10.1002\/humu.20900","volume":"30","author":"AR Cullinane","year":"2009","unstructured":"Cullinane AR, Straatman-Iwanowska A, Seo JK, Ko JS, Song KS, Gizewska M, et al. Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome. Hum Mutat. 2009;30(2):E330\u20137.","journal-title":"Hum Mutat"},{"issue":"4","key":"3486_CR5","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/ng.538","volume":"42","author":"AR Cullinane","year":"2010","unstructured":"Cullinane AR, Straatman-Iwanowska A, Zaucker A, Wakabayashi Y, Bruce CK, Luo G, et al. Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet. 2010;42(4):303\u201312.","journal-title":"Nat Genet"},{"issue":"4","key":"3486_CR6","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1097\/MPH.0b013e3181c3a8d0","volume":"32","author":"SM Kim","year":"2010","unstructured":"Kim SM, Chang HK, Song JW, Koh H, Han SJ. Agranular platelets as a cardinal feature of ARC syndrome. J Pediatr Hematol Oncol. 2010;32(4):253\u20138. https:\/\/doi.org\/10.1097\/MPH.0b013e3181c3a8d0.","journal-title":"J Pediatr Hematol Oncol"},{"issue":"3","key":"3486_CR7","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1007\/s00439-006-0232-z","volume":"120","author":"P Gissen","year":"2006","unstructured":"Gissen P, Tee L, Johnson CA, Genin E, Caliebe A, Chitayat D, et al. Clinical and molecular genetic features of ARC syndrome. Hum Genet. 2006;120(3):396\u2013409.","journal-title":"Hum Genet"},{"key":"3486_CR8","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s13052-014-0077-3","volume":"40","author":"Y Zhou","year":"2014","unstructured":"Zhou Y, Zhang J. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Ital J Pediatr. 2014;40:77.","journal-title":"Ital J Pediatr"},{"issue":"1","key":"3486_CR9","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13256-022-03279-w","volume":"16","author":"Y Satomura","year":"2022","unstructured":"Satomura Y, Bessho K, Nawa N, Kondo H, Ito S, Togawa T, et al. Novel gene mutations in three Japanese patients with ARC syndrome associated mild phenotypes: a case series. J Med Case Rep. 2022;16(1):60.","journal-title":"J Med Case Rep"},{"key":"3486_CR10","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.jclinepi.2017.04.026","volume":"89","author":"DS Riley","year":"2017","unstructured":"Riley DS, Barber MS, Kienle GS, Aronson JK, von Schoen-Angerer T, Tugwell P, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017;89:218\u201335.","journal-title":"J Clin Epidemiol"},{"key":"3486_CR11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372: n71.","journal-title":"BMJ"},{"key":"3486_CR12","doi-asserted-by":"publisher","first-page":"1041080","DOI":"10.3389\/fped.2022.1041080","volume":"10","author":"Y Zhu","year":"2022","unstructured":"Zhu Y, Chen D. Two novel mutations in VPS33B gene cause a milder ARC syndrome with prolonged survival in a 12-year-old patient: case report. Front Pediatr. 2022;10:1041080.","journal-title":"Front Pediatr"},{"issue":"6","key":"3486_CR13","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/humu.10212","volume":"21","author":"PD Stenson","year":"2003","unstructured":"Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. Human gene mutation database (HGMD): 2003 update. Hum Mutat. 2003;21(6):577\u201381.","journal-title":"Hum Mutat"},{"issue":"D1","key":"3486_CR14","doi-asserted-by":"publisher","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","volume":"42","author":"MJ Landrum","year":"2014","unstructured":"Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(D1):D980\u20135. https:\/\/doi.org\/10.1093\/nar\/gkt1113.","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"3486_CR15","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405\u201324.","journal-title":"Genet Med"},{"issue":"7","key":"3486_CR16","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1034\/j.1600-0854.2001.20705.x","volume":"2","author":"MR Peterson","year":"2001","unstructured":"Peterson MR, Emr SD. The class C Vps complex functions at multiple stages of the vacuolar transport pathway. Traffic. 2001;2(7):476\u201386.","journal-title":"Traffic"},{"issue":"6923","key":"3486_CR17","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/nature01348","volume":"421","author":"R Heilig","year":"2003","unstructured":"Heilig R, Eckenberg R, Petit JL, Fonknechten N, Da Silva C, Cattolico L, et al. The DNA sequence and analysis of human chromosome 14. Nature. 2003;421(6923):601\u20137.","journal-title":"Nature"},{"issue":"25","key":"3486_CR18","doi-asserted-by":"publisher","first-page":"4908","DOI":"10.1182\/blood-2012-10-459115","volume":"120","author":"R Flaumenhaft","year":"2012","unstructured":"Flaumenhaft R. alpha-granules: a story in the making. Blood. 2012;120(25):4908\u20139.","journal-title":"Blood"},{"issue":"1","key":"3486_CR19","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s12882-022-02851-2","volume":"23","author":"L Yu","year":"2022","unstructured":"Yu L, Li D, Zhang T, Xiao Y, Wang Y, Ge T. One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype. BMC Nephrol. 2022;23(1):228.","journal-title":"BMC Nephrol"},{"issue":"1","key":"3486_CR20","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1097\/BPO.0b013e3182032c83","volume":"31","author":"WY Jang","year":"2011","unstructured":"Jang WY, Cho TJ, Bae JY, Jung HW, Ko JS, Park MS, et al. Orthopaedic manifestations of arthrogryposis-renal dysfunction-cholestasis syndrome. J Pediatr Orthop. 2011;31(1):107\u201312.","journal-title":"J Pediatr Orthop"},{"issue":"3","key":"3486_CR21","doi-asserted-by":"publisher","first-page":"290","DOI":"10.6002\/ect.2012.0202","volume":"11","author":"SM Dehghani","year":"2013","unstructured":"Dehghani SM, Bahador A, Nikeghbalian S, Salahi H, Geramizadeh B, Malekpour A, et al. Liver transplant in a case of arthrogryposis-renal tubular dysfunction-cholestasis syndrome with severe intractable pruritus. Exp Clin Transplant. 2013;11(3):290\u20132.","journal-title":"Exp Clin Transplant"},{"issue":"5","key":"3486_CR22","doi-asserted-by":"publisher","first-page":"e254822","DOI":"10.1136\/bcr-2023-254822","volume":"16","author":"A Saad","year":"2023","unstructured":"Saad A, Chauhan A, Tripathi S, Kumar M. Arthrogryposis, renal dysfunction, cholestasis syndrome in a neonate: an uncommon association of common problems. BMJ Case Reports. 2023;16(5):e254822. https:\/\/doi.org\/10.1136\/bcr-2023-254822.","journal-title":"BMJ Case Reports"},{"issue":"10","key":"3486_CR23","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1007\/s12098-020-03248-5","volume":"87","author":"A Rai","year":"2020","unstructured":"Rai A, Mandal K, Saxena D, Lallar M, Phadke SR. Distal arthrogryposis: a clue to the etiology of neonatal cholestasis. Indian J Pediatr. 2020;87(10):869\u201370.","journal-title":"Indian J Pediatr"},{"issue":"2","key":"3486_CR24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1093\/ckj\/sfs182","volume":"6","author":"A Holme","year":"2013","unstructured":"Holme A, Hurcombe JA, Straatman-Iwanowska A, Inward CI, Gissen P, Coward RJ. Glomerular involvement in the arthrogryposis, renal dysfunction and cholestasis syndrome. Clin Kidney J. 2013;6(2):183\u20138.","journal-title":"Clin Kidney J"},{"issue":"10","key":"3486_CR25","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1038\/jp.2013.62","volume":"33","author":"A Elmeery","year":"2013","unstructured":"Elmeery A, Lanka K, Cummings J. ARC syndrome in preterm baby. J Perinatol. 2013;33(10):821\u20132.","journal-title":"J Perinatol"},{"issue":"4","key":"3486_CR26","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.ejmg.2016.01.005","volume":"59","author":"M Aflatounian","year":"2016","unstructured":"Aflatounian M, Smith H, Farahani F, Tofighi Naeem A, Straatman-Iwanowska A, Zoghi S, et al. Novel VIPAS39 mutation in a syndromic patient with arthrogryposis, renal tubular dysfunction and intrahepatic cholestasis. Eur J Med Genet. 2016;59(4):237\u20139.","journal-title":"Eur J Med Genet"},{"issue":"3","key":"3486_CR27","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1097\/MPG.0b013e318298108f","volume":"58","author":"O Ackermann","year":"2014","unstructured":"Ackermann O, Gonzales E, Keller M, Guettier C, Gissen P, Jacquemin E. Arthrogryposis, renal dysfunction, and cholestasis syndrome caused by VIPAR mutation. J Pediatr Gastroenterol Nutr. 2014;58(3):e29-32.","journal-title":"J Pediatr Gastroenterol Nutr"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-024-03486-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-024-03486-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-024-03486-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T12:03:50Z","timestamp":1735560230000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-024-03486-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3486"],"URL":"https:\/\/doi.org\/10.1186\/s13023-024-03486-2","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,30]]},"assertion":[{"value":"23 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was not required for this study as it is a case report, which does not fall under the scope of research requiring ethics committee approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication was obtained from the parents of the individuals featured in the manuscript using our institutional consent form.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"496"}}