{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T12:46:11Z","timestamp":1782305171459,"version":"3.54.5"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2026,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Endothelial cell\u2010selective adhesion molecule (\n ESAM<\/jats:italic>\n ) is a tight junction protein essential for blood\u2013brain barrier integrity and angiogenesis. Bi\u2010allelic loss\u2010of\u2010function variants in\n ESAM<\/jats:italic>\n cause NEDIHSS (\u201cNeurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity\u201d), a neurodevelopmental\/neurovascular disorder with antenatal\/neonatal onset, characterized by global developmental delay\/intellectual disability (GDD\/ID), epilepsy, spasticity, ventriculomegaly, and intracranial hemorrhages. Ocular involvement, particularly retinal vascular anomalies, has been variably reported.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A multidisciplinary team of pediatric neurologists, ophthalmologists, and clinical geneticists evaluated the proband through clinical assessment, neuro\/ocular imaging, and whole\u2010exome sequencing.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We describe a 3\u2010year\u2010old male from consanguineous Albanian parents carrying a novel homozygous splice\u2010site\n ESAM<\/jats:italic>\n variant (c.70+1G>T). He presented with GDD, seizures, and brain imaging abnormalities consistent with NEDIHSS. Remarkably, bilateral optic nerve hypoplasia, esotropia, retinal detachment, absent electroretinogram response, and structural eye anomalies, including left eyeball hypoplasia and iris displacement, were observed. Review of our and previous cases indicates that 45% (10\/22) of NEDIHSS individuals present ocular manifestations, mainly retinal vascular defects, reinforcing the emerging role of\n ESAM<\/jats:italic>\n in retinal endothelial integrity.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This case broadens the mutational and clinical spectrum of\n ESAM<\/jats:italic>\n \u2010related disease, underscores the need for detailed ocular evaluations in NEDIHSS, and supports inclusion of retinal anomalies within its core phenotype.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mgg3.70245","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:02:31Z","timestamp":1781064151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Refinement of\n \n ESAM<\/i>\n <\/scp>\n \u2010Related Tight\u2010Junctionopathy: Novel Genetic and Ocular Findings and Literature Review"],"prefix":"10.1002","volume":"14","author":[{"given":"Mauro","family":"Lecca","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Unit of Medical Genetics University of Pavia Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bosetti","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience IRCCS Stella Maris Foundation Pisa Italy"},{"name":"Department of Clinical and Experimental Medicine University of Pisa Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Ruoli","sequence":"additional","affiliation":[{"name":"Pediatric Ophthalmology Unit ASST Grande Ospedale Metropolitano Niguarda Milan Italy"},{"name":"Developmental Neuro\u2010Ophthalmology Unit IRCCS Mondino Foundation Pavia Italy"},{"name":"European Reference Network on Eye Diseases (ERN\u2010EYE), ASST Grande Ospedale Metropolitano Niguarda Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liviana","family":"Fontanel","sequence":"additional","affiliation":[{"name":"Pediatric Ophthalmology Unit ASST Grande Ospedale Metropolitano Niguarda Milan Italy"},{"name":"European Reference Network on Eye Diseases (ERN\u2010EYE), ASST Grande Ospedale Metropolitano Niguarda Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mazza","sequence":"additional","affiliation":[{"name":"Pediatric Ophthalmology Unit ASST Grande Ospedale Metropolitano Niguarda Milan Italy"},{"name":"European Reference Network on Eye Diseases (ERN\u2010EYE), ASST Grande Ospedale Metropolitano Niguarda Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6820","authenticated-orcid":false,"given":"Enza Maria","family":"Valente","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Unit of Medical Genetics University of Pavia Pavia Italy"},{"name":"Unit of Neurogenetics IRCCS Mondino Foundation Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Battini","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience IRCCS Stella Maris Foundation Pisa Italy"},{"name":"Department of Clinical and Experimental Medicine University of Pisa Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-1988","authenticated-orcid":false,"given":"Edoardo","family":"Errichiello","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Unit of Medical Genetics University of Pavia Pavia Italy"},{"name":"Unit of Neurogenetics IRCCS Mondino Foundation Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-024-01297-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.70140"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02621-6"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12010075"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000583"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.4274\/tjo.galenos.2023.72609"},{"issue":"8","key":"e_1_2_10_8_1","article-title":"COL4A1 Gene Mutation Masquerading as Cerebral Palsy: Report of a Rare Case","volume":"16","author":"Chalipat S.","year":"2024","journal-title":"Cureus"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/archophthalmol.2010.42"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0228622"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05480-z"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac461"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-024-02078-0"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32099"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304890200"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/01658107.2022.2072517"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14568"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.03.005"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000528716"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.210"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.10.026"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20584-4"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.02.007"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990604)84:4<330::AID-AJMG4>3.0.CO;2-W"}],"container-title":["Molecular Genetics & Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70245","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.70245","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70245","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:46:38Z","timestamp":1782301598000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70245"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":23,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/mgg3.70245"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70245","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2025-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70245"}}