{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T05:43:19Z","timestamp":1774849399577,"version":"3.50.1"},"reference-count":13,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Norrie disease is a rare X-linked recessive disorder characterized by congenital blindness, with approximately one-third of patients developing progressive sensorineural hearing loss and neurodevelopmental abnormalities. While over 200 pathogenic variants in the\n                      <jats:italic>NDP<\/jats:italic>\n                      gene have been identified, the phenotypic spectrum continues to expand.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case Presentation<\/jats:title>\n                    <jats:p>\n                      We report a 33-year-old Chinese male who presented with acute hydrops of the right cornea as the initial clinical manifestation leading to the diagnosis of Norrie disease. Comprehensive ophthalmological examination revealed bilateral keratoconus (right eye with acute Descemet\u2019s membrane rupture), spherophakia, shallow anterior chambers, and characteristic grayish-white fibrovascular masses in the vitreous cavity. Whole-genome sequencing identified a novel hemizygous mutation in\n                      <jats:italic>NDP<\/jats:italic>\n                      (NM_000266.4: c.140_144delinsTTTTA), resulting in p. Ser47_Ile48delinsPheLeu. This mutation affects highly conserved residues adjacent to the cysteine knot domain critical for Norrin protein function. The proband\u2019s mother was a heterozygous carrier with normal phenotype, confirming X-linked recessive inheritance. In silico analysis using multiple prediction algorithms uniformly indicated pathogenicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This represents, to our knowledge, the first report of Norrie disease presenting with acute keratoconus (hydrops) as the initial diagnostic manifestation in an undiagnosed adult. The novel p. Ser47_Ile48delinsPheLeu mutation expands both the mutational spectrum of\n                      <jats:italic>NDP<\/jats:italic>\n                      and the phenotypic presentation of Norrie disease. These findings emphasize the importance of genetic testing in patients with complex anterior segment abnormalities and provide crucial information for genetic counseling and clinical management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1726644","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T04:11:16Z","timestamp":1774843876000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Acute keratoconus as the presenting feature in undiagnosed Norrie disease: hypothesis from a novel NDP mutation"],"prefix":"10.3389","volume":"13","author":[{"given":"Xu","family":"Cao","sequence":"first","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longhao","family":"Kuang","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiexuan","family":"Lv","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaoyi","family":"Mei","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Su","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufang","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanshan College, Guangzhou Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Zhan","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Guo","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1111\/ceo.14494","article-title":"Hereditary vitreoretinopathies: molecular diagnosis, clinical presentation and management","volume":"53","author":"Ghoraba","year":"2025","journal-title":"Clin Experiment Ophthalmol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1755-3768.1975.tb01156.x","article-title":"Norrie's disease--differential diagnosis and treatment","volume":"53","author":"Warburg","year":"1975","journal-title":"Acta Ophthalmol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1006\/geno.1993.1224","article-title":"Norrie disease gene: characterization of deletions and possible function","volume":"16","author":"Chen","year":"1993","journal-title":"Genomics"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.4103\/ijo.IJO_442_17","article-title":"Next-generation sequencing reveals a novel NDP gene mutation in a Chinese family with Norrie disease","volume":"65","author":"Huang","year":"2017","journal-title":"Indian J Ophthalmol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1038\/cr.2015.92","article-title":"Structural basis of the Norrin-Frizzled 4 interaction","volume":"25","author":"Shen","year":"2015","journal-title":"Cell Res"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.cell.2009.07.047","article-title":"Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization","volume":"139","author":"Ye","year":"2009","journal-title":"Cell"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/08820530701745124","article-title":"The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease","volume":"22","author":"Warden","year":"2007","journal-title":"Semin Ophthalmol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"884722","DOI":"10.3389\/fgene.2022.884722","article-title":"Spectrum of mutations in NDP resulting in ocular disease; a systematic review","volume":"13","author":"Wawrzynski","year":"2022","journal-title":"Front Genet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4057","DOI":"10.1074\/jbc.M609618200","article-title":"Mutational analysis of Norrin-Frizzled4 recognition","volume":"282","author":"Smallwood","year":"2007","journal-title":"J Biol Chem"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1167\/iovs.17-23403","article-title":"Cross-inhibition of norrin and TGF-\u03b2 signaling modulates development of retinal and choroidal vasculature","volume":"59","author":"Seitz","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1055\/s-2008-1046058","article-title":"Keratotorus in Norrie disease","volume":"199","author":"Lang","year":"1991","journal-title":"Klin Monatsbl Augenheilkd"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1007\/978-1-4614-0631-0_86","article-title":"The different functions of Norrin","volume":"723","author":"Braunger","year":"2012","journal-title":"Adv Exp Med Biol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"201","DOI":"10.2174\/1874364101711010201","article-title":"Genetics in keratoconus\u2013what is new?","volume":"11","author":"Moussa","year":"2017","journal-title":"Open Ophthalmol J"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1726644\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T04:11:40Z","timestamp":1774843900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1726644\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":13,"alternative-id":["10.3389\/fmed.2026.1726644"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1726644","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"article-number":"1726644"}}